Draft
Do Not Quote or Cite
                                  External Review Draft No. 2
                                              February 1981
              Air Quality
           for  Particulate  Matter
              and  Sulfur
                       Volume V
                            NOTICE

This document is a preliminary draft. It has not been formally released by EPA and should not at this stage be
construed to represent Agency policy. It is being circulated for comment on its technical accuracy and
policy implications.
             Environmental Criteria and Assessment Office
            Office of Health and Environmental Assessment
                Office of Research and Development
                U.S. Environmental Protection Agency
                 Research Triangle Park, N.C. 27711

-------
                              NOTE TO READER

     The  Environmental  Protection Agency is  revising  the  existing criteria
documents for participate matter and sulfur oxides (PM/SOx) under Sections 108
and 109  of  the  Clean Air Act, 42  U.S.C.  §§ 7408, 7409.   The first external
review draft of a revised combined PM/SO  criteria document was made available
for public comment in April 1980.
     The  Environmental  Criteria  and Assessment Office  (ECAO) filled more  than
4,000 public  requests  for  copies of the first external review draft.  Because
all those who received copies of the first draft from ECAO will  be sent copies
of the  second external  review draft, there is no need to resubmit a request.
     To  facilitate public  review,  the second external review draft  will  be
released  in five volumes on a staggered schedule as the volumes are completed.
Volume I  (containing Chapter 1), Volume II (containing Chapters 2, 3, 4, and 5),
Volume III (containing Chapters 6, 7, and 8), Volume IV (containing Chapters 9
and 10),  and Volume V (containing Chapters 11, 12, 13, and 14) will be released
during January-February, 1981.   As noted earlier, they will be  released as
volumes are completed, not in numerical order by volume.
     The  first  external  review draft was  announced in  the  Federal  Register  of
April 11, 1980  (45 FR 24913).  ECAO received and reviewed 89 comments from the
public, many of which were quite extensive.   The Clean Air Scientific Advisory
Committee  (CASAC)  of the  Science  Advisory Board also provided  advice and
comments  on the first external review draft at a public meeting of August 20-22,
1980 (45  FR 51644, August 4, 1980).
     As with the first external review draft, the second external review draft
will be submitted to CASAC for its advice and comments.  ECAO is also soliciting
written  comments  from the  public  on the second  external  review draft and
requests  that an  original  and three copies of all comments be submitted  to:
Project Officer for PM/SO , Environmental Criteria and Assessment Office, MD-52,
                         f\
U.S.  Environmental Protection Agency, Research Triangle Park, N.  C. 27711.  To
facilitate ECAO's consideration  of comments on this  lengthy and  complex docu-
ment, commentators with extensive comments should index the major points which
they intend ECAO  to  address, by providing  a  list of the major points and a
cross-reference to the  pages in the document.  Comments should  be submitted
during the forthcoming  comment period, which  will be announced in  the  Federal
Register  once all volumes  of the second external  review draft are available.
      XD13A/E                                                               2-15-81

-------
Draft
Do Not Quote or Cite
                                External Review Draft No. 2
                                            February 1981
             Air Quality  Criteria
           for  Participate Matter
              and  Sulfur  Oxides
                      Volume V
                          NOTICE

This document is a preliminary draft. It has not been formally released by EPA and should not at this stage be
construed to represent Agency policy. It is being circulated for comment on its technical accuracy and
policy implications.
          Environmental Criteria and Assessment Office
         Office of Health and Environmental Assessment
              Office of Research and Development
             U.S. Environmental Protection Agency
              Research Triangle Park, N.C. 27711

-------
                                      PREFACE





     This  document  is a  revision of  External  Review  Draft  No.  1,  Air



Quality  Criteria  for  Particulate Matter  and  Sulfur  Oxides,  released  in



April  1980.   Comments received  during  a public  comment period from  April



15,  1980  through July 31, 1980,  and  recommendations made  by the Clean Air



Scientific Advisory Committee  in August have been addressed here.



     Volume V contains Chapters 11, 12, 13, and 14 which cover the respiratory



physiological, toxicological,  clinical, and epidemiological aspects of exposure



to sulfur oxides and particulate matter.
                                      n
      XD13A/E                                                                2-15-81

-------
                                  CONTENTS

                        VOLUMES I, II, III, IV, AND V

                                                                      Page

Volume I.
     Chapter 1.     Executive Summary	      1-1

Volume II.
     Chapter 2.     Physical and Chemical Properties of Sulfur
                    Oxides and Particulate Hatter	      2-1
     Chapter 3.     Techniques for the Collection and Analysis of
                    Sulfur Oxides, Particulate Matter, and Acidic
                    Precipitation	      3-1
     Chapter 4.     Sources and Emissions	      4-1
     Chapter 5.     Environmental Concentrations and Exposure	      5-1

Volume III.
     Chapter 6.     Atmospheric Transport, Transformation and
                    Deposition	      6-1
     Chapter 7.     Acidic Deposition	      7-1
     Chapter 8.     Effects on Vegetation	      8-1

Volume IV.
     Chapter 9.     Effects on Visibility and Climate	      9-1
     Chapter 10.    Effects on Materials	     10-1

Volume V.
     Chapter 11.    Respiratory Deposition and Biological Fate
                    of Inhaled Aerosols and S0?	     11-1
     Chapter 12.    Toxicological Studies	     12-1
     Chapter 13.    Controlled Human Studies	     13-1
     Chapter 14.    Epidemiological Studies on the Effects of
                    Sulfur Oxides and Particulate Matter on
                    Human Health	     14-1
      XD13A/E
2-15-81

-------
                                      CONTENTS
11.  RESPIRATORY TRACT DEPOSITION AND FATE OF INHALED AEROSOLS AND SO,..    11-1
    11.1   INTRODUCTION	    11-1
           11.1.1  General Considerations	    11-1
           11.1.2  Aerosol and S0? Characteristics	    11-2
           11.1. 3  The Respi ratory Tract	    11-4
           11.1.4  Respiration	    11-7
           11.1.5  Mechanisms of Particle Deposition	   11-11
    11. 2   DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS 	   11-16
           11.2.1  Insoluble and Hydrophobic Solid Particles	   11-16
                   11.2.1.1  Total Deposition	   11-16
                   11.2.1.2  Deposition	   11-20
                   11.2.1.3  Tracheobronchial Deposition	   11-20
                   11.2.1.4  Pulmonary Deposition	   11-25
                   11.2.1.5  Deposition in Experimental Animals 	   11-28
           11.2.2  Soluble, Deliquescent, and Hygroscopic Particles....   11-30
           11.2.3  Surface Coated Particles  	   11-32
           11.2.4  Gas Deposition 	   11-33
           11.2.5  Aerosol-Gas Mixtures 	   11-37
    11.3   TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT....   11-38
           11.3.1  Deposited Particulate Material 	   11-38
           11.3.2  Absorbed S0?	   11-48
           11.3.3  Particles and S09 Mixtures	   11-51
    11.4   AIR  SAMPLING FOR HEALTH ASSESSMENT 	   11-51
    11.5   SUMMARY	   11-55
    11.6   REFERENCES 	   11-60

12.  TOXICOLOGICAL STUDIES	    12-1
    12.1   INTRODUCTION	    12-1
    12.2   EFFECTS OF SULFUR DIOXIDE	    12-2
           12.2.1  Biochemistry of Sulfur Dioxide	    12-2
                   12.2.1.1  Chemical Reactions of Bisulfite with
                             Biological Molecules	    12-3
                   12.2.1.2  Metabolism of Sulfur Dioxide	    12-5
                             12.2.1.2.1  Integrated metabolism	    12-5
                             12.2.1.2.2  Sulfite oxidase	    12-6
                   12.2.1.3  Activation and  Inhibition of Enzymes by
                             Bisulfite	    12-7
           12.2.2  Mortal ity	    12-8
           12.2.3  Morphological Alterations	    12-8
           12.2A  Alterations in Pulmonary  Function	   12-14
           12.2. 5  Effects on Host Defenses	   12-21
    12. 3   EFFECTS OF PARTICULATE MATTER	   12-22
           12.3.1  Mortal ity	   12-24
           12.3.2  Morphological Alterations	   12-25
           12.3.3  Alterations in Pulmonary  Function	   12-28
                   12.3.3.1  Acute Exposure  Effects	   12-28
                   12.3.3.2  Chronic Exposure Effects	   12-39
                                        iv

       XD13A/E                                                                2-15-81

-------
           12.3.4  Alteration in Host Defense	    12-41
                   12.3.4.1  Mucociliary Clearance	    12-41
                   12.3.4.2  Alveolar Macrophages	    12-44
                   12.3.4.3  Interaction with Infectious Agents	    12-50
                   12.3.4.4  Immune Suppression	    12-51
    12.4   INTERACTION OF SULFUR DIOXIDE AND OTHER POLLUTANTS	    12-53
           12.4.1  Sulfur Dioxide and Particulate Matter	    12-53
                   12.4.1.1  Acute Exposure Effects	    12-54
                   12.4.1.2  Chronic Exposure Effects	    12-55
           12.4.2  Interaction with Ozone	    12-62
    12.5   CARCINOGENESIS AND MUTAGENESIS OF SULFUR COMPOUNDS AND
           ATMOSPHERIC PARTICLES	    12-65
           12.5.1  Airborne Particulate Matter	    12-67
                   12.5.1.1  lf\ vitro Mutagenesis Assays of Particulate
                             Matter	    12-67
                   12.5.1.2  Tumorigenesis of Particulate Extracts	    12-69
           12.5.2  Potential Mutagenic Effects of Sulfite and SOp	    12-71
           12.5.3  Tumori genes is in Animals Exposed to SO,, or S02 and
                   Benzo(a)pyrene	    12-72
           12.5.4  Effects of Trace Metals Found in Atmospheric
                   Particles	    12-74
    12.6   CONCLUSIONS	    12-79
           12.6.1  Sulfur Dioxide	    12-79
           12.6.2  Particulate Matter	    12-82
           12.6.3  Combinations of Gases and Particles	    12-85
12.7       REFERENCES	    12-87

13.  CONTROLLED HUMAN STUDIES 	     13-1
    13.1   INTRODUCTION 	     13-1
    13.2   SULFUR DIOXIDE 	     13-2
           13.2.1  Subjective reports 	     13-2
           13.2.2  Sensory Effects 	     13-3
                   13.2.2.1  Odor Perception Threshold	     13-3
                   13.2.2.2  Sensitivity of the Dark-Adapted Eye 	     13-5
                   13.2.2.3  Interruption of Alpha Rhythm 	     13-5
           13.2.3  Respiratory and Related Effects 	     13-6
                   13.2.3.1  Respiratory Function	     13-6
                   13.2.3.2  Water Solubility	    13-12
                   13.2.3.3  Nasal Versus Oral Exposure 	    13-12
                   13.2.3.4  Subject Activity Level 	    13-13
                   13.2.3.5  Temporal Parameters 	    13-15
                   13.2.3.6  Mucociliary Transport	    13-16
                   13.2.3.7  Health Status	    13-18
    13.3   PARTICULATE MATTER 	    13-18
    13.4   SULFUR DIOXIDE AND OZONE 	    13-22
    13. 5   SULFURIC ACID AND SULFATES 	    13-26
           13.5.1  Sensory Effects	    13-26
           13.5.2  Respiratory and Related Effects	    13-28
    13.6   SUMMARY 	    13-33
    13.7   REFERENCES 	    13-37

14.  EPIDEMIOLOGICAL STUDIES ON THE EFFECTS OF SULFUR OXIDES AND
    PARTICULATE MATTER ON HUMAN HEALTH	      14-1
    14.1   INTRODUCTION	      14-1
           14.1.1  Methodological Considerations	      14-2
           14.1.2  Guidelines for Assessment of Epidemiological
                   Studies	      14-5

-------
    14.2   AIR QUALITY MEASUREMENTS	      14-7
           14.2.1  Sulfur Oxides Measurements	      14-7
           14.2.2  Particulate Matter Measurements	      14-8
    14.3   ACUTE SO /PM EXPOSURE EFFECTS	     14-11
           14.3.1  Mortal i ty	     14-11
                   14.3.1.1  Acute Episode Studies	     14-11
                   14.3.1.2  Mortality Associated with Non-Episodic
                             Variations in Pollution	     14-15
                   14.3.1.3  Morbidity	     14-17
           14. 3.2  Chronic SO?/PM Exposure Effects	     14-23
                   14.3.2.1  Mortality	     14-23
                   14.3.2.2  Morbidity	     14-23
                             14.3.2.2.1  Respiratory effects in
                                         adults	     14-23
                   14.3.2.3  Respiratory Effects in Children	     14-25
    14.5   CHAPTER SUMMARY AND CONCLUSIONS	     14-31
           14.5.1  Health Effects Associated with Acute Exposures
                   to Sulfur Oxides and Particulate Matter	     14-32
    14. 6  REFERENCES	     14-37

APPENDIX A	       A-l
APPENDIX B	       B-l
APPENDIX C	       C-l
                                              VI


      XD13A/E                                                               2-15-81

-------
                                 LIST OF FIGURES


FIGURE

 11-1  Features of the respiratory tract of man used in the description
       of the deposition of inhaled particles and gases with insert
       showing parts of a silicon rubber cast of a human lung showing some
       separated bronchioles to 3 mm diameter, some bronchioles from 3 mm
       diameter to terminal bronchioles, and some separated respiratory
       acinus bundles	    11-5
 11-2  Representation of five major mechanisms of deposition of inhaled
       airborne particles in the respiratory tract	   11-13
 11-3  Deposition of monodisperse aerosols in the total respiratory tract
       for nasal breathing as a function of aerodynamic diameter except
       below 0.5 pm, where deposition is plotted vs. physical diameter...   11-17
 11-4  Deposition of monodisperse aerosols in the total respiratory tract
       for mouth breathing as a function of aerodynamic diameter except
       below 0.5 urn, where deposition is plotted vs. physical diameter...   11-18
 11-5  Deposition of monodisperse aerosols in extrathoracic region for
       nasal breathing as a function of of D2Q, where Q is the average
       inspiratory flow-rate in liters/min	   11-21
 11-6  Deposition of monodisperse aerosols in extrathoracic region for
       mouth breathing as a function of D2Q, where Q is the average
       inspiratory flow-rate in liters/min	     11-22
 11-7  Deposition of monodisperse aerosols in the tracheobronchial
       region for mouth breathing in percent of the aerosols entering
       the trachea as a function of aerodynamic diameter except below
       0.5 urn where deposition is plotted vs. physical  diameter as cited
       by different investigators	   11-24
 11-8  Total and regional depositions of monodisperse aerosols as a
       function of the aerodynamic diameter for three individual subjects
       as cited by Stahlhofen et al	   11-26
 11-9  Deposition of monodisperse aerosols in the pulmonary region for
       mouth breathing as a function of aerodynamic diameter, except
       below 0.5 urn where deposition is plotted vs.  physical diameter....   11-27
11-10  Deposition of inhaled polydisperse aerosols of lanthanum oxide
       (radio-labeled with 140La) in beagle dogs exposed in a nose-only
       exposure apparatus showing the deposition fraction (A) total dog,
       (B) tracheobronchial region, (C) pulmonary aveolar region, and
       (D) extrathoracic region	   11-29
11-11  Deposition of inhaled monodisperse aerosols of fused
       aluminosilicate spheres in small rodents showing the deposition
       in the extrathoracic region, the tracheobronchial region, the
       pulmonary region, and in the total respiratory tract	   11-31
11-12  Single exponential model, fit by weighted least-squares of the
       buildup and retention of zinc in rat lungs	   11-44
11-13  Example of the sum of exponential models for describing lung
       uptake during inhalation exposure and retention after exposure
       ends for three lung compartments with half-lives 50d, 350d,
       500d, and 20-day exposure rates of 1.4 mg/day, 1.7 mg/day,
       and 2.1 mg/day respectively	   11-45
        XD13A/E                         vli                                    2-15-81

-------
11-14  Example of the use of the power function model for describing
       lung uptake during inhalation exposure and retention after
       exposure ends for a 20-day exposure at 8.5 mg/d	    11-47
11-15  Multicomponent model of the deposition, clearance, retention,
       translocation and excretion of an example sparingly soluble
       metallic compound inhaled by man or experimental animals	    11-49
11-16  Example of the organ retention of an inhaled, sparingly soluble
       metallic compound assuming a single acute exposure demonstrating
       the translocation from lung and build-up and clearance from
       other organs	    11-50
11-17  Comparison of sampler acceptance curves of BMRC and ACGIH
       conventions with the band for the experimental pulmonary
       deposition data of Figure 11-9	    11-54
11-18  Division of the thoracic fraction into the pulmonary and
       tracheobronchial fractions for two sampling conventions (ACGIH
       and BMRC) as a function of aerodynamic diameter except below
       0.5 pm where deposition is plotted vs. physical diameter, from
       International Standard Organization ad hoc group to TC-146,
       1980	    11-56

14-1   Graph  showing effect on 29 bronchitic patients (St. Bartholomew's
       Hospital) of high pollution without fog	    14-19
                                             VI 1 1
         XD13A/E                                                               2-15-81

-------
                                     LIST OF TABLES

Table                                                                       Page

 12-1   Lethal Effects of SCL	    12-9
 12-2   Effects of sulfur dioxide on lung morphology	   12-10
 12-3   Effects of sulfur dioxide on pulmonary function	   12-20
 12-4   Effects of sulfur dioxide on host defenses	   12-23
 12-5   Effects of particulate matter on lung morphology	   12-27
 12-6   Respiratory response of guinea pigs exposed for 1 hour to
        particles in the Amdur et al.  studies	   12-29
 12-7   Effects of acute exposure to particulate matter on pulmonary
        function	   12-40
 12-8   Effects of chronic exposure to particulate matter on pulmonary
        function	   12-42
 12-9   Effects of sulfuric acid on mucociliary clearance	   12-45
12-10   Effects of metals and other particles on host defense mechanisms.   12-46
12-11   Effects of acute exposure to sulfur dioxide in combination with
        particulate matter	   12-56
12-12   Pollutant concentrations for chronic exposure of dogs	   12-59
12-13   Effects of chronic exposure to sulfur oxides and particulate
        matter	   12-63
12-14   Effects of interaction of sulfur oxides and ozone	   12-66
12-15   Potential Mutagenic Effects of S02/Bisulfite	   12-73
12-16   Tumorigenesis in animals exposed to S0? or S0? and
        benzo(a)pyrene	   12-75

 13-1   Sensory effects of S02 	    13-4
 13-2   Pulmonary effects of SOp 	    13-7
 13-3   Pulmonary effects of aerosols 	   13-19
 13-4   Pulmonary effects of S0? and other air pollutants 	   13-25
 13-5   Sensory effects of sulfuric acid and sulfates 	   13-27
 13-6   Pulmonary effects of sulfuric acid 	   13-32

 14-1   Excess deaths and pollutant concentrations during severe air
        pollution episodes in London (1948-75)	   14-12
 14-2   Acute air pollution episodes in New York City	   14-14
 14-3   Average deviation of respiratory and cardiac morbidity from
        15-day moving average, by S0? level (London, 1958-1960)	   14-21
 14-4   Average deviation of respiratory and cardiac morbidity from
        15-day moving average, by smoke level (BS) (London, 1958-1960)...   14-21
 14-5   Symptom-prevalence ratios (persistent cough and phlegm)
        standardised for age and smoking by air-pollution indices	   14-24
 14-6   Frequency of lower respiratory tract infections of children
        in Britain by pollution levels, %	   14-26
 14-7   Summary of quantitative conclusions from epidemiological studies
        relating health effects of acute exposure to SOp and particu-
        late matter to ambient air levels	   14-33
 14-8   Summary of quantitative conclusions from epidemiological studies
        relating health effects of chronic exposure to SO,, and
        particulate matter to ambient air levels	   14-35
                                               IX
        XD13A/E                                                               2-15-81

-------
                          11.  RESPIRATORY TRACT DEPOSITION AND FATE
                                  OF INHALED AEROSOLS AND S02

11.1  INTRODUCTION
11-1.1  General Considerations
     The respiratory  system  is the major route for exposure of people to airborne suspensions
of particles  (aerosols) and  SO- gas.    During  inhalation (and  exhalation)  a portion  of the
inhaled aerosol and  gas may be deposited by contact with airway surfaces or be transferred to
unexhaled  air.   The  remainder  is exhaled.   The  portion transferred to unexhaled air  may be
either deposited by contact with airway surfaces or later exhaled.   These phenomena are compli-
cated by interactions that may occur between the  particles,  the SO- gas,  other gases such as
endogenous ammonia, and the water vapor present in the airways.
     In inhalation  toxicology,  specific terminology is applied  to  these processes.   The term
deposition refers specifically to the removal of inhaled particles or gases by the respiratory
tract  and  to the  initial  regional  pattern  of these deposited materials.  The  term  clearance
refers  to  the  subsequent  translocation (movement of  material  within  the  lung or  to other
organs), transformation, and removal of deposited substances from the respiratory tract or from
the body.   It can also  refer to the removal  of reaction products formed from SOp or particles.
The  temporal   pattern of  uncleared  deposited  particulate  materials  or gases  and   reaction
products is  called  retention.   At the  end  of a  brief aerosol or gas  exposure,  these three
concepts may be described by the relationship:
     RETENTION (t) =  DEPOSITION (t) - CLEARANCE (t)                   (1)  .
where (t)  refers to a function of time after deposition occurs.
     The mechanisms  involved in the deposition of  inhaled  aerosols and gases are affected by
physical and chemical properties, including aerosol particle size distribution, density, shape,
surface area, electrostatic charge, hygroscopicity or deliquescence, chemical composition, gas
diffusivity  and  solubility, and  related reactions.  The geometry  of  the  respiratory airways
from nose  and  mouth to the  lung  parenchyma  also  influences aerosol deposition; the important
morphological parameters include the diameters, lengths, inclinations to vertical, and branch-
ing angles of airway  segments.  Physiological factors that affect deposition include breathing
patterns,   air  flow dynamics in the respiratory tract, and variations of relative humidity and
temperature within the  airways.  Clearance from the respiratory tract depends on many factors,
including  site of  deposition,  chemical  composition and properties of the deposited particles,
reaction products, mucociliary transport in the tracheobronchial tree, macrophage phagocytosis
in the  deep  lung,  and  pulmonary lymph and blood flow.  Paramount to the interpretation of the
results of health  effects  studies  described  in  Chapters. 12-14 is  an understanding  of the
regional deposition and clearance of particles and SO™.
     Translocation  of sulfur  compounds  or  other  materials  from the  lung to  other  organs is
also important, since the  lung can be  the  portal  of entry for toxic agents that have effects

SOX11A/A                                     11-1                                   2-9-81

-------
on other organs of the body.  Hence, muHi compartment models of clearance from the respiratory
tract  to  other organs  can provide  predictive  information about the potential  for  injury of
those  other  organs.   Mathematical  representations of lung retention and translocation require
data on the various factors that affect deposition and clearance.
     Since many conclusions concerning the deposition, clearance,  and health impact of inhaled
aerosols and  S02  are based upon data  obtained  from  animal experiments, care must be taken to
identify differences  in physiological  and anatomical factors between human beings and animals
that  may  influence  these  phenomena.   Emphasis  in  the  following discussion  will  be on  the
regional deposition  and  clearance  that  occur in the human airways,  but  selected comparisons
are  made  with other  mammalian species  to  clarify differences that may  affect  health impact
analyses of experimental  data.
11.1.2  Aerosol and SO,, Characteristics
     An aerosol may  be defined as a relatively stable suspension of liquid or solid particles
in  a gaseous medium.   Airborne  particulate  materials in the environment are  aerosols with a
variety  of  physical  and  chemical  properties.    In  particular, a  given  aerosol may  include
particles  with a  wide spectrum of physical sizes,  even  if all  the particles  have  similar
chemical  composition.   Also,  the   concentration  of  toxic  components  in  particles  may  be
different  for different  sized  particles (Natusch et al.,  1974) or  morphologically  identical
particles  may have totally different chemical compositions (Pawley and Fisher, 1977).   Common
assumptions  that  particles  in  a given aerosol  have  a relatively  homogeneous  chemical  compo-
sition,  toxic potential,  and physical density  may  be  seriously  misleading,  especially when
particles  are found in  combination with S0? gas.
     It is essential  for  evaluation of the possible health effects associated with their inha-
lation  that  the  relevant physical  and  chemical  properties of aerosols  and  gases  be appro-
priately characterized.   These properties then can  provide  predictive  information concerning
regional respiratory  tract deposition  and other  important  dosimetric  factors  that need to be
considered if biological  responses described  in Chapters 12-14 are to be adequately understood.
     If particles  in an aerosol are smooth  and spherical  or nearly spherical, their physical
sizes  can  be  conveniently  described  in terms  of their respective geometric diameters.  However,
unagglomerated  aerosols   of  solids  rarely  contain  smooth,   spherical  particles.   Various
conventions  for  describing  physical  diameters  have been  based  upon  available methods  of
observing  and measuring particle size.  For  example,  the  size  of a particle may be described
in terms of its projected  area diameter (D ), defined as the diameter of a circle with an area
equal  to the apparent cross-sectional  area of the particle when lying on a collection surface
and  viewed with  an optical or electron microscope.  Other conventions for describing physical
size  are  based  on   measurements   of  scattered  light,   surface   area,  electrical  mobility,
diffusional mobility,  or  other physical  or chemical phenomena (see Mercer, 1973; Stockham  and
Fochtman, 1979).
SOX11A/A                                     H-2                                   2-9-81

-------
*
     Aerodynamic properties of aerosol particles depend upon a variety of physical properties,
including  the  size and  shape of  the particles and their  physical  densities.   Two important
aerodynamic  properties  of aerosol  particles  are  the  inertial  properties,  which are  most
important  for  particles  larger than  0.5 urn  in  diameter and are related to the settling speed
in air  under  the influence of the  earth's  gravity,  and the diffusional properties, which are
most  important for particles  smaller than 0.5 urn in diameter and are related to the diffusion
coefficient (Fuchs, 1964)  (see Section 11.2.1).   When particles are inhaled, their aerodynamic
properties, combined  with  various  anatomical and breathing  characteristics,  determine their
fractional deposition  in various regions in the respiratory tract.
     To  avoid  the  complications  associated  with  the  effects of  particle shape,  size,  and
physical  density  upon the  inertial  properties  of  inhaled airborne  particles,  "aerodynamic
diameters"  have been  defined and  used to describe particles with  common  inertial  properties
with  the  same  "aerodynamic diameter."  The  aerodynamic  diameter most generally  used  is the
aerodynamic equivalent diameter (D  ), defined by Hatch and Gross (1964) as "the diameter of a
                                  96
unit  density sphere having the same settling  speed (under gravity) as the particle in question
of  whatever  shape  and  density."   Raabe  (1976)  has  recommended  the  use of  an  aerodynamic
resistance diameter (D  ), defined more  directly with  terms used in  physics  to  describe the
                       ar
inertial properties of a particle.  The difference between these two diameters is only 0.08 urn
or  less over  all  sizes under  normal conditions at  sea  level.  Hence, the  term aerodynamic
diameter can be  used to  refer to either or both of these two definitions.
      Since not all  particles in an aerosol  are of  the same physical or aerodynamic size, the
distribution  of sizes must be described.   If  either  the physical  diameter  (D)  or the aero-
dynamic  diameter is used  to  characterize  particles,  the distribution of  particle  sizes  in a
mixed  aerosol  is  most conveniently  described  as a probability  density  function.  One  such
generally  useful function,  the lognormal function, involves two parameters, the geometric mean
size  (or median) and  the  geometric standard  deviation (o ).  Environmental aerosols have size
distributions  that  are more complicated, reflecting the production of particles in atmospheric
processes, emission sources or other  anthropogenic activities, and the particle dynamics.   They
may  have  several   modes  (Whitby,  1978).    Photochemical  reactions   and  certain  combustion
processes  create small  particles  that are  generally  smaller than  0.1 urn (the  nuclei mode)
while  other  combustion,  condensation,  and  mechanical  particle  generation   processes  yield
larger  particles.   Another mode,  between 0.1 urn  and  2  urn,  is known as the accummulation mode
and  includes   primary  emissions  plus aggregates and  droplets formed by  coagulation  of the
primary  nuclei mode particles and the materials  which  condense on  them from the vapor phase.
The  particle   size  distribution  within  each of the three modes  (nuclei, accumulation,  and
coarse)  is generally lognormal.
     Since aerosols  even from a single source, or in an atmospheric size mode, do not consist
of particles  of a single  size, they  must  be described in terms of parameters of size distri-
bution functions.   It  has  become customary in the absence of detailed data and for the sake of

SOX11A/A                                     11-3                                   2-9-81

-------
generalization  to  describe aerosols  in  terms  of their geometric mean or  median  diameter and
the geometric standard deviation (o ) of the size distribution.   Hence, if the particle number
is being considered, the particle size may be reported as the count median (physical) diameter
(CMD) and o   or the count median aerodynamic diameter (CMAD) and o  if aerodynamic sizes have
been  measured.   Numerically, half the  particles in an aerosol  have physical  sizes  less than
the CMD and half have  larger.  Likewise, half the particles have aerodynamic diameters smaller
than  the  CMAD  and  half have larger  aerodynamic diameters.   Since the mass of a  material  is
usually more  relevant  to its potential toxicity, the mass median (geometrical) diameter (HMD)
or mass median  aerodynamic diameter  (MMAD) and a  is usually preferred in describing aerosols
in  inhalation toxicology  research.   Half the mass  of particles in an  aerosol  is associated
with  particles  smaller than the MMD  and  half  with  larger particles.   Likewise,  half the mass
of  particles  is associated  with particles whose  aerodynamic diameters are  smaller  than the
MMAD  and half with particles having larger aerodynamic diameters.   If an aerosol  is radioactive
or  radiolabeled, mass  measurements may be replaced  by  activity  measurements.   Interrelation-
ships  among  these  various ways to express the  diameter of the aerosol have been examined for
the  lognormal distribution by Raabe (1971).
      In  addition  to  particle  characteristics,  conditions  of  the  gas  medium influence  the
properties  of  aerosol  dispersions.    Such  environmental  conditions  as  relative  humidity,
temperature,  barometric  pressure,  and fluid flow conditions  (e.g., wind velocity  or state of
turbulence) affect the aerodynamics of aerosol particles.
      The concentration of environmental aerosols or gases generally does not affect inhalation
                                                               3        3
deposition and  particle dynamics.  The mass concentration (mg/m  or ug/m ) or concentration of
a  specific  potentially  toxic  species (mg of  constituent/m ) provides  information  needed to
calculate  inhalation  exposure  levels.   For  S09, the concentration may  be  expressed  in parts
                                                             3
per  million  (ppm)  by volume or  in mass  concentrations  (mg/m );  each 1 ppm of SOp equals 2.62
mg/m3  (2620 ug/m3) at  an air temperature of 25°C.
      Sulfur dioxide  gas  is a rapidly diffusing  reactive  gas that is readily soluble in water
and  body  fluids (Aharonson,  1976).   These properties are responsible for the large removal of
S09  in the extrathoracic  region and  in the upper generations of  the tracheobronchial tree.
Extraction of S0?  during nose breathing is significantly greater than during mouth breathing,
and over a four to six hour exposure  to high levels of SOy, no saturation effect for absorption
can be seen (see Section 11.2.4).  Through normal and catalyst mediated oxidation processes in
air,  SOp  gas is  slowly oxidized  to  SO, which  rapidly hydrolyzes to form  H^SO., leading to
sulfate salts.   Since  NHL is formed  in natural  biological processes including endogenously in
the airways,  (NH.)2S04 and NH4HS04 are important products of H2$04 neutralization.
11.1.3  The Respiratory Tract
     The  respiratory  tract  (Figure  11-1)  includes  the passages  of  the nose,  mouth, nasal
pharynx, oral pharynx, epiglottis, larynx, trachea, bronchi, bronchioles, and small ducts and
alveoli of the pulmonary acini.   With respect to respiratory tract deposition and  clearance of

SOX11A/A                                     11-4                                   2-9-81

-------
                                                           LEFT WALL OF NASAL CAVITY
                                                                AND TURBINATES
                                                              ORAL CAVITY
RIGHT MAIN BRONCHUS
UPPER LOBE BRONCHUS
  MEDIAL LOBE.
   BRONCHUS
     1
  LOWER LOBE
  BRONCHUS
                               LUNG PARENCHYMA
                                 AND ALVEOLI
                                                            UPPER LOBE BRONCHUS
LOWER LOBE BRONCHUS
 Figure 11-1.  Features of the respiratory tract of man used in the description of the deposition of
 inhaled particles and gases with insert showing parts of a silicon rubber cast of a human lung show-
 ing some separated bronchioles to 3 mm diameter, some bronchioles from 3 mm diameter to term-
 inal bronchioles, and some separated respiratory acinus bundles.

 Source: Adapted from Hatch and Gross (1964) and Raabe (1979).
                                              11-5

-------
*
inhaled  aerosols,  three  regions can  be  considered:    (1)  extrathoracic  (ET), the  airways
extending from the nares down to the epiglottis and larynx at the entrance to the trachea (the
mouth  is  included in  this  region  during mouth breathing);  (2)  tracheobronchial  region  (TB),
the primary conducting airways of the lung from the trachea to the terminal  bronchioles (i.e.,
that  portion  of the lung respiratory  tract  having a ciliated epithelium);  and  (3)  pulmonary
region  (P),  the  parenchyma! airspaces  of the lung,  including  the  respiratory bronchioles,
alveolar ducts, alveolar sacs, atria, and alveoli  (i.e., the gas-exchange region).  The extra-
thoracic  region,  as  defined above,  corresponds  exactly  to the  ICRP  (Morrow et al.,  1966)
definition of the nasopharynx.
     The nose  is  a  complex  structure of cartilage and muscle supported by bone and lined with
mucosa  (Holmes et  al., 1950).   The  vestibule  of  the nares  is  unciliated  but contains  a
low-resistance  filter   consisting  of  small  hairs.   The  nasal   volume  is separated  into  two
cavities by a  2-  to 7-mm thick  septum.   The  inner nasal  fossae and  turbinates  are  ciliated,
with mucus flow in thf> direction of the pharynx.   The turbinates  are shelf-like projections of
bone  covered by  ciliated mucous membranes with a high surface-to-volume ratio that facilitate
humidification  of  the  incoming air.  The  larynx  consists  of two pairs of mucosal folds that
narrow the airway.
     The trachea, an  elastic tube supported by 16 to 20 cartilagenous rings  that circle  about
3/4  of its circumference,  is the  first  and largest  of  a  series  of branching  airway  ducts
(Tenney and Bartlett, 1967).  The left and right lungs are entered by the two major bronchi of
the  trachea  (Figure  11-1).   The left  lung consists  of two clearly separated lobes,  the  upper
and  lower  lobes; and  the  right  lung  consists of  three  lobes,  the  upper,  middle,  and  lower
lobes.  The  conductive airways  in each lobe of the lung consist  of up to 18  to 20 dichotomous
branches from  the bronchi to the terminal bronchiole (Pump, 1964; Raabe et al., 1976).
      The  pulmonary,  gas-exchange  region  of  the  lung begins with the  partially  alveolated
respiratory  bronchioles.   Pulmonary branching proceeds through  a  few levels of respiratory
bronchioles  to completely alveolated  ducts  (Smith  and Boyden,  1949; Whimster,  1970;  Krahl,
1963)  and  alveolar sacs (Tenney  and Remmers,  1963; Pattle, 1961b; Machlin, 1950; Fraser and
Pare,  1971).   Alveoli  are  thin-walled polyhedron air pouches which  cluster about the acinus
through connections with respiratory bronchioles,  alveolar ducts, or alveolar sacs.
      The  airway  spaces in  the pulmonary  region are  coated with  a complex aqueous  liquid
containing  several  biochemically  specialized  substances   (Green,  1974;  Blank  etal.,  1969;
Balis  et al.,  1971; Pattle,  1961b; Kott et al., 1974; Henderson et al., 1975; Kanapilly,  1977).
An understanding  of  the chemical composition and dynamic nature  of the acellular layer at the
air-alveolar surface is needed to understand the general behavior of material deposited in the
pulmonary  region.   This acellular layer consists of  a surfactant  film of <  0.01 urn thick and
a hypophase  of about 0.1 -  0.2  urn  thick (Clements and Tierney,  1965).  A mixture of phospho-
lipids and  neutral  lipids  are contained  in  the  surfactant film  (Scarpelli,  1968; Pfleger and
Thomas,  1971;  Pruitt  et al.,  1971; Reifenath, 1973).  The  major  phospholipid is dipaltnitoyl

SOX11A/A                                     U'6                                   2-9-81

-------
lecithin, and  cholesterol and  its esters  are  the major neutral  lipids.   Protein  content in
lung  surfactant  is less  than 20  percent  by  weight (Pruitt et al., 1971;  Klass,  1973).   The
composition of the hypophase  is not well understood, with lung surfactant materials, mucopoly-
saccharides,  lipoproteins,  and possibly  serum  proteins such as albumin  likely  being present
(Scarpelli, 1968; Reifenath,  1973; Tuttle and Westerberg, 1974).   The pH of alveolar fluid may
be  similar  to that  of blood  fluid.   Various factors  favoring  and opposing  transudation of
fluid  across the  air-blood  barrier  result  in  the cyclic  movement of  fluid  in  and  out of
alveoli, thereby  helping  to maintain the very thin layer of alveolar fluid (Kanapilly, 1977).
The concentrations  of chelating and precipitating  agents in  the  alveolar fluid influence the
retention and  transport of particles deposited in  the  alveolar  region.   However,  the concen-
trations  of chelating agents  are not  sufficiently  high  to prevent  the  transformation of
polyvalent cations into an insoluble form (Kanapilly,  1977).
     The deep  lung parenchyma includes several  types of  tissue,  circulating blood, lymphatic
drainage pathways,  and  lymph nodes.   In  man,  the weight of the  lung,  including  circulating
blood,  is about 1.4 percent of the total body weight.   Lung blood is equal to about 0.7 percent
of  total body weight  (10 percent  of total blood volume) (Snyder,  1975).   Because a portion of
lung  is occupied by air, the  average  physical  density  of the parenchyma  is about  0.26 g/cm
(Fowler and Young, 1959).
     Models  of  the airways, which simplify the complex array of branching and dimensions into
workable mathematical  functions, are useful in comparing theoretical predictions of deposition
with  experimentally  obtained deposition  data,  thereby  leading  to  more refined  models  and
increasing  our  understanding  of the processes which affect  respiratory  tract  deposition.   An
early  idealized  model of the  airways  of  the  human lung was developed by Findeisen (1935) for
estimating  the  deposition of  inhaled particles.  Findeisen's model assumed branching symmetry
within  the  lung,  with each generation consisting  of  airways  of  identical size.   Other models
based  on a  symmetry  assumption have  been proposed by Landahl (1950),  Davies  (1961), Weibel
(1963),  and Horsfield  and  Gumming (1968).  Asymmetric models which more closely  approximate
the human  lung have been developed by Weibel  (1963),  Horsfield  et al.  (1971), and Horsefield
and Cummings (1968).   Yeh and  Schum (1980) have proposed a typical  pathway lung model and have
made particle deposition calculations for each lobe of the lungs.   Although currently available
particle  deposition  models  ignore the dynamic  nature  of  the  airways,   future  models should
consider this aspect.
11.1.4  Respiration and Other Factors
     Both the humidity and temperature of inhaled aerosols and gases, as well as the subsequent
changes that occur as the aerosol-gas mixture  passes  through various  parts  of the airways,
have  important  influences on  the  inhalation  deposition  of  airborne particles.   Deposition of
hygroscopic  aerosols  will depend  in part  on  the  relative humidity  in the airways, since the
growth  of such particles will directly affect both  the site and extent of  inhalation deposition.
SOX11A/A                                     11-7                                   2-9-81

-------
*
     The complex anatomical structure of the nose is well suited for humidification, regulation
of temperature, and removal of many particles and gases.   The relative humidity of inhaled air
probably reaches near saturation in the nose (Verzar et al., 1953).   Since the human nose is a
short passageway,  tranquil  diffusion  alone cannot account  for  rapid  humidification.   Rather,
convective mixing must play a role, suggesting a mechanism for enhancing SO- collection in the
nose.  The temperature of the inhaled air may not reach body temperature until relatively deep
in the  lung.   Deal  et al.  (1979a,  b,  c)  measured retrocardiac and retrotracheal temperatures
under different  ambient  temperatures  and found airway cooling  associated  with breathing cool
air.    Raabe et  al.   (1976) found  that the  temperature of  the air at  major bronchi  in  a
nose-breathing dog averaged 35°C, 4°C less than the body temperature.
     The  air  deflecting  channels  of  the  anterior  nares  cause  impaction of  large  airborne
particles  and  create  turbulent  air  flow  conditions.   As  the cross-sectional  area  expands
beyond  the  entrance,  flow separation occurs resulting in turbulence and eddies which continue
as the air traverses the passages around the turbinates.   Proctor and Swift (1971) studied the
flow of water  through a clear plastic model of the walls of the nasal  passages and constructed
charts of the  direction and linear velocity of airflow in the model.  With a steady inspiratory
flow  of  0.4 I/sec,  they  found that the  linear  inspiratory velocity  at  the  nasal  entrance
reached  at   least  4.5-5  m/sec and at  most 10 - 12 m/sec,  values  which are significantly
greater  than  the  2  m/sec peak  linear velocity  in the  tracheobronchial tree  during  quiet
breathing.
     The  caliber of  the trachea and major bronchi and their cross-sectional geometry is about
15 percent  larger during  inspiration than during expiration (Marshall  and Holden, 1963; Fraser
and  Pare,  1971; Raabe et al.,  1976).  Bronchial  caliber correlates with body size (Thurlbeck
and  Haines,  1975).   The caliber of the smaller conductive bronchioles may be  up to 40 percent
greater  during inspiration than during expiration (Marshall and  Holden,  1963; Hughes et al.,
1972).
     Schroter  and  Sudlow  (1969)  studied a  wide  variety of flow patterns and  rates  in large
scale symmetrical models  of typical tracheobronchial tree junctions.  For both inspiration and
expiration  and irrespective of entry profile form,  they observed secondary flows at all flow
rates in their single bifurcation model.  When a second bifurcation was added  a short distance
downstream  of  the  first,  the entering  flow  profile  was  found to influence the resulting flow
patterns.   Also,  different results were obtained depending upon the plane in  which the second
bifurcation  was  located relative to the first bifurcation.
     Olson  et  al.  (1973)  studied convective airflow  patterns in  cast  replicas  of the human
respiratory  tract  during  steady  inspiration.   They showed that the effect  of the larynx is
such  that  flow  patterns  typical  of  smooth  bifurcating  tubes  do  not  occur   until  the lobar
bronchi  are  reached.   Small eddies were observed as far down as the sublobar bronchi with 200
ml/s flows  in  the trachea.  In man the glottis of the larynx acts as a variable orifice since
the position of the vocal cords changes.  During inspiration a jet of turbulent air enters the

SOX11A/A                                     H-8                                   2-9-81

-------
trachea  and  is directed  against its  ventral  wall  imparting  additional  turbulence over that
associated with the corrugated walls and  length of the trachea.
     In the tracheobronchial tree with its many branches, changes in caliber and irregular wall
surfaces,  it  is difficult  to  establish  exactly where flow is  laminar,  turbulent,  or transi-
tional.   Viscous  forces  predominate  in  laminar  flow  and  streamlines persist  for  great
distances, while with turbulent  flow there is rapid and random mixing downstream.  As the flow
rate increases, unsteadiness develops and separation of the streamlines from the wall  can occur
leading  to the formation  of  local  eddies.   This type  of  flow  is  termed transitional.   The
Reynolds number, the ratio  of  inertial to viscous forces, is useful in describing whether flow
is  laminar or turbulent.   In  smooth walled tubes values between  approximately  2000  and 4000
are  ascribed  to transitional  flow  with smaller Reynolds numbers  reflecting  laminar  flow and
larger  ones  turbulent  flow.   Fully developed  laminar  flow probably only occurs  in  the very
small  airways;  flow is  transitional  in  most of the tracheobronchial tree, while  true  turbu-
lence  may occur  in  the trachea,  especially  during exercise when  flow velocities  are  high
(West, 1977).
     Turbulence will  gradually decay in  any branch  in  which  the Reynolds number is less than
3000 (Owen, 1969).  Decays  of  15 percent, 16 percent, and 10 percent are predicted to occur in
the first  three generations of bifurcation, respectively, using the theory of Batchelor (1953)
for  the change in turbulent energy at regions of rapid flow  contraction.  While  these  decay
calculations neglect the possible effects of the strong secondary flows generated at the  bifur-
cation,  their  validity is  supported by  the  data  of  Pedley et al.(1971)  which  shows  that the
boundary  layer remains  laminar in the daughter-tube for Reynolds numbers  in the parent-tube up
to at  least 10,000.  Hence, the  turbulent eddies are localized in the center.
     Flow  oscillations in  the segmental  bronchi  attributed to beating of the  heart  are only
detectable  during  breathholding  or during pauses between  inspiration and expiration  (West,
1961).   A peak oscillatory flow rate  of 0.5  1/min was measured, which is about 20 percent of
the peak  flow rate in  the segmental  bronchi during quiet breathing.  Gas mixing is improved by
these  oscillations.
     Gas  flow  dynamics within the  upper  airways may be expected to be turbulent in humans and
dogs but  laminar everywhere in the  airways of small rodents (Dekker, 1961; Fry, 1968;  Schroter
and Sudlow, 1969; Olson et  al.,  1973; Martin and Jacobi, 1972; West, 1961).  The larynx intro-
duces  an important air flow disturbance that can influence  tracheal  deposition (Bartlett et
al.,  1973; Schlesinger  and Lippmann, 1976).   In  the smaller  human  bronchi  and bronchioles,
where  fluid  flow is  relatively  tranquil,  laminar  flow  prevails,  but  branching patterns,
filling  patterns (Grant  et al., 1974),  flow reversals with varying velocity  profiles, and
swirling  complicate a  description of flow in the small airways (Silverman and Billings,   1961;
Cinkotai,  1974).   Because  actual  flow  in  the respiratory airways  is  difficult to describe,
simplifying assumptions,  such  as parabolic laminar  or  uniform velocity profiles,  are usually
incorporated into analytic  descriptions.

SOX11A/A                                     H-9                                   2-9-81

-------
*
     Inspiratory  flow  rate  and  depth  of  inhalation  influence  the  deposition  of  inhaled
particles.  The  air  inspired in one breath is the tidal volume (TV).   The average  inspiratory
flow rate, (Q), and tidal volume (Bake et al., 1974; Clement et al., 1973) affect both inertial
and diffusional deposition processes (Altshuler et al., 1967).   The total air remaining in the
lungs  at  the  end of  normal  expiration  affects  the relative mixing of  inhaled  particles  and,
when  compared  with total  lung capacity,  is  indicative of the extent  of aerosol  penetration
into  the  lung (West,  1974;  Luft,  1958).   Guyton (1947a,  b) and  Stahl  (1967)  have  developed
interspecies relationships describing respiratory volumes and patterns.
     The  inspiratory  capacity, the  maximum volume of  air that can be  inhaled  after  a given
normal  expiration,  is  contrasted  to the  vital  capacity,  which is the  maximum  volume  of air
that  can  be expelled from  the  lungs with effort after maximum forced  inspiration.   Air  that
remains  in  the conductive airways  (from  nose or mouth to terminal bronchioles) at  end expi-
ration  is considered to occupy the anatomical dead space, since the conductive airways are not
involved  in gas exchange.
     Representative  values  for  normal  human respiratory  parameters, which  can be  used for
deposition  and dosimetric predictions,  are available from various  sources  (Zenz,  1975; Higgs
et  al., 1967; American Heart Association,  1973;  Jones et  al., 1975;  Intermountain Thoracic
Society,  1975; Snyder,  1975).  It should be noted that considerable variability in  respiratory
parameters may occur among  individuals in the population, particularly when healthy adults are
contrasted  with  children,  aged,  and ill  individuals.   Average tidal volume  has a reasonably
fixed  relationship with body weight of  7-10  ml/kg from birth to  adulthood  (Doershuk  et  al.,
1970,  1975).   Gas-exchange  area  increases proportionally  with  age, and  more or  less  with
                                                                                         2
height,  but not  with body  surface  area.   Average values for gas-exchange area are 6.5 m ,  32
 2           2
m  ,  and 75  m  at  3 months,  8 years, and adulthood, respectively (Dunnill, 1962).   Respiratory
frequency decreases from  about 35 breaths/min at birth to 12-16 breaths/min with normal  respi-
ration  in adulthood (Polgar  and Weng, 1979).
      In some  instances,  the  total  and  regional deposition data  presented in Section  11.2
exhibit considerable  scatter.   Some of this variability might  be  expected given the range of
breathing frequencies,  tidal volumes,  and  average  inspiratory  flow  rates used in  the various
deposition  experiments.  Previously, an  interlaboratory comparison  study  of lung deposition
data  (Heyder  et  al.,  1978),  besides identifying possible sources of errors connected with the
experimental  technique,  identified  different  deposition  data among the  subjects.   Yu and
coworkers (1979) used Monte  Carlo techniques to determine the total and regional deposition of
inhaled particles  in  a population of human lungs by taking into account variability in airway
dimensions.   Their results  for  particle sizes  ranging  from 0.1  urn to  8 pm  D=Q suggest that
                                                                               36
observed  subject deposition  variability is  caused primarily by differences in airway dimensions.
When  studying  total  respiratory tract deposition  of particles  between  0.3 pm and 1.5 urn D   ,
                                                                                           36
expressing  the data  as a  function  of  the  relative  expiratory reserve  volume to the normal
expiratory  reserve volume of a subject greatly  reduces  the  intersubject variability (Tarroni
et al., 1980).
SOX11A/A                                     H-10                                   2-9-81

-------
X
     The  vast  majority of studies  on  the  deposition of particles  in man  have been conducted
using young  healthy adults.   Consequently, there  is  a  paucity of data on deposition in other
subpopulations, such as children, asthmatics, chronic bronchitics, etc.   Significant pathologic
changes in airways  and parenchyma can markedly alter the deposition of particles.  For example,
Lippmann et al. (1971) found substantially increased bronchial deposition in chronic bronchitic
and  asthmatic  subjects.    These  increases  may  vary with  different  phases  of the  disease
(Goldberg  and  Lourenco,  1973).   Tracheobronchial  deposition appears to  be enhanced  at  the
expense of  pulmonary deposition in most abnormal  states.  For example,  the deposition of 2 urn
particles  in  patients  with  bronchiostasis  is  frequently more  central  than that  in  normal
subjects  (Lourenco  et al., 1972).  Partial or complete airway obstruction in bronchitis, lung
cancer, emphysema,  fibrosis, and atelectasis may decrease or eliminate deposition of particles
in  some  regions  of the  lungs (Taplin et  al.,  1970).   The  numerous  and  complex  mechanisms
responsible  for alterations in the pattern of deposition in various disease states  need to be
studied.
     Currently available  human  deposition  data  have been collected from  volunteers inhaling
aerosols  through either  mouthpieces  or nose masks.  Differences in mass  burden of particles
between these  controlled  inhalations and normal, spontaneous mouth breathing or nose breathing
are  possible.   Studies in which the nose of the subject is completely occluded with a clip do
not  simulate oronasal  breathing since  no air  passes  through  the nose and  the  oral  airway is
wider  than  usual.   With  partial   nasal obstruction  or in exercise,  human beings  resort to
oronasal  breathing.   However,  a  significant  number of healthy  persons breathe through  the
mouth  and nose even when  at  rest  (Niinimaa,  1979).  Also, with any of the common obstructive
forms  of  nasal pathology such  as  allergic,  viral, or vasomotor rhinitis or septa!  deviation,
the  proportion of  ventilation passing  through the  mouth is higher at rest and at any level of
exercise.   Healthy  young  adults without nasal pathology, who breathe predominantly through the
nose at rest,  shift to breathing through the nose  and mouth when minute ventilation  is approxi-
mately 35  liters/min (Niinimaa,  1979; Saibene et al., 1978).   Niinimaa (1979) found  that during
exercise  requiring  a  rate of  ventilation  of  30-40 liters/min, 56 percent  of  the  air  passed
nasally.  Thus,  studies on  subjects breathing through a mouthpiece at rest (minute ventilation
of  6-8 liters/min) provide conservative estimates  of the  mass burden  of particles, since the
total  quantity of  ventilation passing  through the  mouth is significantly less than that which
would  pass  through the mouth  in the same subjects  breathing freely through the nose and mouth
while  performing enough  exercise to require a minute ventilation of 35 liters/min.  A minute
ventilation  of 35  liters/min corresponds anywhere  from  light to moderate exercise according to
various  sources (Zenz, 1975;  Higgs et al.,  1967;  American Heart Association,  1973; Jones et
al., 1975;  Intermountain  Thoracic  Society, 1975; Snyder, 1975).
11.1.5  Mechanisms  of  Particle  Deposition
     The  behavior  of  inhaled  airborne particles  in the respiratory airways and their alter-
native  fate of either deposition  or exhalation  depend  upon  aerosol mechanics under the given

SOX11A/A                                     11-11                                  2-9-81

-------
physiological and  anatomical  .condition  (Yeh  et al.,  1976;  DuBois and Rogers, 1968).   It  is
usually described in terms of nonreactive stable spherical particles whose physical  properties
do not vary during the breathing cycle.   Behavior of hygroscopic and deliquescent  particles  is
more complex.
     Figure 11-2 illustrates the five primary physical processes that lead to aerosol  particle
contact with the wall of the airways.  Contact of particles with moist airway walls  results  in
attachment and  irreversible  removal  of  the particle  from  the  airstream.   The contact process
can  occur  during inspiration or expiration of  a  single breath or  subsequently if  a  particle
has been transferred to unexhaled lung air (Engel  et al., 1973; Davies, 1972; Altshuler,  1961).
     Electrostatic attraction of particles to the walls of the respiratory airways is  probably
a minor mechanism of deposition in most circumstances.  Pavlik (1967) predicted that light air
ions (which would include some atmospheric aerosol  nuclei) would be deposited by electrostatic
attraction in the  mouth and throat  and  suggested  that the tonsils were naturally charged for
this purpose.   Fraser  (1966)  found  that  an  average of  1000  electronic units of  charge per
aerosol  particle,  a  very  large  charge  not  normally  occurring,   doubled  the  inhalation
deposition in  experimental  animals.   Melandri  et  al. (1977)  reported  enhanced deposition  of
inhaled monodisperse  aerosols by people  when the  particles were charged.  Longley  (1960) and
Longley and  Berry  (1961)  found the  charge of the  subject to have an influence on deposition.
Similar observations  have been made  in ijn vitro studies (Chan et al., 1978).  The airways are
covered by a relatively conductive  electrolytic liquid that probably precludes the  buildup  of
forceful  electric  fields.    Charged particles  are  therefore collected  primarily by  image
charging as  they near the wall of an airway  or by mutual repulsion from a unipolarly charged
cloud with a high  concentration of  particles  (Yu,  1977).   The role of this mechanism depends
on particle  source,  concentration,  age,  and  special  electrical  phenomena  in the  environment,
as well as the  residence time of the aerosol  in the airways.  It is reasonable to expect this
mechanism  to have  a  small   role,  if any,   in the deposition  of atmospheric  environmental
aerosols.
     Interception consists  of noninertial  incidental meeting of a  particle  and  the lining  of
the  airway and  thus depends on the  physical  size  of the particle.   It is important primarily
for particles with  large aspect ratios,  such as long fibrous particles of asbestos (Harris and
Fraser, 1976).   Interception may be expected to play a minor role in the inhalation  deposition
of most environmental aerosols.
     Impaction  dominates  deposition  of  particles  larger than  3 urn D    in  the nasopharyngeal
and  tracheobronchial  regions  (Rattle,  1961a;  Bohning et  al.,  1975).  In this process, changes
in airstream direction or  magnitude of  air  velocity streamlines or  eddy  components  are not
followed by  airborne particles  because  of their  inertia.   For  example,  if  air  is  directed
toward an airway surface (such as a branch carina) but the forward velocity is suddenly reduced
because of change  in flow direction, inertial  momentum  may  carry larger particles  across the
air  streamlines  and onto  the surface of  the  airway.   Impaction at an  airway  branch  has been

SOX11A/A                                      H-12                                  2-9-81

-------
                              INTERCEPTION
              ELECTROSTATIC

              ATTRACTION
                                                                  IMP ACTION
                                                       BROWNIAN DIFFUSION
              GRAVITATIONAL SETTLING
Figure  11-2. Representation of five major mechanisms of deposition of inhaled airborne particles
in the respiratory tract.

Source: Raabe (1979).
                                             11-13

-------
*
likened to  impaction  at  the bend of a  tube,  providing theoretical  estimates of the impaction
probability (Johnston and Muir, 1973; Yeh, 1974; Cheng and Wang,  1975) and has been studied in
a  bifurcating  tube model  by  Johnstone and  Schroter (1979).  Aerodynamic  separation  of  this
type  is  satisfactorily  characterized   in  terms  of  the  particle aerodynamic  diameter.   The
airflow in  the  trachea  and major bronchi  in  man  is  turbulent and disturbed  by the larynx so
that turbulent  impaction  plays a role   in  deposition  in  these larger airways (Schlesinger and
Lippmann,  1976).   Breathing  patterns   involving  higher  volumetric   flow  rates would  tend  to
impact smaller  particles.   In contrast, the passages of the nose contain smaller airways, and
the  convective mixing  spaces  of  the  nasal  turbinates  would  be  expected  to collect  some
particles as  small  as 1 or 2  urn D   by impaction.   Hence,  impaction  is  an important process
                                  ae
affecting  the  inhalation deposition in the human airways of  environmental  aerosol particles
greater than 1 urn in aerodynamic diameter.
     Gravitational settling occurs  because of the influence of the earth's gravity on airborne
particles.   Deposition  of particles by this  mechanism  can occur in all  airways  except  those
very few  that  are vertical.   The probability of gravitational deposition is usually estimated
with equations  describing  gravitational  settling of particles in an inclined cylindrical  tube
under  laminar flow conditions (Wang, 1975; Heyder and Gebhart, 1977).  This deposition depends
on  the residence  time  and particle concentration  distribution   in  the airway  segments,  the
incline  angle  with  respect  to gravity,  and  the  aerodynamic diameter  of  the  particle.
Deposition by gravitational settling is therefore characterized in terms of the particle  aero-
dynamic  diameter.   This mechanism  has  an important  influence on the  deposition  of particles
larger than  0.5  urn  D  .   Settling  has  an important role in  the deposition  of environmental
                      36
aerosols in the distal region of the bronchial airways and in the alveolar region.
     Deposition by diffusion results from the random (Brownian) motion of very small particles
caused by bombardment  of  the  gas  molecules  in air.   The  magnitude  of  this motion can  be
described  by  the  diffusion   coefficient  for  a  given   physical  particle  diameter.   Since
particles larger than 0.5 (jm have relatively small diffusional mobility compared with sedimen-
tation or inertia, diffusion primarily affects deposition of particles with physical diameters
smaller than 0.5  urn.   For particles of 0.5  urn  with  a physical  density of  about 1 g/cm  , the
influences  of  inertial  properties   and  diffusional  properties  on  lung deposition  are  about
equal.   Accurate calculation of the diffusional  deposition of aerosols in the airways requires
information  concerning  the  three-dimensional  velocity  profile   of  air  flow  in  each airway
segment.   If the  flow of a given segment  is  laminar and approximately Poisueille, the proba-
bility of deposition  by  diffusion  might  be approximated  using the  Gormley-Kennedy (1949)
equation for a  cylindrical  pipe.   However, this  assumes  the aerosol is mixed at the entrance
of the cylinder and that the flow is constant.   It therefore overestimates deposition in lung
segments where  there  is  minimal mixing between tidal  and residual  air and reversible laminar
flow between segments.
SOX11A/A                                     11-14                                  2-9-81

-------
*
     It  is  important  to  note that  the  diffusivity and  interception  potential  of a particle
depend on its physical size, while the inertial properties of settling and impaction depend on
its  aerodynamic  diameter.  These  two measures  of  size may be  quite  different,  depending on
particle  shape  and  physical  density.   Because the main  mechanism  of  deposition  is diffusion
for particles whose  physical (geometric) size  is less than 0.5 urn D and impaction and settling
above  0.5  urn Dae, it  is  convenient  to use  0.5 urn as the boundary.  Although this convention
may  lead to confusion in  the  case of very dense particles, most  environmental  aerosols have
densities  below  3   g/cm  ,  and the  deposition  probability  tends  to  have a  minimum  plateau
between  0.2 urn and 1 pm D   .
                          3G
     It  is possible  to use  information concerning breathing patterns and respiratory physiology,
the  anatomical  and  geometrical  characteristics  of the airways, and the  physical  behavior of
insoluble spherical  particles  to develop theoretical models of regional deposition (Findeisen,
1935;  Landahl  et al., 1951; Landahl,  1963;  Beeckmans,  1965).   In these models,  deposition of
inhaled  aerosols  in a  given region  of  the  respiratory tract or  in  the  entire tract  is
expressed  as  a fraction of inhaled  particles.  Deposition fraction is the ratio of the number
or  mass  of  particles  deposited in  the  respiratory  tract to the number or mass  of particles
inhaled.   The  undeposited fraction  represents those particles  that are  exhaled  after inhala-
tion.   For example,  pulmonary (alveolar)  deposition  is  the ratio  of the number  or  mass of
particles  deposited  in the unciliated small airways and gas exchange spaces of the parenchyma
of  the lung to the  number  or  mass of particles entering the nose or mouth.   The fraction not
deposited  in  the pulmonary  region  is  either  deposited in  some  other  region  or  exhaled.
Similarly, deposition  fractions can  be defined for the other regions of the respiratory tract.
     Most  model  calculations  treat  the  various  mechanisms of  deposition  as  independently
occurring phenomena.   However, such  processes  as Brownian diffusion and gravitational settling
will interfere with  each  other when  their  effects are of comparable magnitude, and that inter-
ference  can reduce  the combined deposition  to less  than the sum of  the  separate depositions
(Goldberg  et al., 1978).   Taulbee and Yu  (1975) have developed a theoretical  deposition model
which  allows for  the  combined effects  of the primary deposition  mechanisms  and features an
imaginary  expanding tube  model  of the airway system  (Weibel,  1963)  based on cross-sectional
areas  and airway  lengths.
     Historically,  the most  widely  used  models  of  regional deposition  versus  particle size
were developed  by the International Commission  on  Radiological  Protection Task Group on Lung
Dynamics under the  chairmanship  of P.  E. Morrow (Morrow  et  al.,  1966).  These models were
developed to determine radiation exposure  from inhaled radioactive aerosols.   Although the ICRP
aerosol  deposition  and clearance  models were not intended  for  broad  application to environ-
mental aerosols,  they have been so  applied  by some scientists.  The  ICRP Task Group used the
anatomical model  and impaction and sedimentation equations of Findeisen (1935) and the general
methods  of  Landahl  (1950,  1963)   for  calculating  deposition  in the  tracheobronchial  and
pulmonary  regions.   The  Gormley-Kennedy  (1949) equation  for  cylindrical tubes  was used for

SOX11A/A                                    11-15                                  2-9-81

-------
*
calculating diffusional deposition.   For  head deposition, inhalation through the  nose  with a
deposition efficiency  given  by  the empirical equation of  Rattle  (1961a)  was used.   Particles
were  assumed  to be insoluble, stable, and  spherical  with physical  densities of 1  g/cm ,  and
the aerosols  were  assumed to be log  normally distributed with  a o  as  high as  4.5.  When the
results were  expressed in  terms  of  the  mass median  diameter  (HMD) for these  various sized
distributions  of  unit density  aerosols  (equivalent  to  the  MMAD),  the range of  the expected
regional deposition values was relatively narrow.
     At the  time the  ICRP Task Group  models were  developed,  the available human data were
primarily  total  deposition values  for  polydisperse and  sometimes  unstable  aerosols (Landahl
and  Herrmann,  1948;   Davies,  1964b;  Van  Wijk  and  Patterson,  1940;   Brown  et   al.,  1950;
Dautrebande and Walkenhurst, 1966; Morrow et al.,  1958; Landahl  and Black, 1947).   Since then,
the deposition in humans  of monodisperse  insoluble,  stable aerosols of different sizes  has
been  measured under  different breathing conditions.  Extensive  studies  have been conducted by
Lippmann (1977), Heyder et al. (1975, 1980), Stahlhofen et al.  (1980), Chan  and  Lippmann (1980),
and Giacomelli-Maltoni et al.  (1972).  Additional useful data are reported  by Palmes and Wang
(1971),  Shanty (1974),  George and Breslin  (1967),  Altshuler  et al.  (1967),  Hounam  et  al.
(1971a,b),  Foord  et al.  (1976),  Pavia et  al.  (1977),  among  others (Muir  and  Davies, 1967;
Taulbee et al., 1978;  Hounam,  1971; Heyder,  1971; Heyder  and  Davies,  1971;  Fry  and  Black,
1973).
11.2  DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS
11.2.1  Insoluble and Hydrophobic Solid Particles
11.2.1.1   Total Deposition—With  the background  information in Section  11.1,  it  is  evident
that  understanding  and interpreting the health effects  associated with  exposure  to particles
and S0?  is critically influenced by  knowing where particles  of  different sizes  deposit in the
respiratory tract  and  the extent of their deposition.  As was seen, the respiratory tract can
be  divided into regions  on  the  basis of structure,  size, and  function.   Insoluble particles
depositing  in the  various regions contact or affect different cell  populations  and have large
differences in retention  times and clearance pathways (see Section 11.3).
      If  the  quantity  of  aerosol  exhaled  is compared  with that  inhaled,  the  data  can be
expressed  as  total  deposition,  but regional  involvement  cannot  be  distinguished.   By tagging
the test  aerosols with  radio labels,  investigators  have been able to  separate  deposition by
region, beginning  with either nasal and nasopharyngeal  deposition  for  nose breathing or oral
and pharyngeal deposition  for  mouth breathing.   The measurement of clearance  of  the radio-
labeled aerosol from the  thorax can be used to separate early clearance, indicative of tracheo-
bronchial  (TB)  deposition, from more  slowly cleared pulmonary (P) deposition.
     Total respiratory tract deposition with nose breathing  is given in Figure 11-3, and total
deposition with mouth  breathing is depicted in Figure 11-4.   Analyses based on the difference
between concentrations of  inhaled and exhaled particles, as well as those based on  external in
vivo  measurements  of  radiolabeled particles, are  represented in  the studies comprising these

SOX11A/A                                     H-16                                  2-9-81

-------
 I
t—»
•-J
   1.0



   0.9



   OS



   0.7




   0.6
g  OA
ui
O

   0.3




   0.2



   0.1
                 I          I       I     I
           SOURCE               TIDAL VOL, ml

  O  GIACOMELU-MALTONI •! il. (1972)    1500

  O  HEYOER Mil. (19751                1000

" A  SHANTY 11974)                    1150

  O  GEORGE AND BRESLIN (19671     550-760

-—HEYDER, (til. (1980)                1000

 — — HEYOER. «t •!. (1980)                1000
                                                                                                                    I     I     I   I   I   I
     0.1                0.2                0.4    0.5   0.6

               PHYSICAL DIAMETER, ^m 	
                                                                        0.8    1.0
                                                                             2.0                4.0

                                                                 AERODYNAMIC DIAMETER, ion	
6.0    8.0    10.0
                Figure 11-3.  Deposition of monodisperse aerosols in the total respiratory tract for nasal breathing as a function of aerodynamic
                diameter except  below 0.5 (urn where deposition is plotted vs. physical diameter. The data are individual  observations, averages.
                and ranges as cited by the various investigations.

-------
 I
I—•
CO
SOURCE TIDAL VOL, ml RES. RATE, breattw/min SOURCE TIDAL VOL, ml RES. HATE, br««
O LANDAHL tt al. (19511 500 15
DLANDAHL.ttl. (19521 1500 15
A ALTSHULER Mil. (1957) 500 15
V GEORGE AND BRESLIN (1967) 760 11
OGIACOMELLI-MALTONI«II. (1972) 1000 12
• CHAN & LIPPMANN (1980)* 1000 14
• FOORDm •1.11976) 1000 16
A MARTENS ft JACOB! (1973) 1000 14
1.0
0.9

0.8
0.7
0.6
ZO .5
v«v
O
1-
i o*
a.
^j
Q
03


0.2
0.1
0
•USED MMD FOR D < 0.5 Jim
I I I I I I I I I I
__

	
	
	
- *
^
~~ * * T T
— * ~ * o L •
T ^rn T
^ 	 I I I
— ^** "? ^*" £
12 .
..til
i i i i i i i i i 1 1
T LEVER (1974) 600 16
4 MUIR & DAVIES (19671 500 16
O DAVIEStt 11.11972) 600 16
B HEYDER (1975) 1000 15
A SHANTY (19741 1140 18
T STAHLHOFEN at al. (1980) 1500 16
<> STAHLHOFEN it •!. (1980) 1000 7.6
^ SWIFT « •!. (1977) 500 IS
$$£ HEYDER 11973) 500 16
1 I 1 1 1 1 1 1 1 1 1 lo| 1 I
tl^ J* s~
•mjr\ «P * *
*T* Tf * **• ~~
if..* -
I *.'
V
a
j '
! * T t B
" T -fc. •** *
A F* °
A 1 A -L
4a » —
1 1 1 1 1 1 i II 1 1 1 1
               0.01
 0.02         0.04    0.06  0.080.10

	   PHYSICAL DIAMETER,/im
                                                                   0.20
0.4 0.5 0.6  0.8  1.0          2.0          4.0     6.0  8.0 10.0

	4>	AERODYNAMIC DIAMETER, ion	»
             Figure 11-4. Deposition of monodisperse aerosols in the total respiratory tract for mouth breathing as a function of aerodynamic
             diameter except below 0.5 pm, where deposition is plotted vs. physical diameter. The data are individual observations, averages,
             and ranges as cited by the various investigators.

-------
figures.  With  nose  breathing,  complete deposition can  be  expected for particles larger than
about 4 um Dae-   Mouth breathing  bypasses  much of the filtration  capabilities  of  the naso-
pharyngeal region, and there is a  shift  upward  to around 10 um  0    before there is complete
deposition of the inhaled particles.
     The  various  studies all  appear to  show the same trend.  The  particle  size for minimum
deposition is less clear for nasal  breathing as compared to mouth breathing, for which minimum
deposition is  at  about 0.5 um  diameter.   Heyder and  coworkers (1973a, 1973b, 1975)  carefully
matched  breathing  patterns  among subjects in  studying the  deposition of 0.5 um D   particles
                                                                                  ac
upon  which there  were  no electrical  charges;  their data are the deposition  minima  in Figure
11-4.   Thus  far,  deposition of  particles  less than 0.1 um diameter  has only  been studied  in
human subjects  by Swift et al.  (1977).
     Comparison of  the effects  of  respiratory  parameters   on  aerosol  deposition  have  been
conducted  by Heyder  and co-workers  (1975, 1980) in systematic experiments comparing deposition
of  different  sized monodisperse aerosols in human volunteers at different tidal volumes,  flow
rates,  and breathing frequencies.   For particles between 0.1 um and 4.0 um in diameter, Heyder
et  al.  (1975)  measured total  respiratory  deposition  during either  nose  or  mouth  breathing
while sequentially maintaining  a given tidal  volume,  breathing rate, or inspiratory  flow rate
and then varying  the  other  two parameters.    They demonstrated several  important features  of
aerosol  deposition  in  the  human respiratory  airways.   Heyder and  co-workers  (1980) extended
these studies  to  particles as  large  as 9 um D   ; in the mouth-breathing experiments  they also
                                               ae
determined alveolar  deposition.
     With  volumetric flow rate held  at 15 liter/minute while breathing through the mouth,  the
particle  size  yielding the lowest  deposition  changed  from  0.66  um  at TV 250 ml to 0.46 um at
TV  2000 ml.   Breathing at TV 1000  ml changed this minimum deposition size from 0.58 um at 30
BPM to  0.46  um at 3.75 BPM.   Hence,  the particle size of minimum deposition was reduced with
increased  residence  time of particles in the  lung and the net deposition for all particles  was
increased.   In  fact, as the breathing rate  went from  3.75 BPM to 30 BPM,  the deposition at 1
um  D   went  from 0.08  to 0.4,  an increase of a factor of 5.  In contrast to mouth breathing,
     36
however,  the particle  size  of  minimum  deposition with nose  breathing was  independent of  the
residence  time  of particles in  the  respiratory tract when 1000 ml  of aerosol at different flow
rates were inhaled.
     When  Heyder  et  al. (1975)  kept  the  breathing  frequency constant while changing the flow
rate  and having the subjects breathe through  the mouth,  the deposition for particles smaller
than  1  um remained  essentially unchanged,  indicating  that  inertial  impaction was  of little
importance in  the deposition of submicrometer aerosols.   On the other hand, the deposition of
particles  larger  than 1 um D    was enhanced at high  flow rates, indicating  the  influence of
inertial  impaction on  the deposition  of larger particles.
     Sedimentation and impaction are competing deposition mechanisms, being  governed by mean
residence  time  and flow rate,  respectively.   Hence, impaction will  be the dominant mechanism

SOX11A/A                                     H-19                                  2-9-81

-------
at high  flowrates  and short residence times,  while  most particles will be deposited by sedi-
mentation at  low flow rates and long residence times.  Heyder et al. (1980) showed that for 1
Mm Dae Partic1es, total deposition for mouth breathing at 1000 ml TV increased with increasing
mean residence time,  indicating these particles were mainly deposited by sedimentation.   For 8
Mm Dae,  increasing flow rate increased deposition so that these particles were mainly deposited
by impaction.  A transition region was observed for particles about 4 urn D  .  while Heyder and
                                                                          aC
co-workers  (1980)  noted  the transition region was shifted  towards smaller particles for nose
breathing.
11.2.1.2  Deposition—The  fraction  of inhaled aerosol depositing  in  the extrathoracic  region
can  be  quite variable, depending upon particle size, flow rate, breathing frequency, and whe-
ther breathing is through  the nose or through the mouth.   During exertion, the flow resistance
of the  nasal  passages cause a shift to mouth breathing in almost all individuals, thereby by-
passing  much  of  the  filtration capabilities of the head and leading to increased tracheobron-
chial  deposition.   Nasopharyngeal deposition  is  shown  for nose breathing  in  Figure 11-5 and
for  mouth breathing  in Figure 11-6.  Deposition  in  this region is usually plotted as a func-
          2
tion  of  DO since this is a convenient parameter for normalizing impaction dominated deposi-
          d6
tion data when the actual  flowrates are not identical (Rattle, 1961a; Stahlnofen et al., 1980;
National  Academy of Sciences, 1980; Hounam et al., 1969,  1971a).  For reference, a scale show-
ing  aerodynamic  diameter when Q = 30 liters/min is also shown since this flow rate approximates
the  average flow rate for  the studies comprising these figures.
     Particles entering  the nose larger than about 10 urn D   are effectively deposited in the
                                                           36
extrathoracic region  (Figure 11-5).  Also, deposition is slight (10 percent) for particles less
than 1 urn D   .   Similarly,  for 10 urn and 1 urn D,  particles under conditions of mouth breathing
            36                                  36
(Figure  11-6),  extrathoracic  deposition is about 65 percent and 2 percent, respectively.  The
regression  curve shown in  Figure 11-6 is from Chan and Lippmann (1980) who used their own data,
as well  as  the data  of  Lippmann  (1977)  and Stahlhofen et al. (1980) for Q = 45 liters/min in
their  analysis.   As   indicated by Chan and Lippmann (1980), some of the lower values of extra-
thoracic  deposition  may  be due to partial  clearance  to  the stomach before the measurement of
head  deposition  was  obtained.   Particles  can be swallowed even when  the subject consciously
tries to  avoid swallowing  (Lippmann, 1977; Stahlhofen et al., 1980).
11.2.1.3  Tracheobronchial  Deposition—As  was  seen earlier, when aerosols are inhaled through
the  nose, relatively efficient extrathoracic filtration eliminates the passage of most parti-
cles  larger than  about  10 urn  D,.  to the tracheobronchial  region.   Mouth breathing markedly
                                 dc
alters the  deposition of  inhaled particles in  humans in that  larger particles can  enter both
the tracheobronchial  and pulmonary regions (Morrow et al., 1966; Lippmann, 1977; Heyder et al.,
1980;  Stahlhofen  et  al.,   1980).   For  mouth-breathing  tracheobronchial  deposition expressed
as a  fraction of the  particles entering  the  trachea is  shown  in  Figure 11-7 plotted against
particle  size.   Approximately  80-90 percent of 8-10 urn D   particles entering the trachea are
deposited in  the tracheobronchial region,  as  compared to  less  than  10 percent for particles

SOX11A/A                                     11-20                                   2-9-81

-------
1.0

0.9

OS

0.7

0.6

0.5

0.4

0.3

02

0.1
                                      AERODYNAMIC DIAMETER (at 30 liters/min), pm
                                             2              3         4        5
                                                                                               8   9  10
       SOURCE
D HOUNAM.t .1.11969)
O LIPPMANN (1970)
O MARTENS & JACOB! (1973)
A GIACOMELLI-MALTONI « al. (1972)
O RUDOLF & HEYDER (1974)
                                     TIDAL VOL, ml
          I          I
RESP. RATE, brmths/min
                                          1000
                                          1000
                                          1000
                                                                                   I
                                                                                              I      I     I
   10
              20
                  40
60   80 100
                                                      200
                                                          400    600  800 1000
                                          2000
4000   6000    10,000
                                                            D2Q
Figure 11-5. Deposition of monodisperse aerosols in extrathoracic region for nasal breathing as a function of D Q, where Q is the
average inspiratory flow rate in liters/min. The solid line is ICRP deposition model based on the data of Pattle (1961a), Other data
show the median and range of the observations as cited by the various investigators.

-------
                                          AERODYNAMIC DIAMETER (at 30 liters/minium
                                                2             345
                                                                                       8   9  10
                                                                                                       14
   0.9

   0.8

   0.7

   0.6
Z0.5
80.4
CL.
   0.3

   0.2

   0.1
O
D
V
O
     SOURCE
LIPPMANN ( 1977)
STAHLHOFEN, «t al. (1980)
CHAN & LIPPMANN (1980)
STAHLHOFEN,« al. (1980a)
CHAN & LIPPMAN (1980)
TIDAL VOL, ml   RESP. RATE, breattu/min
     1000                14
     1000                 7.5
     1000                14
     1500                IS
     REG. LINE OF ALL DATA
                                                                                                        I     I    I   I   I  II
     10
       20
                             40
                       60   80  100
                                              200
                             400
                           D2Q_
600  800H 000
2000
4000   6000 8000 10,000
   Figure 11-6.  Deposition of monodisperse aerosols in extrathoracic region for mouth breathing as a function of D^Q, where Q is
   the average inspiratory flow rate in liters/min. The data are the individual observations as cited by the various investigators. The
   solid line is the overall regression derived by Chan and Lippmann (1980).

-------
*
less than  1  pm Dag.   The increased penetration of large particles deeper into the respiratory
tract when a person breathes through the mouth can be seen from the 20-30 percent experimental
tracheobronchial  deposition  data  for  particles  8-10 urn  D   (Stahlhofen et  al.,  1980).   The
                                                           36
solid curve in Figure 11-7 is from Chan and Lippmann (1980) depicting the experimental tracheo-
bronchial  deposition  data  from their investigations using the average value of a new anatomic
parameter, the bronchial deposition size, for the average Q value measured in their study (Q =
39  liters/min).   This parameter enables the classification of various individuals and popula-
tions according to their tracheobronchial deposition efficiencies.
     Deposition in the  tracheobronchial  region is influenced by both impaction and sedimenta-
tion, with the relative contribution of these two  mechanisms  changing with particle size and
air  flow  rate.   Impaction  predominates for deposition of particles larger than about 3 pm D
                                                                                            ae
and  flow  rates greater than  about  20 liters/min, while  sedimentation deposition  becomes  a
larger  fraction  of a diminishing tracheobronchial  component for  smaller particles  and lower
flows (Lippmann,  1977).   Importance of impaction for tracheobronchial deposition is reflected
                                                                       2
by  deposition  often  being  plotted against the  inertial  parameter,  D  Q (Stahlhofen et al.,
1980 and  Lippmann, 1977).
     For  a given particle  size,  tracheobronchial  deposition  varies greatly  from subject to
subject  among  nonsmokers,  cigarette smokers,  and patients with lung disease (Lippmann et al.,
1971).   On  the  average,  tracheobronchial  deposition  is  slightly  elevated  in  smokers  and
greatly elevated  in patients with  lung-disease (Lippmann et al., 1977; Cohen, 1977).   However,
each subject exhibits a characteristic and reproducible relationship between particle size and
deposition as  indicated by the data of Stahlhofen et al. (1980), depicted in Figure 11-8.  For
the  two  breathing patterns shown, the steep  increase  of  the nasopharyngeal deposition values
with  increasing particle  size is  accompanied by  a  corresponding decrease in tracheobronchial
deposition,  so that  tracheobronchial  deposition, as a function  of particle aerodynamic dia-
meter,  may  be described by  a bell-shaped curve  with  a maximum (Stahlhofen et  al.,  1980).
Although  these investigators  did not experimentally  study particles  larger  than 9  (jm D   ,
                                                                                           CtC
extension  of their bell-shaped  curves would  support  the conclusion of Miller  et al.  (1979)
that  about 10 percent  of  particles  as  large as  15  |jm  D    can  enter  the tracheo bronchial
                                                          ae
region during  mouth  breathing.   Miller et al. (1979) had used the tracheobronchial deposition
data of  Lippmann  (1977) and aerodynamic diameters  computed at  a mean flow rate of 30 liters/
min.  This flow  rate is bracketed  by the mean  flow rates of  15 and 45  liters/min used by
Stahlhofen et  al.  (1980).
     The  data  of  Stahlhofen et al. (1980) in  Figure  11-7 on three subjects show  lower values
and  less  scatter  than the other  data  contained  in the figure.   Chan and Lippmann (1980) cite
two  possible explanations  for the differences.  Stahlhofen and coworkers (1980) used constant
respiratory flowrates in comparison to the variable flowrates used  by Chan and Lippmann (1980).
Also, the  two  laboratories used  different bases  to separate the  initial thoracic burden into
tracheobronchial  and  pulmonary components.   Stahlhofen et al. (1980)  extrapolated  the thoracic

SOX11A/A                                     11-23                                  2-9-81

-------
   1.0

   0.9

   0.8

   0.7

   0.6

O  05
K
V)
g  04
UJ
O
   02

   02

   0.1
      I
   I
I
           SOURCE
O   LIPPMANN & ALBERT (1969)
O   LIPPMANN (1977)
A   STAHLHOFEN, et «l. (1980)
O  CHAN AND LIPPMANN (1980)'
^—CHAN AND LIPPMANN (1980)
— ICRP MODEL FOR 1450 ml TV
    •USEDMMD FOR O
-------
retention values measured during the week after the end of bronchial clearance back to the time
of inhalation; they considered pulmonary deposition to be the intercept at that time, with the
remainder of  the thoracic  burden considered  as  tracheobronchial  deposition.  This  approach
yields results  similar  to,  but not identical with those obtained by treating tracheobronchial
deposition as equivalent to the particles cleared within the first day.
     Deposition calculations usually group lung regions without regard to nonuniformity of the
pattern of deposited particles within the regions.  Schlesinger and Lippmann (1978) found that
nonuniform deposition in the trachea could be caused by the air flow disturbance of the larynx.
Bell and  Friedlander  (1973) and Bell (1978) observed and quantified particle deposition as it
occurs at a single airway bifurcation and found it to be highly nonuniform and heaviest around
the carinal  arch.   Raabe et al.  (1977)  observed  that the relative lobar pulmonary deposition
of  monodisperse aerosols  was  up to  60 percent higher  in  the right  apical  lobes  of  small
rodents  (corresponding  to  the human right upper  lobe) and that the difference was greater for
3.05 urn  and  2.19  urn  D    particles  than for  smaller particles.    In  addition,  Raabe  et  al.
                       d6
(1977) showed that  these differences in relative  lobar  deposition were related to the geome-
tric mean  number of airway bifurcations between  trachea and terminal bronchioles in each lobe
for rats  and hamsters.  Since similar morphologic differences occur in human lungs, nonuniform
lobar  deposition  should also occur.   Schlesinger and  Lippman  (1978)  found nonuniform deposi-
tion  in  the  lobar  branches of  a hollow model of the tracheobronchial  airways  with enhanced
carinal  deposition  and  were able to demonstrate  a  correlation of higher lobar deposition and
the reported  incidence  of  bronchogenic  carcinoma in the different human lobar bronchi.  Occu-
pational  lung diseases, such as silicosis and asbestosis, also show distinctive distributional
features  (Morgan and Seaton, 1975).
11.2.1.4  Pulmonary Deposition—Pulmonary deposition  as  a function of  particle  size is shown
in  Figure 11-9.   All  of  the  experimental  points plotted  were  obtained  in mouth-breathing
studies on nonsmoking normal subjects who inhaled monodisperse aerosols.
     The eye-fit band approximately encompasses the range of deposition values obtained in the
studies  cited;  a variety of tidal volumes and breathing frequencies were used.  Also shown in
Figure 11-9 are the deposition curve from the predictive model of Yu (1978) and an estimate of
the alveolar  deposition that could be expected for nose breathing (Lippmann, 1977).  Lippmann
(1977) derived the estimate by analysis  of the difference in head retention during nose breath-
ing and mouth breathing.
     The  pulmonary  deposition  curve  peaks at  about 3.5  urn D   with the middle of the eye-fit
band  in   Figure  11-9 being located  at about  50 percent deposition.   However,   the  data of
Stahlhofen et al.  (1980) for a tidal volume of 1000 ml and 7.5 breaths per minute (reflective
of  breathing very slowly and deeply)  show  that pulmonary deposition  of  3.5 pm D   particles
can be as high as 70 percent.
     For  nose breathing,  the size associated with maximum deposition  shifts downward to about
2.5 pm D  .   Also, the deposition peak is much less pronounced (about  25 percent) with a nearly
        ae
constant pulmonary  deposition  of about  20 percent  for all sizes  between 0.1 urn and 4 urn Dae-
SOX11A/A                                     11-25                                  2-9-81

-------
                TV - 1000 ml. BPM - 7.5/min
i
ro
         ui
         Q
           1.0
               TV - 1500 ml, BPM - 15/min
           0.8
           0.4
          0.2 -;
I  SUBJ. 1
•   SUBJ. 3
                                               89             2           4      6891


                                                   AERODYNAMIC PARTICLE DIAMETER, urn
                                                                                                  8  9
         Figure 11-8.  Total and regional depositions of monodisperse aerosols as a function of the aerodynamic diameter for three individual

         subjects as cited by Stahlhofen et al. (1980). (T = Total, TB = Tracheobronchial, P = Pulmonary, ET = Extrathoracic, TV = Tidal

         Volume. BPM = Breaths Per Minute)

-------
    1.0

    0.9

    0.8

    0.7

Z   0.6
O
I-
35   0.5
2
HI
0   0.4

    0.3

    0.2

    0.1
                O
                &
                O
                O
  I       I    I   I   I   I  I  II           I
           SOURCE           TIDAL VOL. ml
 STAHLHOFEN at al. (19801
 STAHLHOFEN at al. (198Ob)
 STAHLHOFEN at al. (1980)
 ALTSHULER at al. (1967)
 GEORGE & BRESLIN (19671
 SHANTYI1974)
 LIPPMANN ft ALBERT (1969)
 CHAN & LIPPMANN (19801*
•YU (19781
 LIPPMANN (1977)

 •USED MMD FOR D < 0.5 Jim
                                                                I    I   I   I  I  II I
                                                               RES. RATE (BPM)
                    I       I    I   I   I   I  I  II   •*•
       .01
                  .02         .04     .06  .08  .1

                           PHYSICAL DIAMETER,>
                                       .2         .4  .5 .6    .8  1.0         2.0         4.0    6.0  8.0 10.0

                                                         	AERODYNAMIC DIAMETER, fim
Figure 11-9.  Deposition of monodisperse aerosols in the pulmonary region for mouth breathing as a function of aerodynamic dia-
meter, except below 0.5 pm where deposition is plotted vs. physical diameter. The eye-fit band envelops deposition data cited by the
different investigators. The dashed line is the theoretical deposition model of Yu (1978) and the broken line is an estimate of pul-
monary deposition for nose breathing derived by Lippmann (1977).

-------
     Pulmonary and total deposition of Fe203 (density 3.2 g/cm3) particles and di-2-ethylhexyl
sebacate droplets  for  mouth breathing was evaluated by  Heyder  et al.  (1980) as a function of
aerodynamic diameter for  two breathing patterns.   Some  results with  di-2-ethylhexyl  sebacate
particles  were  reported  by Heyder  et  al.  (1980)  in  terms of  particle  diameter.   They  are
presented  here  for  uniformity  in terms  of  aerodynamic diameter  since  these  particles  were
close  to  unit  density.   Keeping  the  mean volumetric  flow rate constant  at 250 ml/sec  and
allowing the  mean  residence time to vary between  2  and 8 sec,  they observed that as the mean
residence  time  increased,  there was a decrease for the particle size having the greatest pro-
bability of  deposition.   With  this  mean flow  rate,  particles  smaller than  about 2.4  urn  Dge
were  exclusively deposited  in  the alveolar region,  indicating their inertia  was  not  suffi-
ciently high for impaction  loses.  When the mean flow rate was increased  to 750 ml/sec and the
mean  residence  time  was  2  sec, particles with  an  aerodynamic  diameter smaller than about 1.5
urn were  exclusively  deposited  in the alveolar region of the respiratory  tract.   From the data
of Heyder et al. (1980) it  can also be seen that the particle size associated with the peak of
the deposition  curve and  the magnitude of the  peak  decrease as the mean flow rate increases.
In the  above  studies,  maximum  pulmonary deposition  was at 3.5  urn and  3 urn  D   when  Q  was
                                                                                uC
15 liters/min and 45 liters/min, respectively.
11.2.1.5   Deposition in Experimental Animals—Since much   information  concerning  inhalation
toxicology is  collected with beagles or rodents,  it  is  important to consider the comparative
regional deposition  in  these experimental  animals to help  interpret,  from a dosimetric view-
point, the possible implications for man of animal toxicological results.
     The study by Holma  (1967)  on rabbits examined mucociliary  clearance  rates  but Lippmann
(1977)  derived tracheobronchial deposition  information  by further analyzing the  data.   Lung
retention  curves indicated  that  the tracheobronchial  deposition of 6 urn polystyrene spheres
varied  from  40  to 93  percent  of the total  lung  deposition,  with a median  of  60  percent.   A
median of  29  percent was  found  for  3  urn  particles.   The above values are remarkably close to
the available  data for man.  Cuddihy et al.  (1973)  measured the regional deposition of poly-
disperse aerosols  in beagles with TV about 170 ml  at about 15 BPM and expressed the results as
mass  deposition percentage  versus  mass  median aerodynamic  resistance diameter (MMAD  ) that
                                                                                      3T*
ranged from 0.42 urn  to 6.6  urn  with  geometric  standard deviation a  = 1.8.  These results are
summarized in  Figure 11-10 and compared with the  Task  Group Values for  man  with  TV 1450 ml,
integrated to  account  for  a a  = 1.8.   In  comparison  to  the  tracheobronchial  deposition of
large particles  in rabbits exposed to monodisperse aerosols  for  one test at 6.6  pm D   ,  the
                                                                                       3f*
tracheobronchial deposition was about  44  percent of  the  total  lung  deposition.   With sizes
between 2.5 and 3  urn D  .  the tracheobronchial deposition ranged from 5  to 39 percent,  with a
                       ar
median  deposition  of  9  percent.   The particle   size  for  minimum  pulmonary  deposition  was
approximately  0.6  urn D   ,  with pulmonary deposition  at this  size  ranging  from  about 12-35
percent and total deposition from about 18-55 percent.
SOX11A/A                                     H-28                                  2-9-81

-------
 1.0
 0.5
 0.2
O  0.1

I"
oc
u.
O

§  1-0
a.
8
 050
0.20
0.10
0.05
      V269A
      O284A
     	I	i   i  i  i mi
                    0.5
                     1.0
                                    I  I  I III
                                                     0.10
                                                     0.05
                                                          1     I   I 1  | | IJ6T
                                                           B. TRACKED-
                                                          . BRONCHIAL
                                                                                          5.0    10
:     111      I
_C. PULMONARY
                                   i              tfl
                                                 ^
0.03»—
   0.1
                              =   I    I  I I  Mill     I/TJ,
                              —1D. EXTRATHORACIC       x
                                                      C>
                                                      0.1
                                                     0.05
                                                     0.02
1.0     2.0       5.0     10   0.1   0.2      0.5    1.0   2.0

      ACTIVITY MEAN AERODYNAMIC DIAMETER, pm
                                                                                           5.0
                                                                                          10
Figure 11-10.  Deposition of inhaled polydisperse aerosols of lanthanum oxide (radio-labeled with 140La)
in beagle dogs exposed in a nose-only exposure apparatus showing the deposition fraction (A) total dog,
(B) tracheobronchial region,  (C) pulmonary aveolar  region, and (D) extrathoracic region  (adapted from
Cuddihy et al. 1973). Dashed lines represent range of observed values.
                                                 11-29

-------
     Somewhat different results were obtained by Phalen and Morrow (1973) in dogs exposed to a
silver metal aerosol of 0.5 urn D   with a a  of 1.5 |jm.  Total deposition averaged 17 percent,
                                oC         y
with  a  range  of  15-19  percent.    In  the Phalen  and  Morrow  (1973)  study,  the  dogs  inhaled
through  a  tracheal tube  so that  there  was  no head deposition, while  head  deposition varied
from negligible  to 5  percent for  0.5  urn  particles in  the study of Cuddihy et al. (1973).   In
experiments  using  donkeys  (Albert el al., 1968, 1969;  Spiegelman et al., 1968), eight animals
were tested periodically with monodisperse 3-3.5 urn D   Fe90, aerosol.   Tracheobronchial  depo-
                                                     36   c, -j
sition  averaged 50-70  percent of  the total  lung  deposition,  with a  median  of  54  percent.
     Raabe  et  al.  (1977)  have measured the regional deposition of 0.1 urn to 3.15 urn Dae  mono-
disperse aerosols  in rats  (TV about  2  ml,  70 BPM) and  Syrian hamsters (TV about 0.8  ml  at
about 40 BPM).  Their results are  summarized in Figure 11-11.  The pulmonary deposition of  1-3
urn  Dae  particles is about 6-9 percent in rats and hamsters, while in man deposition of  these
same  size  particles varies from  21-24 percent for nose breathing and  from  20-50 percent  for
mouth  breathing.   For particles  smaller than  1  urn D  ,  differences  in pulmonary deposition
                                                      36
between  man and these species decrease.  Tracheobronchial deposition of particles 5 urn D   is
                                                                                         ac
slight  (-v  5 percent)  in rodents  due to very efficient removal of these particles in the  head.
In  contrast,  50 percent of 5 urn  D   particles inhaled via the mouth  deposit  in the tracheo-
                                   ae
bronchial  region of  man  (Figure   11-7),  so  that  large differences can  exist between  man  and
rodents  in  the  tracheobronchial   deposition of  large particles.   In  rodents,  the  relative
distribution among the respiratory regions of particles less than 3 urn D   during nose breath-
                                                                        ae
ing  follows a  pattern  that is similar to  human  regional  deposition  during  nose breathing.
Thus,  in this  instance, the use of rodents or dogs in inhalation toxicology research for  extra-
polation to  humans entails differences in regional deposition of insoluble particles less than
3 urn D  „ that  can  be  reconciled from available data.
       ae
11.2.2   Soluble, Deliquescent, and Hygroscopic Particles
     Most  deposition  studies and  models  tend  to  focus on insoluble and stable  test  aerosols
whose  properties  do  not  change   during  the course of  inhalation and  deposition.   However,
environmental  aerosols  usually  contain deliquescent or hygroscopic particles that may grow in
the  humid  respiratory airways.   That growth  will  affect deposition  (Scherer  et al., 1979).
Although the  ICRP  Task Group on  Lung  Dynamics (Morrow et al., 1966) addressed this problem by
considering  the  equilibrium diameter for deliquescent materials at  relative humidities  near,
but  less than, 100 percent, the  residence times in the respiratory tract may be too short for
large particles to reach their equilibrium size (Nair and Vohra, 1975; Charlson et al., 1978).
Also,  environmental  aerosols may consist of  a  combination of  components,  including complex
mixtures,  that may not  behave like  pure substances.   Since the  temperature of the  inspired
aerosol  will  usually  be less than that  of  the respiratory tract environment, supersaturation
of water vapor, with  respect to the aerosol particles,  may exist.
     Ferron  (1977)  has  described  the  factors affecting soluble particle growth  in the airways
during  breathing.   His  results suggest that particles  1  urn Dge will  increase  by a factor of

SOX11A/A                                     H-30                                  2-9-81

-------
     0.6
     0.5
     0.4
  c
  u.
  Z  03
  O
     0.2
     0.1
          RAT
          A
          D
          O
    I      I     I    I   I   I  I
HAMSTER

   A    EXTRATHORACIC

   •    TRACHEOBRONCHIAL

   •    PULMONARY
Sr
^,.

&
                     "I
 ^
                        I        "
                     --^-g.zi.rn
                     0.2       03    0.4

            PHYSICAL DIAMETER, nm
                                 0.5  0.6 0.7      1.0             2.0      3.0   4.0  5.0

                                     	AERODYNAMIC DIAMETER (Dar),Aim	
Figure 11-11.  Deposition of inhaled monodisperse aerosols of fused aluminosilicate spheres in small
rodents showing the deposition in the extrathoracic (ET) region, the tracheobronchial (TB) region, the
pulmonary (P) region, and in the total respiratory tract based upon Raabe et al. (1977).
                                             11-31

-------
three  to  four  in aerodynamic  diameter  during passage  through the  airways.   Extrathoracic,
tracheobronchial,  and pulmonary deposition of the enlarged particles would be greater than the
deposition expected  for  the  original  particle size.   Submicrometer particles, including those
as small as 0.05 urn, will grow by a factor of two in physical diameter,  with relatively little
effect  on  deposition.   However,  the  hygroscopic  growth  of particles  in the  diffusion  size
range  (<  0.5 urn  physical  diameter) may  alter their deposition pattern  substantially  as the
diffusional displacement is related to the actual  size and not the aerodynamic diameter.   Pul-
monary  deposition of  particles smaller than  0.3 urn may  be reduced with growth because  of
reduced diffusivity.
     Atmospheric  sulfate aerosols can be  described as  sulfuric acid partially or completely
neutralized  by  NH,.   Growth of  these  particles  will  occur in  the  respiratory  airways  during
respiration.  This  growth  involves chemical  dilution of the electrolyte or acid with absorbed
water.  A  particle  growing  a  factor  of  three in  physical  diameter must absorb  a  volume  of
water  equal  to  26 times its original  particle volume.   Also,  the increased size will  enhance
losses  by  inertial  mechanisms,  including impaction in the  upper  airways.  A 1 urn D   particle
                                                                                   ac
of  H2$04  or (NH4)2$04 may grow  to  nearly  3  urn D   in the nasal region, increasing both nasal
deposition  and tracheobronchial  deposition  by  a  factor  of  2 or  more  over  the deposition
expected for  a  1  pm D   particle,  with  the  net  result that pulmonary  deposition  is reduced.
                      ae
Particle growth in  the airways may in some  cases be protective since the reduced electrolyte
or acid concentration will probably reduce the level of local toxicity.
11.2.3  Surface Coated Particles
     Some  environmental  particles  may  consist  of  a  relatively  insoluble core  coated  with
various chemical  species including metallic  salts, (NH.^SO.,  (NH.)HS04,  H^SO,,  organic  com-
pounds  including  polynuclear aromatic  hydrocarbons,  and small  particles of other  sparingly
soluble materials.   Although some surface growth due to water adsorption may occur in the air-
ways,  growth  will  be limited by the availability of deliquescent or hygroscopic components  on
the  particle  surface.   In general, the  increase  in  aerodynamic diameter  that may occur would
be much less  for coated  particles than for more pure forms of insoluble  materials.
     Important  examples  of  coated  particles are  the  fly ash, soot, or  other  residual  solid
particulate aerosols released  into the environment by combustion  of fossil  fuels.  The exact
chemical form of the relatively  inert core of these particles will vary from nearly pure fused
aluminosilicate particles produced  during  the  combustion  of  coal  to  carbonaceous  or  metal
oxide  particles produced by internal  combustion  engines.  Volatile  trace metal compounds and
organic compounds condense on these particles during the cooling of the  effluent stream in the
power  plant  smoke  stack or engine  exhaust  line  and  during release  to  the atmosphere.   In
addition,  gases such as  SO^ can adsorb  to the particle surfaces or finer aerosols can aggre-
gate onto  the particle surfaces.  If these  processes are  diffusion limited, the condensation
and  coagulation will  be  quantitatively proportional to particle diameter for particles larger
than 0.5 urn  D and to particle  surface  for smaller particles.  In  either case  the fractional

SOX11A/A                                     11'32                                  2-9-81

-------
mass of the surface coating material will be greater on smaller particles than on larger ones.
In other  words,  the condensed material coats the particles with a relative mass concentration
that increases with decreasing particle size.   Important  elements  such as Se, Cd, As, V, Zn,
Sb, and  Be  have  been found to  exhibit this size dependence in coal fly ash aerosols (Davison
et al.,  1974;  Natusch  et  al.,  1974;  Gladney et al.,  1976).   Therefore,  the  growth of such
surface-coated particles in the airways should be expected to be much less than for pure deli-
quescent  particles.   Such  growth should be only  a  minor  influence on the deposition of large
particles.   On  the other  hand,  small  submicrometer coated particles may  be  principally com-
posed  of  a  deliquescent surface coating and  subject  to more extensive relative growth.  (See
also Chapters 3, 5, and 6.)
11.2.4  Gas Deposition
     The  major  factors affecting  the  uptake  of gases in the respiratory  tract  are  the mor-
phology  of  the  respiratory tract, the physicochemical properties of the mucous and surfactant
layers,  the  route of breathing and  the  depth and rate of airflow, physicochemical properties
of  the gas, and  the physical  processes  which  govern  gas transport.   A  brief discussion of
these  factors  serves to illustrate  their  general  role in the deposition  of  gases  and convey
some aspects specific to the uptake  of S02-
     The  complex  morphological  structure of the human respiratory tract has been discussed in
section  11.1.3.   The  nature and structure  of  the  respiratory  tract in man and animals criti-
cally  influences the  deposition of gases  since the  relative  contribution of  gas  transport
processes  varies  as  a  result of  this morphology.   The  human  tracheobronchial  tree  is more
symmetric, with  respect to diameter ratios and  branching  angles,  than  that of dogs,  rats, or
hamsters,  but  is closest  to that  of  the  dog  (Phalen et al.,  1978).   The  structure  of the
tracheobronchial  tree is  variable from species  to  species,  from lobe to  lobe  within  a given
lung,  and from one  depth to another  in the  lung.
     Physicochemical  properties of  a gas  relevant to respiratory  tract deposition  are  its
solubility and diffusivity in mucus,  surfactant, and water and its reaction-rate constants in
mucus,  surfactant,  water,  and  tissue.   Henry's law  relates  the gas-phase  and liquid-phase
interfacial  concentrations and  is  a  function  of  temperature  and pressure.   In general,  the
more soluble a  gas  is  in biological fluids the higher it is removed in the respiratory tract.
The  solubility  of  most gases  in  mucus and  surfactant is  not  known.   However,  Henry's  law
constant  for many gases in water  is known, the value for SOp being 59.7 mole fraction in air
per  mole fraction  in water  at  37°C  and  one atmosphere  of  pressure  (Washburn,  1928).   The
diffusivities of  most gases in mucus,  surfactant, tissue, and water are also unknown, thereby
complicating efforts  to model gas  uptake  in the respiratory tract.  Diffusivity  may be much
smaller in a viscous mucous fluid than in water, but ciliary activity induces turbulence which
effectively  increases mass  transfer.  In the general  case,  transport  rates of the gas across
the mucus-tissue  interface,  tissue  layer,   and the  tissue-blood  interface are needed to fully
understand the absorption and desorption of gases in the respiratory tract.  However,

SOX11A/A                                     11-33                                  2-9-81

-------
information  on  biochemical  reactions  may  enable  one  or  more of  these  compartments  to  be
ignored for a given gas.
     The major processes  affecting  gas  transport involve convection, diffusion,  and chemical
reactions.   The bulk  movement  of inspired gas in the  respiratory  tract is induced by a pres-
sure gradient and  is  termed convection.   Molecular diffusion  due  to local concentration gra-
dients  is  superimposed on  this  bulk flow at all times,  with  the  transport of the  gas being
accomplished by the coupling of  these  two mechanisms.  Convection  can  be  decomposed into the
processes of advection and eddy dispersion.   Advection is  the horizontal movement  of a mass  of
air that causes changes  in temperature or in other physical properties, while eddy dispersion
occurs when air is mixed by turbulence  so that individual  fluid elements transport the gas and
generate the flux.    Due  to the morphology  of  the respiratory tract and  respiratory airflow
patterns, the relative  contribution of  the various  processes to transport  and deposition is a
function of  location and point in the breathing  cycle.
     During  the respiratory cycle,  the  volumetric flow rate of  air varies from zero  up  to a
maximum  (dependent  upon tidal volume,  breathing frequency, and  breathing pattern)  and then
back to zero.  Usually expiration is longer than inspiration, and intervening  pauses may occur.
The net result of these variables is to impart complicated flow patterns and turbulence in some
portions of the respiratory tract (see  Section 11.1.4).
     In  studying  the  nature of gas mixing in the tracheobronchial  tree  and its effects on gas
transport there have been numerous modeling efforts  utilizing an approach in which all pathways
from the mouth  or trachea  to the alveoli are combined into one effective pathway  whose cross-
sectional area  is  equal  to the  summed cross-sectional area of all  bronchial  tubes at a given
distance from the mouth or  trachea  (Davidson and Fitz-Gerald, 1974;  Paiva,  1973;  Pedley, 1970;
Yu, 1975;  Scherer  et  al.,  1972).   In this formulation,  the mechanical  mixing  imparted by tube
bifurcations, turbulence,  and secondary  flows  and  the  mixing  due to molecular diffusion are
represented  by  the  functional  form of  the effective axial  diffusion coefficient (Scherer
et al., 1975).  Thus, this  coefficient of diffusion incorporates the effect of axial convection.
The effective axial diffusion coefficient is a constant equal to the molecular diffusivity only
in  the alveolar region  where  gas  velocity  is  very small.   However, in other regions of the
tracheobronchial tree, the  local  average gas velocity and  the tube  geometry will  jointly deter-
mine the value.   Various functional forms have been proposed in the studies cited above for an
appropriate expression for  the effective axial diffusion coefficient.
     By constructing  individual streamline pathways from the trachea to the alveoli, Yu (1975)
derived  an  expression for the effective axial diffusion  coefficient which equalled the alge-
braic  sum  of the  molecular diffusion coefficient and an  apparent  diffusion coefficient.  The
apparent diffusion  coefficient arises  from two independent mechanisms:   1) the nonhomogeneous
ventilation  distribution  in the  lung,  and 2) the  interaction  of nonuniform velocity  and con-
centration profiles due  to Taylor's mechanism in individual airways.  Using an average  stand-
ard deviation of  airway lengths  based upon  the  data  of Weibel (1963)  and various flow  theory

SOX11A/A                                     11-34                                   2-9-81

-------
limiting  values,  Yu  (1975)  demonstrated  that Taylor diffusion is everywhere  in  the tracheo-
bronchial  tree dominated  by  the  apparent  diffusion due  to nonhomogeneous  distribution  of
ventilation, rather  than being a major mechanism for gas transport in some airways as claimed
by Wilson and  Lin (1970).
     In  all  of the  previously described studies the diffusivity expressions used assume fully
developed flow in straight pipes to describe gas mixing, a condition not truly applicable over
most of  the tracheobronchial tree.  Since flow patterns at tube bifurcations are different for
inspiration  and expiration  (Schroter  and  Sudlow,  1969),  the mixing  process and  hence  the
effective  diffusivities  are different.   To obtain  diffusivities  applicable to  the  tracheo-
bronchial tree, Scherer  et al. (1975) used airway lengths and diameters from Weibel (1963) and
branching  angles  from Horsfield and Cumming (1967) to construct a five-generation symmetrical
branched tube  model  and to experimentally determine effective axial  diffusivity for laminar
flow of  a gas  as a  function of mean axial  velocities up to 100 cm/s in the zeroth generation
tube.  The  relationship  was approximately linear and diffusivities  for expiration were about
one-third those for  inspiration.  The values obtained by Scherer et al. (1975) for steady flow
can  be  applied to oscillating flow in the tracheobronchial  tree provided the oscillating flow
can  be   considered quasi-steady,  i.e.,  steady at any instant of time.   This  condition should
hold in  the first ten generations whenever  flow rates  are  approximately greater than 0.1 1/s
(Jaffrin and Kesic,  1974).
     Additional  experimental uptake data are needed to obtain a better  understanding of the
effects  of various  factors  affecting the transport  and  removal  in the lung of gases, such as
SOp.  Also needed  along with  these experimental data are  refined theoretical  approaches,  as
well as  more flexible computational models, such as that of Pack et al. (1977).  The amount of
S0?  removed depends  upon  solubility,  the  velocity  and turbulence of  the  air,  the diffusing
capacity across  the air-tissue interface and through the tissue,  the volume of tissue avail-
able  for gas  storage,  and  the  rate  of fluid exchange between these  tissues  and the storage
reservoirs  in  the  body  for  S0? (Aharonson, 1976).  The rate controlling factor in the deposi-
tion of  SO,  is probably  the  vapor pressure of dissolved S09 in buffered body fluids.
                                                                            2
     The diffusion coefficient of S0« in air at body temperature is 0.144 cm /sec at sea level
(Fish and Durham,  1971;  Sherwood et al., 1975).  The complicated flow patterns and turbulence
in  the  upper respiratory tract and upper generations of the tracheobronchial tree in combina-
tion with high solubility  in body fluids are responsible for the large removal of S0« in these
regions.   Frank  et  al.   (1969) surgically isolated the upper respiratory tract of anesthetized
dogs with separate  connections for the  nose  and mouth.   Sulfur dioxide  labeled  with 35S was
passed through this isolated nasopharyngeal region for 5 min, and nearly complete removal was
                                         33
observed for concentrations  of 2.62 mg/m   to  131 mg/m  (1 to 50  ppm)  at a flow rate through
the nose of  3.5 liters/min.  Uptake of the mouth averaged more than 95 percent at 3.5  liters/min
                             3              3
with S0? levels of 2.62  mg/m and 26.2 mg/m  (1 and 10 ppm).  However, when flow was  increased
tenfold  to 35  liters/min, uptake by the mouth fell to under 50 percent.  Strandberg (1964) used

SOX11A/A                                    H-35                                  2-9-81

-------
a trachea! cannula with two outlets that allowed sampling of inspired and expired air to study
the uptake of  S0? in the respiratory tract  of  rabbits.   He observed 95 percent absorption in
the respiratory  tract  at 524 mg S02/m3 (200  ppm)  but at 0.13 mg S02/m3 (0.05 ppm) absorption
was  lowered  to  about  40 percent during inspiration, demonstrating  an  apparent concentration
effect.  Absorption  of  SO,  at expiration was 98%  in  the 524 mg/m  (200 ppm) studies compared
                                       o
to 80%  for  experiments using 0.13 mg/m  (0.05 ppm).   Dalhamn and Strandberg (1961) found that
rabbits  exposed  to  262-786  mg  S02/m3  (100  - 300  ppm)  absorbed  90% -  95% of  the S02>   They
noted  that  absorption was  to some extent  dependent upon the technique whereby tracheal  air
samples were obtained.
     Corn et  al.  (1976)  studied the upper  respiratory tract deposition  of S02  in  cats  and
computed mass  transfer coefficients  which can be used with surface area data to calculate the
amount  of  SO- removed  in various parts  of  the respiratory tract.   Utilizing  a theoretical
approach, their  own  empirical data,  and information  available from  the literature, Aharonson
et  al.  (1974) examined  the effect of  respiratory airflow  rate  on nasal  removal  of soluble
vapors.  The  only assumption made regarding factors affecting local  uptake was that there was
no  back pressure  in the blood.   Hence,  whether the  rate  of uptake is  limited by diffusion
through  the  gas  phase,  diffusion through  the  tissue,  chemical   reactions  in the  tissue,  or
local  blood  flow  in the tissues, the  analytical  approach  is valid,  as long as  the rate  of
uptake  is  proportional to the  gas phase  pressure  of the vapor.   Their  analysis for  acetone,
ether, ozone, and  sulfur dioxide showed that the uptake coefficient,  which defines the average
flux  of soluble  vapors  into  the nasal  mucosa per gas-phase  unit  partial  pressure,  increases
with increasing  airflow  rate.
     In  experiments  described by Brain (1970b) there was  a 32-fold  increase in the amount  of
S02 present in the trachea of dogs when the air flow-rate was increased 10-fold.   However,  had
the  uptake  coefficient  not  changed  with the flow rate,  Aharonson et  al.  (1974)  pointed  out
that penetration would have increased 500-fold.  If the uptake coefficient for SO- is concen-
tration  dependent,  as  the  data of  Strandberg (1964)  suggest,  increasing airflow  rate  may
increase uptake  due  to higher  levels of S0?  being present along the center  of  the airstream
for the same inspired concentration.
     The  deposition  and clearance of sulfur  dioxide  also has been studied  in  j_n vitro model
systems.   In   a  model  of  the  tracheobronchial  airways lined with  a  simulated airway fluid
(bovine serum albumin dissolved  in saline), it was observed that S0? was primarily absorbed in
the  upper  third  of  the simulated airway with  only  a small fraction of  the  S0? reaching the
simulated alveolar or bronchiolar regions (Kawecki, 1978).
     Uptake and  release of S02  in the  nose  of human subjects breathing 42.2 mg/m  (16.1 ppm)
through  a  mask  during  a 30  minute exposure  period was studied by  Speizer and Frank  (1966).
During  inspiration the concentration  of S02  had dropped  14% at  a distance  1-2  cm within the
nose and was  too small  to detect at the pharynx with the analytical method used.  Expired gas
in the pharynx was also  virtually free of S02, but in its transit through the nose the  expired

SOX11A/A                                      11-36                                  2-9-81

-------
air acquired  S02 from  the nasal mucosa.   The  expired S02 concentration at the  nose  was 5.2
mg/m  (2.0 ppm),  or about 12% of the original mask concentration.   In most subjects the nasal
mucosa continued  to release  small amounts  of SCL  during the first 15 minutes  after cessation
of the S0? exposure (see Section 11.3.2).
                                                                      o          o
     Melville (1970)  exposed  humans  to S02 levels ranging from 4 mg/m  to 9 mg/m  (1.5 ppm to
3.4 ppm)  for  periods up to 10 min.   Respiratory tract extraction of S0? during nose breathing
was significantly greater  (p < 0.01) than during mouth breathing (85% versus 70%, respectively)
and was  independent of the inspired concentration of  S00.   Andersen et al. (1974) found that
                             3
at least 99% of 65.5 mg S02/m  (25.0 ppm) was absorbed in the nose of subjects  during inspira-
tion.   Values  obtained after  one to  three hours of  exposure  were not  different from those
obtained  after   four  to  six  hours  of  exposure,  thereby  indicating  there was  no saturation
effect during this  period  of time.
11.2.5  Aerosol-Gas Mixtures
     Gases  readily  diffuse to  the  surface of  particles and can participate  in  a variety of
surface  interactions.   Surface  adsorption  related to temperature  and  gaseous vapor pressure
occurs if  adsorption sites for  the gas molecules are present on the particles.  Such physical
adsorption  can  be  described  by  the  Langmuir isotherm or  more  complex  isotherms (Gordieyeff,
1956).  In addition chemical adsorption can occur involving chemical transformations and bonds
that enhance transfer of gaseous materials  to the particulate phase.  Such transformations can
include both  inorganic and organic  vapors.  In addition, aerosols of liquid droplets can col-
lect and  carry  volatile species that are dissolved in the droplets.  In these  cases, aerosols
can serve as vectors  carrying  molecules  of  various substances deeper  into the airways than
would occur if the  substances were in their gaseous forms.
     Sulfuric acid  in the  environment may be reduced in acidity by naturally occurring ammonia
(NH,)  to  form  ammonium  sulfate (NH.KSO. and ammonium bisulfate (NH.HSO.).    Larson et al.
(1977) made  short-term measurements  which suggest that  endogenously  generated ammonia (NH^)
gas in the human airways  may  rapidly  and  completely neutralize sulfuric acid  aerosols in the
concentrations  that are  normally encountered in  the  ambient environment.  Also, ammonia is
generated  from  food and excreta in inhalation chambers used to expose experimental animals to
sulfuric  acid (H?SO.)  so  that some neutralization of  sulfuric  acid in these test atmospheres
probably occurs.
     Since S0? is found in the gas phase in various environmental aerosols, the reactions that
occur between S0? and aerosols,  and the gas-to-particle conversions that may occur, can greatly
influence the regional deposition of biologically active chemical species.  Since S02  is highly
soluble  in water,  droplet aerosols,  including those  formed by  deliquescent  particles, will
collect  dissolved S0? and can carry  some  of  the resulting  sulfurous  acid  not neutralized by
NH., deep  into the lung.    The presence  of  certain sulfite species formed by such  reactions in
  *5
environmental aerosols  has been suggested (Eatough et  al. , 1978).  S02  is also known to be
converted  to  sulfate by reactions catalyzed by some aerosols, including those containing iron

SOX11A/A                                     11-37                                  2-9-81

-------
*
or manganese.  The  simple adsorption of S0~ to aerosol surfaces by chemical reaction may lead
to the aerosol's acting as a vector for transporting SCL to the deep lung.
     The  deposition  of the  aerosol  and gaseous  fractions  of the sulfur  species  can  be pre-
dicted  from  the properties  of  these fractions.   Hence, the  problem  of  estimating deposition
(and  subsequent  biological  effects) requires  an understanding  of  the  proportion  of sulfur
species associated with the aerosol fraction and their chemical properties.  Since these reac-
tions  are dynamic processes, the  rate  and mechanics  of the  gas-particle  chemical reactions,
especially as  they  may occur in the airways,  must  be understood, such as the potentiation of
increased  airway  resistance in guinea  pigs  with  SCL by some  particles  (Amdur and Underhill,
1968).
11.3 TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT
     Particulate material  deposited  in  the respiratory tract may eventually be cleared by the
tracheobronchial mucociliary conveyor or nasal mucous flow to the throat and is either expec-
torated or swallowed.   Other deposited  material may be cleared by either the lymphatic system
or  transfer  to  the  blood.   S02  reacts   rapidly   with  biological  constituents to  produce
S-sulfonate  (Gunnison  and Denton,  1971).  The role of clearance as a protective mechanism for
the  respiratory  tract depends on  the  physicochemical characteristics  of the  particles  (or
gaseous species),  the  site of deposition,  and  respiratory  physiology.   If the particles dis-
solve  rapidly  in body  fluids, their deposition in the nasal turbinates with subsequent absorp-
tion  into the  blood  is  important, and total deposition of soluble particles may be more criti-
cal than  regional deposition.  For relatively inert and insoluble particles, deposition in the
pulmonary region,  where they may be tenaciously retained, may be more hazardous, unless their
action is mediated  through  nasal  deposition.  The  deposition by  dissolution of S0? in the
extrathoracic  region may  be protective, since  it may  involve less serious biological effects
than  deposition in the  bronchial or pulmonary airways.  Mouth breathing would lessen the nasal
absorption and increase the S02 levels entering the lung.   If the particles or S02 chemically
react  with body fluids, transformations of  the material  can  affect clearance.  In all respi-
ratory regions, the  dissolution of particles competes with other clearance processes.
      Since respiratory  tract clearance  may begin immediately after the initial deposition, the
dynamics  of  retention  can become quite complicated when additional deposition is  superimposed
on  clearance  phenomena,  especially  if  the  deposited  material  affected  clearance mechanisms.
Extended  or  chronic  exposures are the general rule for environmental aerosols, and particulate
material  may accumulate in some portions of the lung  (Davies, 1963, 1964a; Walkenhorst, 1967;
Einbrodt,  1967).
11.3.1 Deposited Particulate Material
     An  understanding  of  regional  deposition  is requisite  to  an evaluation of respiratory
clearance and  a description of the retention of deposited particulate materials.   In addition,
there  may be significant differences between the mechanisms of clearance in different  mammalian
SOX11A/A                                     11-38                                   2-9-81

-------
species.    Particle deposition,  in  the  extrathoracic  region  is  limited primarily  to  larger
particles deposited by  inertial  impaction.   Deposition of various  aerosol  particles may lead
to specific biological effects associated with this region.   For particles that do not quickly
dissolve or  do not  react with body  fluids, clearance  from  this  region  is  mechanical.   The
anterior third of the  human nose  (where  most particles >5  urn may  deposit) does  not  clear
except  by  blowing,  wiping,  sneezing,  or  other  extrinsic  means,  and  particles may not  be
removed  until  1  or more days after deposition (Proctor and Swift, 1971; Proctor et al.,  1969,
1973; Proctor  and Wagner, 1965, 1967).
     The posterior portions  of  the  human  nose,  including the  nasal  turbinates,  have  muco-
ciliary  clearance  averaging 4  to 6 mm/min  with  considerable  variation among  individuals
(Proctor and  Wagner,  1965 and 1967;  Ewert,  1965;  van Ree and van Dishoeck, 1962).   Particles
are  moved  with this mucus to the throat and are swallowed or expectorated.  Various reactions
can  occur in the gastrointestinal tract, and some assimilation into the blood is possible even
for  particles  that were relatively  insoluble in the nose.  The ICRP Task Group (Morrow et al.,
1966) adopted  a  4-minute half-time for physical clearance from the human extrathoracic (naso-
pharyngeal) region by mucociliary transport to the throat and subsequent swallowing.
     Soluble particles or droplets  are readily assimilated by the mucous membranes of the nose
directly into  the  blood.   Solubility is graded from extremely insoluble to instantly soluble,
and  the dissolution  rate  constant for the  particles must be  considered for  each aerosol.
     Since the tracheobronchial region includes both very large and very small airways, parti-
cles of  various  sizes can be deposited.  The  retention of  deposited materials in this region
can  differ  markedly  among  individuals  and  can be  affected  by   such  factors  as  cigarette
smoking, pathological  abnormalities,  or  responses  to  inhaled  air pollutants.   Clearly,  the
more rapid  the clearance, the less time available  for untoward responses or latent injury at
the  site of original deposition.   In mouth breathing of aerosols, such as  during  smoking or
under physical exertion,  the beneficial  filtering of  large  particles  in the nasal  airways is
lost, and  a  greater  fraction of  these  large particles  can  be deposited in the  TB region.
     An  important  characteristic of the TB  region is that it is both ciliated and equipped with
mucus-secreting  cells.    Mucociliary  clearance mechanisms have  been reviewed  by Schlesinger
(1973).   For relatively insoluble and inert particles, the primary clearance mechanism for the
TB region is mucociliary transport  to the glottis, with subsequent swallowing and passage into
the  gastrointestinal  tract.  Mucous  flow  influences  the ciliary mucous conveyor (Van As and
Webster, 1972; Besarab and Litt, 1970; Dadaian et al., 1971).
     Th^e rate  of  mucous movement is  slowest in the finer, more distal airways and greatest in
the  major  bronchi  and trachea.   In addition,  coughing can  accelerate tracheobronchial clear-
ance by  the  mucociliary conveyor.   The size distribution of particles affects their  distribu-
tion  in the   tracheobronchial  tree.   The  average  clearance  time  for small  particles that
preferentially deposit  deep  in  the  lung  is longer than for larger  particles,  which tend to
deposit  in  the larger  airways  (Albert  et  al.,  1967,  1973;  Camner  et al.,  1971;  Luchsinger
et al.,   1968).
SOX11A/A                                     11-39                                   2-9-81

-------
     The clearance  of material  in  the TB  compartment  cannot  be described by a  single  rate.
Data from experimental  studies imply that the  larger airways  clear  with a half-time of  about
0.5 hours,  intermediate  airways  with a half-time of 2.5 hours, and finer airways  with a  half-
time of  5  hours  (Morrow et al.,  1967a; Morrow, 1973).   There is also considerable variability
among  individuals  (Camner et  al., 1972,  1973a,b;  Camner  and Philipson, 1972; Albert  et  al.,
1967).    Material  with  slow  dissolution  rates in  the  TB compartment  will  usually  not  per-
sist longer  than  about  24 hours  in healthy humans.   Cigarette  smoking has been reported  under
various  conditions  to either increase, decrease, or have  little  effect on the efficiency and
speed of TB clearance (Camner and Philipson, 1972; LaBelle et al., 1966; Bohning  et al.,  1975;
Albert et al., 1974;  Thomson and  Pavia, 1973).
     Particles smaller  than  about 10  (jm D    are deposited to  some extent  in the  pulmonary
                                           36
region of  the lung upon inhalation,  although the deposition of particles smaller  than 0.01 urn
may be quite  limited  because of the competing diffusional  deposition  in the NP and TB regions.
Particles that deposit in the pulmonary region land on surfaces kept  moist by  a complex liquid
containing  pulmonary  surfactants.  Slowly dissolving materials that  deposit in the human  pul-
monary region are usually retained for years.  For example, McEuen and Abraham (1978) reported
that birefringent  particle  counts  were significantly higher in 37 cases of pulmonary alveolar
proteinosis  both   in  regions  of  alveolar  proteinosis  and  perivascular and  peribronchiolar
regions  (dust retention  areas) than  in 13 control subjects.   Out of  8619 particles,  4817  were
<  1  urn in  physical diameter,  3771 were  1-10 urn in physical diameter,  and  31 were > 10  urn in
physical diameter,  with  59  percent being round,  19  percent  fibrous,  and 22 percent irregular
in shape.
     Usually, relatively insoluble particles are rapidly phagocytized by pulmonary macrophages
(LaBelle and Brieger, 1961;  Sanders and Adee,  1968;  Green,  1971,  1974; Ferin,  1967,  1976,
1977;  Camner et al., 1973a,b, 1974; Chapman  and  Hibbs,  1977; Ferin et al.,  1965;  Brain and
Corkery, 1977; Brain  et al., 1977; Brain, 1970a).  Some  particles may enter the alveolar  inter-
stitium  by  pinocytosis  (Strecker,  1967).   Some particles  may  be  cytotoxic to alveolar macro-
phages  and  thus  influence   this  clearance  mechanism (see  Section 12.3.4.2).  Migration and
grouping of macrophages  laden with  particles  can lead  to redistribution  of  evenly dispersed
particles  into clumps and focal  aggregations of particles in the deep lung.   Such events have
been described in the sequence of pathological changes observed in experimentally-induced sili-
cosis (Heppleston, 1969).  Silica particles ranging in size from less than 1 to 3 |jm in physi-
cal  diameter have  been  found post  mortem  in fibrotic  lesions  associated with  deposits of
crystalline  silica  (Craighead and Vallyatin,  1980).  Sherwin and coworkers  (1979) found an
abnormal number of  birefringent  particles in  the  lungs of seven patients in association with
early to late interstitial inflamation and fibrosis.  Also, using scanning electron microscopy
and  energy  dispersive X-ray  analysis  of particles  <  5  urn  in physical  diameter, they   found
mostly silicates  (especially  aluminum, sodium,  and potassium), with 5  to  10 percent silicon
dioxide.

SOX11A/A                                     11-40                                  2-9-81

-------
*
     Macrophages  containing particles  may  enter  the  boundary region  between  the  ciliated
bronchioles and the respiratory ducts and then can be carried with the mucociliary flow of the
TB region.  Some  insoluble particles deposited in the lung are eventually trapped in the pul-
monary interstitium (Strecker, 1967), impeding mechanical redistribution or removal (Felicetti
et al.,  1975).   Although protein molecules may pass across the airblood barrier intact with a
clearance halftime of hours by pinocytotic vesicular transport (Bensch et al., 1967), there is
conflicting evidence  at best on the passage of very small particles (< 10 nm in physical dia-
meter) across the airblood barrier.  For example, the data of Kanapilly and Diel (1980) on the
                           239
dissolution  of ultrafine     Pu02  are  in  disagreement with  the  data and  interpretations  of
Raabe et al. (1978).
     Another  possible clearance route  for migrating particles  and particle-laden macrophages
is the  pulmonary  lymph drainage system with trans location first to the tracheobronchial lymph
nodes  (Thomas,  1968; Lauweryns and  Baert,  1977;  Leeds et al., 1971).   Little  information  is
available about  the clearance rates for transfer from  lung  to lymph nodes in  man,  but half-
times of  1  to 2 years  have been estimated from data on dogs and monkeys (Leach et al., 1970).
Like transfer  to  the TB region with clearance by the mucociliary escalator, transfer to lymph
nodes may affect only a portion of the material deposited in the lung.
     Waligora  (1971)  reported  the  pulmonary clearance of extremely insoluble and inert parti-
                                            95
cles  of zirconium  oxide radiolabeled with    Nb.   Although his results were  not precise,  the
biological clearance  half-life in man was about 1 year, a value about the same as for beagles.
By  contrast,   murine  species  have a more  rapid pulmonary clearance  (Morgan et  al.,  1977).
Leach et al. (1970, 1973) exposed experimental animals to insoluble U02 (MMAD of about 3.5 urn)
and  observed  lung retention half-times of  19.9  months for dogs and  15.5  months for monkeys.
Ramsden  et  al.  (1970)  measured  the retention of  accidentally inhaled,  relatively  insoluble
239pug   (piutonium  dioxide) in a man's  lungs and found the clearance half-time to be about 240
to 290  days;  some of that  material  was dissolved  into blood and excreted in the urine.  Pul-
monary  clearance  half-times as  long  as 1000 days  have been  reported  for extremely insoluble
particles  of  piutonium dioxide  in dogs  (Raabe and  Goldman,  1979).   Cohen  et al.   (1979)
reported  an  apparent half-time of about 100  days  for  nonsmokers and about 1 year for  smokers
for pulmonary clearance of magnetite particles.
     Because  of  the slow clearance by  the  various  mechanical pathways, dissolution and asso-
ciated physical and biochemical transformations are often the dominant mechanisms of clearance
from  the pulmonary  region  (Morrow, 1973).   The  term "dissolution"  is  taken in its broadest
context  to  include whatever processes  cause material  in a discrete  particle to be dispersed
into  the lung fluids and  the  blood (Green,  1975).   Many chemical  compounds  deposited  in the
lung  in  particulate form are mobilized faster than can be explained by known chemical  proper-
ties  at  the  normal  lung   fluid  pH of about 7.4  (Kanapilly,  1977).    Raabe  et  al.   (1978)
suggested that  the  apparent dissolution of  highly insoluble  PuO,, actually may  be due  to frag-
mentation  into particles  small  enough  to  move  readily  into the blood,  rather than  to true
dissolution.
SOX11A/A                                     11-41                                   2-9-81

-------
     Mercer (1967) developed  an  analysis of pulmonary clearance based on particle dissolution
under nonequilibrium  conditions.   If the dissolution  rate  constant  (k)  is known  for  a  mate-
rial, the time required to dissolve half the mass of (monodisperse) particles  of initial  physi-
cal diameter (D ) is given by:

                   = 0.618 a  pD /a k                           (2)

with p  the  physical  density of the particles and  ay  and a^ the volume and surface shape fac-
tors, respectively (for spherical particles a /a  = 6).
The particles would be expected to be completely dissolved at a time,  t^, given by:

              tf = 3av p DQ/ask                                 (3)

Mercer  (1967)  also calculated the expected dissolution half-time for polydisperse  particles
when their mass median (physical) diameter in the lung is known:

              Tl/2 = °'6 % P(MMQ)/ask                          W
Further, he showed that the resulting apparent lung retention function R(t) could be described
as the  sum of two exponentials of the form:

              R(t) = fl6~XlP + f2<

where f,  = (l-f?),  p  = a Kt/a p(MMD) and f,,  f2,  A,,  and \2 are functions  of the  geometric
standard deviations as defined by Mercer (1967).
     For  dissolution-controlled  pulmonary clearance,  smaller  particles  will  exhibit  propor-
tionately shorter clearance half-times.   When the dissolution half-times  are much shorter than
the  half-times  associated with the translocations  of  particles  to the TB  region  or to  lymph
nodes  (i.e.,  much  less  than  1  year),   dissolution will dominate retention  characteristics.
Materials usually thought to be relatively insoluble (such as glass)  may have high dissolution
rate constants and short dissolution half-times for the small particles found in the lung; the
dissolution  half-time  for  1  urn  D glass  spheres  is about 75 days (Raabe,  1979).   Changes in
structure  or  chemical   properties,  such as  by  heat treatment of  aerosols  (Raabe, 1971), can
lead to important changes in dissolution rates and observed pulmonary retention.
     Usually the retention time of material in the respiratory tract is measured (such as with
radiolabeled aerosols)  rather than the  clearance  rates  (Sanchis  et  al. , 1972; Camner et al.,
1971; Edmunds  et al.,  1970;  Luchsinger et al., 1968; Aldas et al., 1971; Ferin, 1967;  Barclay
et  al.,  1938;  Morrow  et al.,  1967a,b; Friberg  and Holma,  1961;  Holma, 1967;  Kaufman and
Gamsus,  1974).   The lung burden  or  respiratory tract burden can  be  represented by an  appro-
priate  retention function with time as the independent variable (Morrow, ,1970a,b).   For  models
SOX11A/A                                     11-42                                  2-9-81

-------
*
based on  simple  first-order kinetics,  the lung burden, y,  at a given time during exposure is
controlled by the instantaneous equation:

              Ht = E ' V                                      <6)

where E is the instantaneous deposition rate of particulate material  deposited in the lung per
unit time during an inhalation exposure and \, is the fraction of material  in the lung cleared
from  the  lung per  unit  time (Raabe, 1967).   For an  exposure that lasts a time  t  ,  the  lung
burden from the exposure is given by:

                          -\,t
              ye = (E - Ee  ^ e)/\1                             (7)

where E  is  the average exposure rate.   After the exposure ends, the  clearance is governed by:

              dy. _  . A,y                                       (8)
              dt ~     1

and the lung burden is given by:
              y = ye e                                          (9)

where y   is the lung burden at  the  end of the exposure period (t ).   Hollinger et al.  (1979)
used  this  simple  model  to describe the deposition and clearance of inhaled submicronic  ZnO in
rats  (Figure 11-12) where  the concentration  of  zinc (as  Zn)  in the lungs  (as  described by
Equations  7 and 9)  is  superimposed  on the natural  background concentration of  zinc in  lung
tissue.  The normally insoluble zinc has only a 4.8-hour dissolution half-time (A., = 0.21  h  )
for this aerosol.  Of course, environmental aerosol exposures are likely to continue so  that a
steady state lung burden may be expressed by:

              yss = EAi                                        do
      If several deposition and clearance regions, subregions, or special  pools are involved, a
more  complicated multicompartmental  model may  be required to  describe  lung  or respiratory
tract buildup and retention of inhaled aerosols.  If each compartment can be described by first
order kinetics,  a  general  model  can be specified by 1) subscripting E, \, and Y with the  sub-
script  i  whenever  they  appear on the right-hand side of Equations 7, 9, 10, and 2) performing
a  summation over  i  from one to  the  number of compartments.  Each of the X. values translates
to  a clearance  rate for  each of the  compartments  given  by  half-time  T,/?  =  In  2/X.  (for
example see Figure 11-13).
     For chronic exposures  where the several  pools  are  in  complex arrays of change, a simple
power function  may  serve  as a satisfactory model of pulmonary retention (Downs et al.,  1967).
SOX11A/A                                     11-43                                  2-9-81

-------
Ul
3
v>
CO
Z
O
UJ


>
cc
0

p

o
Z
N
U
      50
-20   -15
                                   0     5    10    15    20    25   30

                                      POST EXPOSURE TIME.hr
   Figure 11-12.  Single exponential model, fit by weighted least-squares of the buildup (based on text

   equation 7) and retention (based on text equation 9) of zinc in rat lungs.


   Source: Hollinger et at. (1979).
                                               11-44

-------
   100
                                          CLEARANCE PHASE
                                          E3 - 2.1 ma/day, T  - SOOd
                 200
400
600         800
   TIME, days
1000
                                               1200
1400
Figure 11-13.  Example of the use of the sum of exponential models for describing lung uptake during
inhalation exposure and retention (clearance phase) after exposure ends for three lung compartments
with half-lives 50d, 350d, 500d, and 20-day exposure rates of 1.4 mg/day (E^, 1.7 mg/day (E2), and
2.1 mg/day (£3), respectively.

Source: Raabe(1974).
                                           11-45

-------
In such  a  model,  the pulmonary region  is  treated as one complex, we 11 -mixed  pool  into which
material is added and removed during exposure, as given by the instantaneous equation:
dt
                 = E - Apy/t [y = 0 at t = 0]                          (11)
where  y  is the  total  lung  burden  at a  given time, t,  E is the average  deposition rate of
inhaled  particulate  material  in  the lung,  and  \   is  the fraction of  available lung burden
being  cleared.   Unlike  the A. of the exponential  retention  models,  A  is dimensionless.  The
time coordinate  is  not  arbitrary; time is  taken  as  zero only at the beginning of the inhala-
tion exposure, when the lung burden  is nil.  Thus, during an exposure lasting until time (te),
the pulmonary burden (y )  is given by (Raabe, 1967):

              ye = Ete/(Ap + 1)                                        (12)

On  this  basis,  no steady-state concentration  is  reached  even though clearance is progressing
and  the  lung concentration  continues to  increase  during chronic  exposures to environmental
aerosols.   This model  is  therefore not  applicable  to  relatively soluble  species.   The lung
burden,  y,  after the exposure  has ended for a time, t ,  is given by (Raabe, 1967):

              y = ye te p  t  P = At  p [t = te + tp]                   (13)

This model  is illustrated  in Figure  11-14.
     Deposited  particulate material  cleared  from the  lung  is  usually  transformed chemically
and  transferred to other  tissues of the  body.   The injurious properties  of a toxic material
translocated  from  the lung may therefore be expressed  in other organs.   Identification of the
potential  hazards  associated  with  inhalation exposures  to  toxicants  is  compounded when the
respiratory tract  is not the  only  target  for injury but still serves as  the portal of entry
into  the body.   The metabolic behavior and excretion of  inhaled toxicants after deposition in
the  lung may define the probable target organs and  indicate potential  pathogenesis of result-
ing disease.
     Multicompartmental models that  describe biological  behavior can become  extremely complex.
Each toxicant or component of  aerosol particles deposited  in the respiratory  tract may need to
be  described by a  separate rate constant and pool  or  compartment.  A general  model of the
metabolic  behavior of  inhaled particles  developed  by  Cuddihy  (1969)  identified 39  different
places where  rate  constants may need to  be determined.  In this general model,  the  pulmonary
region of  the  lung  is  visualized as consisting  of  three independent  clearance  compartments,
and the  particles  are presumed to  be converted  from their original particulate  state to  some
other  physicochemical form or  transformed state prior to  clearance from  the  respiratory  tract.
Such  a  transformed  state  can be used  to  describe,  for  example,  the  behavior of  hydrolytic
aerosols in the  respiratory  tract.
SOX11A/A                                     11-46                                  2-9-81

-------
  n 10
CD Q
    0.1
                     I  I   I  I  I   I  I  I   I
              II  III   111   I  I  I   I
      1  2  5 10
102     103

TIME, days
104    105
  Figure 11-14.  Example of the use of the power
  function model for describing lung uptake dur-
  ing inhalation  exposure (text Equation 12) and
  retention (clearance phase) after exposure ends
  (text Equation 13) for a 20-day exposure at
  8.5mg/d(E).

  Source: Adapted from Raabe (1967).
                    11-47

-------
     To illustrate the potential complexity of models, a systemic metabolism model  is shown in
Figure  11-15 for  cerium trichloride  (144CeC13)  contained  in  particles  of cesium chloride
(CsCl) with a MMAD   of about 2 urn (Boecker and Cuddihy, 1974).   The resultant pattern of com-
                  a i
bined  uptake and  retention  in  various  organs  after  inhalation  exposure  is  illustrated  in
Figure  11-16.   In this  case,  the exposure  is short-term; the  fate of relatively insoluble
materials  in  chronically inhaled  environmental  aerosols may  involve  more complex relation-
ships.
11.3.2  Absorbed SO,,
     S09 coming  in  contact  with the fluids  lining the airways (pH 7.4) should  dissolve into
                                                                                   2-
the  aqueous  fluid and  form some  bisulfite  (HSCL-) and considerable sulfite  (SO^  ) anions.
Because of the chemical reactivity of these anions, various reactions are possible, leading to
the oxidation of sulfite to  sulfate (see Section 12.2.1).
     Clearance of sulfite from the respiratory tract may involve  several  intermediate chemical
reactions and transformations (see Section 12.2.1.2).   Gunnison and Denton  (1971) have identi-
fied  S-sulfonate  in  blood as a reaction  product of inhaled  SCL.   The  reaction rate is rapid,
if not nearly instantaneous, so that there is no long-term clearance to  characterize.  However,
intermediate and  potentially  toxic products  may be formed.   These products  may have residence
times  that are  long  enough to demonstrate  an elevation  of  the sulfur content of the lung.
     Desorption from the upper respiratory tract may be expected  whenever the partial pressure
of SCL on mucosal surfaces exceeds that of the air flowing by.   Desorption  of SCL from mucosal
surfaces was  still  evident  after 30 minutes  of  flushing  with  ambient  air  the airways of dogs
which  had  breathed  2.62 mg/m  (1.0 ppm) for 5 min. (Frank et al., 1969).   Frank et al. (1967)
reported S09 in the lungs of dogs that apparently was carried by  the blood  after nasal deposi-
                                            3
tion.  In human subjects breathing 42.2 mg/m  (16.1 ppm) through  a mask for 30 minutes, 12% of
the  S0?  taken up  by the tissues  in inspiration  reentered  the  air stream  in  expiration and
another 3% was desorbed during the first 15 minutes after the end of S0? exposure (Speizer and
Frank, 1966).  Thus,  during expiration,  SO- was desorbed  from the nasal mucosa in quantities
totaling approximately 15% of the original inspired concentration.
     The effects  of S02  on tracheobronchial  clearance  in 9 healthy,  nonsmoking  adults were
studied by Wolff  et  al. (1975) (see Section  13.2.3.5).   Technetium Tc 99m albumin aerosol (3
|jm MMAD, o  = 1.6) was inhaled as a bolus under controlled conditions.   A  three hour exposure
           9     3
to 13.1 mg SOp/m  (5.0 ppm)  had no significant effect on mucociliary clearance in resting sub-
jects, except  for a  small  transient increase (p < 0.05) after 1 hour.   A significant decrease
in nasal mucus  flow  rates during  a  six  hour exposure of 15 young  men  to  13.1 mg  S00/m  (5.0
                      3                                  3
ppm) and 65.5 mg S02/m  (25.0 ppm), but not 2.62 mg SOVm  (1.0 ppm), was observed  by Andersen
et al.  (1974).   Decreases were greatest  in  the  anterior nose and  in  subjects with  initially
slow mucus flow  rates.   Newhouse et al.  (1978) assessed the effect of oral exposure  to  S02 on
bronchial  clearance  of  a  radioactive  aerosol (3  \im MMAD) in  healthy nonsmoking males and
SOX11A/A                                     11-48                                  2-9-81

-------
                         RESPIRATORY ENVIRONMENT
                                      EXTRATHORACIC (ET)
                                      TRACHEOBRONCHIAL (TB)
                                                                  INITIAL
                                                               DISTRIBUTION
                                                               PERCENTAGES
COM
PART-
MENT
ET
TB
P a
b
c
d

39
7.0
7J2
41
34
2A
 STOMACH

    15

 -1—
  0.0005 -
  SMALL
INTESTINE
	I	

  LARGE
 INTESTINE
   0.85
a
b
c
d
30
0.5
0.02
0.00122
TRACHEOBRONCHIAL
   LYMPH NODES
      LIVER
•0.0001*"
— 0.1
0.04 -
                                                              SOFT TISSUE
0.2 —
- 1.0 —
"* 0.0001
                                                  SKELETON
0.1 —
- 0.04 «-
""* 0.0001
                                                        TRANSFER RATE CONSTANTS
                                                        EXPRESSED AS FRACTION OF
                                                        COMPARTMENTAL CONTENT
                                                        PER DAY

Figure 11-15. Multicomponent model of the deposition, clearance, retention, translocation and
excretion of an example sparingly soluble metallic compound ("^CeCIs continued in CsCI
particles) inhaled by man or experimental ai.imals; the rate constants are based upon first order
kinetics as in text Equation 8.

Source:  Adapted from Boecker and Cuddihy (1974).
                                      11-49

-------
  100
i

-------
females who exercised periodically during exposure at an exertion level  sufficient to keep the
heart rate at  70% - 75% of the  predicted maximum.   After a 2 hour exposure to 13.1 mg SO^/m
(5.0 ppm), clearance was increased.
11.3.3  Particles and S02 Mixtures
     The presence of  adsorbed S0? or other sulfur compounds on aerosol  surfaces may alter the
clearance  processes  of both.   Chemical  reactions  involving  sulfur  compounds on  particle
surfaces may enhance  the apparent solubility of  the  aerosol  particles.   These aerosol parti-
cles  may  also  undergo reaction with  sulfite  or other species upon contact with body fluids.
     The formation of sulfate anions by oxidation of S0? to SO, may be catalyzed by manganese,
iron,  or  other aerosol  components.   The  S03  reacts immediately with water  to  form sulfuric
acid that can react with other materials, such as metal oxides on fly ash aerosols,  to produce
sulfate compounds.   Since sulfate  is  a normal  constituent of body  fluids  (Kanapilly, 1977),
the clearance of sulfate anions probably  involves simple dissolution into body fluids.
11.4  AIR SAMPLING FOR HEALTH ASSESSMENT
     The objective  of air  sampling in  relation  to  health  assessment is to obtain data on the
nature and extent of potential nealth hazards resulting from the inhalation of airborne parti-
cles.  To  be  effective the techniques  used  in  air  samplers must be based on a recognition of
the  size-selecting characteristics  of the  human respiratory tract  (see Section  11.2).   Of
course  the usual variables affecting  the selection of methods,  such as  the  physical limita-
tions  of  the  collection process and sensitivity  and  specificity  properties of the analytical
procedures, must still be addressed.
     An increasing recognition of the importance of the selective sampling of "respirable" dusts
has occurred in recent years.   The commonly measured index of gross air concentration provides
a  crude and  sometimes misleading indication of  health  hazard.   Since most aerosols are poly-
disperse,  with  a a  >2, the mass median  size approaches the diameter of the largest particles
in  the sample, resulting  in  a  relatively few  large particles strongly  influencing the value
reported  for  the  mass  concentration.   The  measured total mass  concentration  then  will  not
relate to  the inhalation hazard if these  particles are not inhaled.  Also, the true total air-
borne  mass concentration may  be underestimated when the aerosol  contains very large particles
since  every sampler has its own characteristic upper size cut-off.  This cut-off is dependent
on  its entry shape, dimensions and flowrate.
     The best  dose  estimates  for a substance whose toxicity  is  proportional to absorbed mass
are obtained from information on the mass concentrations within various size ranges.   Lippmann
(1978)  cites  several  ways  such data  can be obtained:   (1) during  the  process of collection
separate the aerosol  into  size fractions which correspond to anticipated regional  deposition;
(2) analyze the size  distribution of the airborne aerosol; and (3) analyze the  size  distribu-
tion  of  the  collected  sample.   The  most reliable and  useful  information  is obtained using
methods of fractionation  based  upon  aerodynamic diameters  similar  to  the way fractionation
occurs within  the  respiratory  tract,   thereby  automatically  compensating  for differences  in
particle shape and density.
SOX11A/A                                     11-51                                   2-9-81

-------
     There have  been  many recent advances  in  the  technologies needed to develop samples that
will separate particles during the process of collection into "respirable" and "nonrespirable"
fractions.   The  absence  of  uniform  criteria for "respirable" mass  concentrations  has been a
major  factor limiting  the  application of  selective  sampling concepts  in  the United States.
Regulations  established on  the basis of  only  gross  concentration limits do not promote field
measurements of  "respirable" mass.
     The  recommendations  by Miller  et al.  (1979)  on  size  considerations  for establishing a
standard  for "inhalable"  particles  indicate  a  possible  future  departure from  the current
approach  to  the  setting  of a  particulate standard  in  the  United  States.   Also,  the recent
report  on respirable  dust by the International  Standards  Organization ad hoc Group  to TC 146
(1980)  contains  recommendations  for  size definitions  for particle  sampling  for the healthy
normal  segment  of the  population and high risk subpopulations.  A perspective on these recent
events  can be obtained by examining the  development of the field of  respirable dust  sampling.
      In 1952,  the British Medical Research Council (BMRC) adopted a  definition of "respirable
dust"  which  essentially  considered  respirable  dust  to  be  that  dust  reaching  the alveoli,
thereby making  "respirable  dusts"  applicable  to  pneumoconiosis  producing dusts.   The  hori-
zontal  elutriator was  chosen as  a  particle size selector and respirable dust was  defined as
that dust passing  an  ideal horizontal elutriator.  The elutriator cut-off was chosen  to result
in the  best  agreement with experimental lung deposition data.  The Johannesburgh International
Conference on Pneumoconiosis in 1959 adopted the same standard (Orenstein, 1960).
      In January 1961  at  a meeting  in  Los  Alamos  sponsored by  the Atomic Energy Commistion
(AEC)  Office of  Health and Safety a second standard was established,  which defined "Respirable
Dust"  as  that portion of  the inhaled dust which penetrates to the non-ciliated portions of the
lung (Hatch and  Gross, 1964).   This  definition  was not  intended  to  be  applicable to dusts
which  are readily  soluble  in body  fluids or are primarily  chemical intoxicants,  but rather
only for "insoluble"  particles which exhibit prolonged  retention  in the lung.  Criterion for
respirability  were  such  that all  2  urn  D    particles  were  considered  respirable,  while
                                             36
particles 10 pm  D   were  considered to be nonrespirable.
                 3c
     Other groups, such  as  the  American  Conference  of  Governmental  Industrial  Hygienists
(ACGIH),  have incorporated  respirable  dust sampling concepts  in  setting acceptable exposure
levels  to other toxic dusts.   Such  applications are more complicated  since  animal   and human
exposure  data,   rather  than  predictive calculations,  form the data base  for standards.  The
size-selector  characteristic specified in  the ACGIH standard  for respirable dust  (Threshold
Limits  Committee,  1968) is almost identical to  that  of the AEC,  differing  only at  2 urn D   ,
                                                                                           36
where  it allows  for  90 percent passing the first stage collector  instead of 100 percent.  The
difference between them appears to be a recognition of the properties of real  particle separa-
tors  so that for practical purposes the  two standards may be considered equivalent  (Lippmann,
1978).
SOX11A/A                                     11-52                                   2-9-81

-------
*
     The sampler acceptance criteria of the BMRC and of the ACGIH and the pulmonary deposition
curves  from  Figure 11-9 are shown  in  Figure 11-17.   The cut-off characteristics  of  the pre-
collectors preceding  respirable  dust samplers are defined by these criteria.  The two sampler
acceptance curves  have  similar,  but not identical,  characteristics,  due mainly to the use of
different  types  of collectors.   Recall  that the  BMRC  curve  was chosen to  give  the  best fit
between  the  calculated characteristics  of an ideal horizontal  elutriator  and available lung
deposition data.   On  the  other hand, the AEC curve was designed mainly after the upper respi-
ratory tract deposition data of Brown et al. (1950).  The separation characteristics of cyclone
type  collectors  simulate  the AEC curve.   Whenever  the  particle size distribution has a a  >2
urn, samples  collected with instruments meeting either criterion will be comparable (Lippmann,
1978).   Various  comparisons  of samples collected on the  basis  of the two criteria are avail-
able  (Knight and  Lichti,  1970;  Breuer,  1971;  Maguire and Barker, 1969;  Lynch,  1970;  Coenen,
1971; Moss and Ettinger, 1970).
      The  various  definitions of respirable dust are somewhat arbitrary, with the BMRC and AEC
definitions  being  based upon the "insoluble" particles which reach the pulmonary region.   Since
part  of the aerosol  which penetrates to  the alveoli  remains  suspended in the  exhaled air,
respirable dust  samples are  not intended  to  be  a measure of pulmonary  deposition  but only a
measure  of aerosol concentration for particles that are  the  primary candidates for pulmonary
deposition.  Given that the  "respirable" dust standards  were  intended for   "insoluble dusts,"
most  of  the  samplers  developed to satisfy their criteria have been relatively simple two-stage
instruments.   In  addition to  an  overall  size-mass  distribution curve, multi-stage  aerosol
sampler  data can provide  estimates of the "respirable" fraction and deposition in other func-
tional  regions.   Field sampling application of these samplers  has been limited due to the in-
creased  number  and cost of  sample analyses and the lack of suitable instrumentation.   Many of
the  various  samplers,  along with their  limitations  and deficiencies,  have been reviewed by
Lippmann  (1978).
      Size  definitions  for particle  sampling  which  expand the  area  of concern  beyond just
"insoluble"  dust  penetrating  to  the pulmonary region have recently  been  advanced (Miller et
al.,  1979;  International  Standards Organization ad hoc Group to TC 146, 1980).  As our knowl-
edge  of  the  regional  deposition of  particles  increases  through experimental  studies, such as
those discussed  in Section 11.2, it is logical to envisage using samplers which broadly simu-
late  the  relative collection  efficiencies  of  the major  regions  of  the  respiratory tract.
These devices would first  select from the total airborne material the  inspirable fraction, and
then  sequentially  divide  this fraction into extrathoracic (nasopharyngeal),  tracheobronchial,
and pulmonary fractions.
      Such  a  scheme has  been  recommended  by the  International Standards  Organization §d hoc
Group to TC 146  (1980) with  various  options depending  upon the  at risk population  (healthy
adults,  children,  sick and infirm) and upon the use of 10 IJID D   or  15  urn 0    as the 50 percent
                                                              ac           36
SOX11A/A                                     11-53                                   2-9-81

-------
     1.0

     0.9

     0.8

     0.7
 Z  0.6
 O
 5  °5
 Ul
 Q
    0.4
    0.3

    0.2

    0.1
    T  TT  T
SAMPLER ACCEPTANCE CRITERIA
      — — — ACGIH
      — — VIANOSE
      — -^ BMRC
     0.1         0.2         0.4  0.50.6  0.8 1.0

       PHYSICAL DIAMETER,/urn
                                         2.0        4.0    6.0  8.0)10.0

                                   • AERODYNAMIC DIAMETER, urn
20.0
Figure 11-17.  Comparison of sampler acceptance curves of BMRC and ACGIH conventions with the
band for the experimental pulmonary deposition data of Figure 11-9.

-------
cut-point  for  material  penetrating to  the tracheobronchial  region.   Their division  of  the
thoracic fraction  into the  pulmonary  and tracheobronchial  fractions, where  the  target popu-
lation  is  healthy adults,  is  shown in  Figure 11-18  using  15 urn D   as the  50  percent cut-
                                                                    36
point  for  the  total  thoracic  fraction.    The  50 percent cut-point  refers  to  the aerodynamic
diameter for which  50 percent of the particles that enter the mouth or nose are considered to
pass the larynx.   Thus,  the material not passing the larynx forms the extrathoracic fraction,
which  includes the  oral  pharynx.   Particles larger  than  15  (jm D   can enter and be deposited
                                                                 36
in the  extrathoracic  region.   If any of these larger particles are readily soluble, they will
be  absorbed  into the  bloodstream just  as quickly  as  smaller particles, with one  20  urn  D
                                                                                            36
particle contributing as much to the systemic dose as a thousand 2 urn D   particles.
                                                                       36
     Also  shown  in the  figure  are the experimentally based pulmonary deposition curves from
Figure  11-9  and  the  tracheobronchial  deposition data  from one of  the subjects  studied  by
Stahlhofen and coworkers  (1980).   The  ad  hoc group basically followed the BMRC and ACGIH con-
ventions for  pulmonary deposition  in  healthy adults,  although their definition  of the pul-
monary  fraction differs slightly because it is defined as a fraction of the inspirable material
rather  than the  total  aerosol.   A  "high-risk"  selection  curve  for  children  or the  sick
and  infirm used  a 50 percent cut-point  at 2.5 urn D   instead of 3.5 urn D   in recognition of
                                                    36                    36
the  fact that a  similar shift is  seen  in lung deposition  in  these  groups (Lippmann,  1977);
this  strategy  is  surprising since a conservative  approach  for protection of these subpopula-
tions  would  not  lower the cut-point.  Taken to its ultimate, by using size selective samplers
that  separate  inspirable  material  into extrathoracic or nasopharyngeal,  tracheobronchial,  and
pulmonary  components,  standards  for airborne particles could  specify which of these regional
fractions  should  be  measured,  taking into account the biological effects of the material,  and
in the  case of the tracheobronchial and pulmonary fractions, the population at risk.
11.5   SUMMARY
                                                                                   \
     Besides being  a  target of inhaled particles and gases, the respiratory tract is also the
portal  of entry by which other organs may  be affected.  An understanding of the mechanisms and
patterns of  translocation  to other organ  systems  is required  for evaluation of the potential
for  injury or  response in those organs.   When aerosols or S0?  are  inhaled by man or experi-
mental  animals,  different fractions of  the inhaled  materials deposit by a variety of mecha-
nisms  in various  locations  in  the  respiratory  tract.  Particle  size  distribution, particle
chemical properties, physicochemical properties of S0?, respiratory tract anatomy, and airflow
patterns all influence the deposition.   The three functional  regions (extrathoracic or naso-
pharyngeal, tracheobronchial, and  pulmonary)  of the  respiratory tract  can  each be  character-
ized by major mechanisms of deposition and clearance.
     Of  the  five mechanisms  of deposition, impaction,  gravitational  settling, and diffusion
predominate  for  the  deposition  of  most  types  of particles  in the respiratory tract, with
electrostatic  attraction  and interception being of  relatively minor importance.   Diffusivity
and  interception  potential of a  particle  depend on  its geometrical  size,  while the inertial

SOX11A/A                                     11-55                                   2-9-81

-------
01
                                       i   -r-44J I  I  I
                                                        I
                                              — ACGIH CONV.
                                              — BMRC CONV.
                                              _ STAHLHOFEN »t ll
                                                  (1980)
                                                PULMONARY VIA
                                                  MOUTH
                                              — PULMONARY VIA
                                                  NOSE
                                          PULMONARY FRACTION
                                                                                      TRACHEO-
                                                                                      BRONCHIAL
                                                                                   l\ FRACTION

                                                                                    \
0.5   0.7  1.0
                AERODYNAMIC DIAMETER,
                            0.1       0.2   0.3

                         PHYSICAL DIAMETER,
                       Figure 11-18.  Division of the thoracic fraction into the pulmonary and tracheobronchial fractions for
                       two sampling conventions (ACGIH and BMRC)  as a function of aerodynamic diameter except below
                       0.5 nm where deposition is plotted vs. physical diameter, from International Standard Organization ad
                       hoc group to TC-146, 1980. Also shown are the band for experimental pulmonary deposition data of
                       Figure 11-9 and the tracheobronchial deposition  data of one subject from Stahlhofen et al. (1980).

-------
properties of  settling  and impaction depend on  its  aerodynamic  diameter.   Gravitational set-
tling  is  important  for  the  deposition  of particles  in  the tracheobronchial  and pulmonary
regions, while  impaction  contributes to deposition  in  the  extrathoracic  and tracheobronchial
regions.  Diffusion  primarily  affects respiratory tract deposition of particles with physical
diameters  smaller than  1  urn.   The  major processes  affecting  the  transport  of  SO-  in  the
respiratory tract are convection, diffusion, and chemical reactions.  The rapid diffusivity of
SCK in combination with its high solubility in body  fluids is responsible for the large removal
of SO^ in the extrathoracic region and upper generations of the tracheobronchial tree.
     After deposition, inhaled particles will be translocated by processes that depend on their
character and  site  of deposition.   The anterior third of the human nose does not clear except
by blowing, wiping,  sneezing, or other extrinsic means, and particles may not be removed until
one or  more  days after deposition.   If  the particles are quite soluble in  body fluids,  they
will readily enter the bloodstream.   Relatively insoluble material  that lands on ciliated epi-
thelium,  either in  the extrathoracic region or tracheobronchial  airways,  will be translocated
with  mucus  flow to  the throat  and will  be swallowed or expectorated.  Depending on particle
size,  relatively insoluble material  that deposits  on  nonciliated surfaces  in the pulmonary
region  may  be  phagocytized, may enter the interstitium and remain in the lung for an extended
period,  or may be  translocated by  phagocytic cells,  blood,  or lymphatic  drainage.   Some
material  from the pulmonary region may enter the tracheobronchial region and be cleared by the
mucociliary conveyor.  Dissolution can contribute to the clearance of particles in all regions
of the  respiratory tract.
     Nose breathing  and mouth breathing provide somewhat contrasting deposition patterns  for
some respiratory tract regions.  With nose breathing nearly complete  respiratory tract deposi-
tion can  be expected for  particles larger than about 4 urn D   .  Since mouth breathing bypasses
                                                           36
much  of the filtration capabilities  of  the extrathoracic region,  there is  a shift upward to
about  10  urn D   before there is complete deposition of inhaled particles.  However, given the
              36
three general  regions into which the  respiratory tract can be divided on the  basis  of anatomi-
cal structure,  function,  particle retention times, and clearance pathways, regional deposition
data  for particles  of  various  aerodynamic  diameters are more  useful  than total  respiratory
tract deposition information.
     Particles  about 10 urn D   or  larger are deposited in the extrathoracic region  during nose
                            36
breathing as  compared to about  65 percent  deposition of 10  urn D   particles under conditions
                                                                 36
of mouth  breathing.  On the other hand, for both routes of breathing, extrathoracic deposition
of  particles  smaller than about  1   urn  D._  is slight.   The increased penetration of larger
                                          QC
particles deeper into the respiratory tract when a person breathes through the  mouth is reflec-
ted  by experimental  deposition  data showing that tracheobronchial deposition  of 8-10 um D
                                                                                            36
particles is  on the order of 20-30  percent.   Also,  about 10 percent of particles  as  large as
15 um D   are predicted to enter the  tracheobronchial region  during mouth breathing.
        36
SOX11A/A                                     11-57                                   2-9-81

-------
     For nose breathing,  as  compared to mouth breathing, the peak of the pulmonary deposition
curve shifts downward  from 3.5 urn D    to  about  2.5 urn D  .   Also, the peak is much less pro-
                                    etc                   36
nounced (about 25 percent compared to about 50 percent for mouth breathing) with a nearly con-
stant pulmonary  deposition of  about  20 percent  for all  sizes  between 0.1 urn and  4  urn Dge.
     It should be stressed that the deposition data cited above are based upon studies in which
usually young healthy  adult  subjects were used.   Although children  are usually considered to
be a subpopulation more susceptible to the effects of environmental pollutants, deposition data
for children are not currently available, nor likely to be soon obtained.  What little data is
available on other  subpopulations,  such as asthmatics and chronic bronchitics, indicates that
tracheobronchial deposition appears  to  be enhanced at the expense of pulmonary deposition in
most  abnormal  states.   Partial or  complete  airway  obstruction  in  bronchitis,  lung  cancer,
emphysema,  fibrosis,  and  atelectasis  may decrease or eliminate the deposition of particles in
some regions of the lungs.
     Regional deposition studies of particles less than 3 urn D   have been conducted using dogs
                                                              Oc
and  some  rodents.   In these species, the  relative  distribution  among the respiratory regions
of  particles less  than  Sum  D   during nose breathing  follows  a pattern that  is  similar to
                              ae
regional  deposition in man during nose breathing.  Thus, in this instance, the use of rodents
or  dogs  in  toxicological  research for extrapolation to humans entails differences in regional
deposition  of insoluble particles less than 3um D   that can be reconciled from available data.
                                                 ac
     When breathing through the nose under resting conditions, S02 removal by nasal absorption
is  nearly complete in both man and  laboratory  animals.   Expired air  acquires  S0?  from nasal
mucosa  with small  amounts of  S02  continuing  to  be released  after cessation  of  exposure.
Extraction  of S0? by the total respiratory tract during mouth breathing is significantly lower
than during nose  breathing,  although regional uptake has not been studied in man during mouth
or  oronasal  breathing.   However,  studies in which  SO- was  passed through the surgically iso-
lated extrathoracic  (nasopharyngeal)  airways  of  dogs showed that S0? absorption in the extra-
thoracic  region can be decreased to less  than 50 percent by mouth breathing at elevated air-
flow  rates.   Sulfur dioxide may also  enter  into a variety  of  gas-to-particle conversions or
gas-particle chemical  reactions.   As  a consequence of these reactions with particles, SO- can
be  carried  deeper  into  the  respiratory  tract,  thereby  increasing  the  potential  for adverse
effects.
     Both deposition  and  retention play roles in determining  the effects of inhaled particu-
late  toxicants  and SO-.   Everyone is  environmentally  exposed to a  variety  of dusts, fumes,
sprays, mists,  smoke, photochemical  particles,  and  combustion  aerosols, as  well  as  S02 and
other potentially  toxic  gases.   The particle size distribution and chemical and physical com-
position of airborne  particulate  material require  special attention in toxicological evalua-
tions since a wide variety of  physicochemical  properties may be  encountered in both experi-
mental and ambient  inhalation exposures.  The need to characterize the aerosols to which indi-
viduals are exposed so that potential health hazards can be  identified requires the  development

SOX11A/A                                     11-58                                   2-9-81

-------
of  appropriate  air  sampling  techniques.   For insoluble  dusts  whose  site  of action  is  the
pulmonary  region,  inhalation  hazard  evaluations  based  on  "respirable"  mass  are  clearly
superior to  estimates  based on gross air concentrations.  Appropriate selective sampling pro-
cedures  can and  are  being developed to  provide more  meaningful  data on  inhalation  hazard
potential for particles  as a function of  their  regional deposition in the respiratory tract.
Gross concentration  sampling techniques  are appropriate for  highly  soluble  aerosols or where
the particle size distribution is relatively constant.  They can also be used if the particle
size  distribution is relatively constant  and  there  is a known fixed  ratio  between  the gross
concentration and the concentration in the size range of interest.
 SOX11A/A                                     H-59                                  2-9-81

-------
*
11.6  REFERENCES

Aharonson, E. F., H. Monkes, G. Gurtner, D.  L.  Swift,  and  D.  F.  Proctor.   Effect of respiratory
     airflow  rate  on removal of  soluble vapors by the nose.   J.  Appl.  Physiol.  27:654, 1974.

Aharonson, E.  F.  Deposition  and Retention of Inhaled Gases  and Vapors.  In:   Air  Pollution
     and  the  Lung.   E.  F. Aharonson,  A. Ben-David,  and M.  A.  Klingberg, eds. ,  John  Wiley and
     Sons, New York, 1976.   pp. 13-24.

Albert, R. E., M. Lippmann,, J. Spiegelman,  C.  Strehlow, W.  Briscoe,  P.  Wolfson,  and  N.  Nelson.
     The  Clearance  of  Radioactive Particles  from  the  Human  Lungs.   In:   Inhaled Particles and
     Vapours  II.  C. N. Davies, ed.,  Pergamon  Press, Oxford,  1967.   p.  361.

Albert, R. E., J. R. Spiegelman,  M.  Lippmann,  and  R. Bennett.   The characteristics of bronchial
     clearance in the miniature donkey.  Arch.  Environ. Health 17:50-58,  1968.

Albert, R. E., J. R. Spiegelman,  S.  Shatsky,  and M.  Lippmann.   The effect of  acute exposure to
     cigarette  smoke on  bronchial  clearance  in the miniature donkey.    Arch. Environ.  Health
     18:30-41, 1969.

Albert,  R.  E.,  M.  Lippmann,  H.  T.  Peterson,  Jr.,  J. Berger,  K.  Sanborn,  and  D.  Bohning.
     Bronchial  deposition and clearance  of  aerosols.  Arch.  Intern. Med. 1.31:115-127, 1973.

Albert,  R.  E. ,  J.  Berger, K.  Sanborn,  and  M.  Lippmann.  Effects  of cigarette smoke components
     on bronchial clearance  in the  donkey.   Arch.  Environ. Health 29:96-101,  1974.

Aldas,  J. S. ,  M.  Dolovich, R.  Chalmers,  and  M.  T. Newhouse.  Regional  aerosol  clearance in
     smokers  and nonsmokers.   Chest  59:25,  1971.

Altshuler, B. ,  L.  Yarmus, E.  Palmes,  and N.  Nelson.   Aerosol  deposition in the  human respira-
     tory tract.  AMA Arch.  Ind.  Health 15:293,  1957.

Altshuler, B.  The-Role of the Mixing of Intrapulmonary Gas  Flow in the Deposition of Aerosols.
     In:   Inhaled Particles  and Vapours.  C.  N.  Davies, ed.,  Pergamon Press,  Oxford,  1961.  p.
     47.

Altshuler, B., E. D. Palmes, and  N.  Nelson.   Regional  Aerosol  Deposition in the  Human Respira-
     tory Tract.   In:   Inhaled Particles and Vapours  II.   C.  N.  Davies, ed.,  Pergamon Press,
     1967.  p. 323.

Amdur, M.  0., and D. Underbill.   The effect of various aerosols on the  response  of guinea pigs
     to sulfur dioxide.   Arch. Environ. Health 16:460-468, 1968.

American  Heart  Association,  Committee  on Exercise.  Exercise testing:   performance and inter-
     pretation.  Ind. Med. Surg.  42:20-28,  1973.

Andersen,  I., G. R. Lundqvist, P.  L.  Jensen,  and  D. F. Proctor.   Human response to controlled
     levels of sulfur dioxide.  Arch.  Environ.  Health  28:31-39, 1974.

Bake, B.,  L.  Wood,  B. Murphy,  P.  Macklem, and J. Milic-Emili.   Effect of inspiratory flow rate
     on regional distribution  of  inspired gas.   J. Appl. Physiol. 37:8, 1974.

Balis, J.  V., S. A. Shelley,  M.  J.  McCue,  and E.  S.  Rappaport.   Mechanisms of damage to the
     lung surfactant system.   Exp. Molec. Path.  14:243, 1971.

Barclay,  A.  E. ,  K.   J.  Franklin,  and R. G.  Macbeth.  Roentgenographic studies of  the excretion
     of dusts from  the lungs.  Am. J.  Roen.  Rad. Ther.  39:673, 1938.
SOX11A/C                                      11-60                                   2-9-81

-------
Bartlett,  D. ,  J.   E.  Remmers,, and  H.  Gautier.   Laryngeal  regulation of  respiratory  airflow.
     Respir. Physio!.  18:194, 1973.

Batchelor,  G.   K.   Symmetrical   Contraction  on   Isotropic  Turbulence.   _In:   The  Theory  of
     Homogeneous Turbulence.  London,  Cambridge University  Press,  1953.   p.  74.

Beeckmans,  J.  B.   The deposition of  aerosols  in  the respiratory  tract.   Can.  J.  Physiol.  and
     Pharmac. 43:157, 1965.

Bell, K. , and S. Friedlander.  Aerosol deposition  in models  of  a  human  lung  bifurcation.   Staub
     Reinhalt.   Luft 33:183,  1973.

Bell, K.  A.   Local Particle  Deposition  in  Respiratory  Airway Models.  J_n:   Recent Development
     in  Aerosol  Science.   D. T.  Shaw, ed. , John  Wiley and  Sons,  New York,  1978.  pp.  97-134.

Bensch,  K.  G. ,  E.  Dominguez, and A. A.  Liebow.  Absorption  of  intact protein  molecules across
     the pulmonary air-tissue barrier.   Science 157:1204, 1967.

Besarab,  A.,  and  M.  Litt.   Model  studies  on the adhesive properties  of  mucus and  similar
     polymer solution.  Arch. Intern.  Med.  126:504, 1970.

Blank,  M. ,  A.  B.   Goldstein,  and  B. B. Lee.  The surface  properties  of  lung  extract.   J.  Coll.
     Int.  Sci.  29:148, 1969.
                                                    144               144
Boecker,  B. B. , and  R.  G.  Cuddihy.   Toxicity of    Ce inhaled  as     CeCl,  by the  beagle:
     Metabolism and Dosimetry.  Radiation Res. 60:133,  1974.

Bohning,  D.  E. ,   R.  E.   Albert,  M.  Lippman,  and W.   M.  Foster.   Tracheobronchial  particle
     deposition and clearance.  Arch.  Environ. Health 30:457, 1975.

Brain,  J.  D.   Free cells  in  the  lungs—some aspects of  their role, quantitation and  regulatory-
     Archives  of Internal  Medicine  126:477-487, 1970a.

Brain,  J.  D.   The  uptake of  inhaled gases by the nose.  Ann.  Otol. 79:529-539,  1970b.

Brain,  J.   D. ,  and G. C.  Corkery.   The  Effect  of Increased  Particles on  the Endocytosis  of
     Radiocolloids by  Pulmonary  Macrophages  jn   vivo:   Competitive and  Toxic  Effects.   In:
     Inhaled  Particles  IV,  Part  2.   W.  H. Walton,  ed. , Pergamon  Press, Oxford,  1977.   pp.
     551-564.

Brain,  J.  D.,  J. J. Godleski, and S.  P.  Sorokin.   Quantification,  origin and fate of pulmonary
     macrophages.   I_n:   Respiratory Defense Mechansims.  J.  D. Brain,  D.  F.  Proctor and L.  M.
     Reid,  eds., Marcel Dekker, New York, NY,  1977.  pp.  849-892.

Breuer,  H.   Problems  of Gravimetric Dust Sampling.  In:   Inhaled  Particles III.   W.  H.  Walton,
     ed.,  Unwin Bros., London,  1971.   pp. 1031-1042.

Brown,  J.   H. ,  K.  M.  Cook,   F.  G.  Nex,  and T.  Hatch.    Influence of  particle size  upon  the
     retention  of  particulate  matter in the  human lung.   Am. J.  Pub.   Health  40:450,  1950.

Camner,  P.,  K.  Philipson,  L.  Friberg,  and B. Holma.  Human  tracheobronchial  clearance studies.
     Arch.  Environ. Health 22:444,  1971.

Camner,  P.,  and  K.  Philipson.   Tracheobronchial  clearance  in  smoking-discordant  twins.
     Environ. Health  474:   ,  1972.

Camner,  P.,  K.  Philipson,   and  L.   Friberg.   Tracheobronchial  clearance  in  twins.   Arch.
     Environ. Health  24:82,  1972.


SOX11A/C                                     11-61                                   2-9-81

-------
*
Camner, P.,  P.  Hellstrom,  and.M. Lundborg.  Coating 5 mm particles with carbon  and  metals for
     lung clearance studies.  Arch. Environ. Health Z7:331, 1973a.

Camner, P.,  P.  Hellstrom,  and K.  Philipson.   Carbon dust  and mucociliary clearance.   Arch.
     Environ. Health 26:294, 1973b.

Camner, P.,  M.  Lundborg,  and P.  Hellstrom.   Alveolar macrophages and 5 mm particles  coated
     with different metals.  Arch. Environ. Health 29:211, 1974.

Chan, T.  L. ,  M.  Lippmann,  V  R. Cohen, and R. B. Schlesinger.  Effect  of  electrostatic  charge
     on particle  deposition  in  a  hollow cast of the  human  larynx-tracheobronchial tree.   J.
     Aerosol Sci.  9:463, 1978.

Chan,  T.  L. ,  and  M.  Lippmann.   Experimental  measurements  and  empirical  modelling of  the
     regional deposition of inhaled particles in humans.  Am.  Ind. Hyg. Assoc.  J. 41:399-409,
     1980.

Chapman,  M.  A.,  and J. B.   Hibbs.   Macrophage tumor killing:   Influence of  the  local  environ-
     ment.  Science 197:279, 1977.

Charlson,  R.  J. ,  D.  S.  Covert,  T.  V.  Larson,  and A.  P.  Waggoner.    Chemical  properties  of
     tropospheric sulfur aerosols.  Atmos. Environ. 12:39, 1978.

Cheng,  Y.  S. ,  and C.   S. Wang.   Inertial  deposition of particles  in  a  bend.  J.  Aerosol  Sci.
     6:139, 1975.

Cinkotai, F. F.  Fluid flow in a model alveolar  sac.  J. Appl.  Physiol. 37:249,  1974.

Clement,  J., M. Afschrift, J. Pardens, and K.  Van de Woestline.   Peak expiratory flow  rate and
     rate of change of pleural pressure.  Respir. Physiol. 18:222, 1973.

Clements,  J.  A.,  and D.  F.  Tierney.   Alveolar Instability Associated  with  Altered  Surface
     Tension,   Iji:  Handbook of Physiology.  W.  D. Fenn and H.  Rahn, eds. , Section 3,  Respira-
     tion,  Vol.  II,  Chapter  69 (Washington:   Am Physiol.  Soc.),  1965.   pp.  15-65  -  15-84.

Coenen, W.   Berechnung von Umrechnungsfaktorem  for Verscheidene Feinstaubmessverfahren.   In:
     Inhaled  Particles III.  W.  H.  Walton,  ed. , Unwin  Bros., London, 1971.    pp.  1045-1050.

Cohen,  V. R.   The  effects of  glyceryl  guaiacolate  on  bronchial clearance in  patients  with
     chronic bronchitis.   M.S. Thesis, New York  University, New York, NY,  1977.

Cohen,  D.,  S.  F.  Arai, and J.  D.  Brain.   Smoking  impairs  long-term  clearance  from the  lung.
     Science 204:514,  1979.

Corn,  M.  ,  N.  Kotsko,  and D.  Stanton.    Mass-transfer  coefficient  for  sulphur dioxide  and
     nitrogen  dioxide removal  in  cat upper  respirator tract.   Ann.  Occup. Hyg.  19:1,  1976.

Craighead,  F.  E.,  and N.  V.  Vallyathan.   Cryptic pulmonary  lesions  in workers  occupationally
     exposed to dust  containing silica.  JAMA  244:  1939-1941,  1980.

Cuddihy,  R.  G.  Analog  simulation of the biological  behavior of inhaled radionuclides.   In:
     Fission  Product  Inhalation Program Annual  Report 1968-1969.   LF-41,  Lovelace Foundation,
     Albuquerque, NM,  1969.  p. 136.

Cuddihy,  R.  G., D.  G. Brownstein, 0.  G.  Raabe, and G. M. Kanapilly.   Respiratory tract depo-
     sition of  inhaled polydisperse aerosols  in  beagle dogs.   Aerosol  Sci.  4:35, 1973.

Dadaian,  J.  H. ,  S.  Yin.,  and G. A. Laurenzi.  Studies of  mucus flow  in the  mammalian respira-
     tory tract.  Am.  Rev.  Respir. Dis. 103:808,  1971.

SOX11A/C                                      11-62                                    2-9-81

-------
Dalhamn, T.,  and  L.  Strandberg.  Acute  effect of sulfur dioxide  on rate of ciliary  beat in
     trachea  of  rabbit HI vivo  and  jj\ vitro, with  studies  on absorptional capacity of  nasal
     cavity.  Int. J. Air Water  Pollut. 4:154,  1961.

Dautrebande,  L.,  and W.  Walkenhurst.   New  studies on aerosols XXIV.   Arch.  Int.  Pharmacodyn.
     162:194, 1966.

Davidson,  M.  R. ,  and  J.  M.  Fitz-Gerald.   Transport of 0?  along  a model pathway  through  the
     respiratory  region of the  lung.   Bull.  Math.  Biol.  36:275-303,  1974.

Davies, C.  N.  A  Formalized Anatomy  of the  Human  Respiratory Tract.   J.n:  Inhaled Particles  and
     Vapours.  C.  N. Davies,  ed.,  Pergamon  Press,  Oxford,  1961.  p.  82.

Davies, C.  N.   The  handling  of  particles by the  human  lungs.   Brit. Med. Bull.  19:49,  1963.

Davies,  C.  N.   A comparison between  inhaled  dust  and the  dust  recovered from  human lungs.
     Health Phys.  10:1029, 1964a.

Davies, C.  N.   Deposition and  retention  of dust  in  the human respiratory tract.   Ann. Occup.
     Hyg.  7:169,  1964b.

Davies,  C.  N.  An algebraical  model for the deposition of  aerosols in the human respiratory
     tract  during steady  breathing.  J. Aerosol  Sci.  3:297,  1972.

Davies,  C.  N. ,   J.  Heyder,   and M.   C.   Subba  Ramu.   Breathing  of  half-micron-aerosols.   I.
     Experimental.   J. Appl.  Physiol.  32:592-600,  1972.

Davison, R.  L.,  D. F.  S.  Natusch,  and  J.  R.  Wallace.   Trace  elements in fly ash.  Environ.  Sci.
     Technol. 8:1107,  1974.

Deal,  E.   Chandler,  E.  R. McFadden, R. H.  Ingram, R. H.  Strauss,  and J. J. Jaeger.   Role of
     respiratory  heat exchange  in  production  of exercise-induced asthma.  J.  Appl.  Physiol:
     Respirat. Environ. Exercise Physiol. 46:467,  1979a.

Deal,  E. C.,  E.  R. McFadden,  R.  H. Ingram,  and  J.  J.  Jaeger.   Hyperpnea and heat flux:   initial
     reaction  sequence  in  exercise-induced asthma.   J.  Appl.  Physiol:  Respirat.  Environ.
     Exercise Physiol. 46:476,  1979b.

Deal,  E.  C. , E.   R.  McFadden, R. H.  Ingram,  and  J.  J.  Jaeger.  Esophageal  temperature during
     exercise  in asthmatic and  nonasthmatic subjects.   J. Appl.  Physiol:   Respirat.  Environ.
     Exercise Physiol. 46:484,  1979c.

Dekker, E.   Transition between  laminar and  turbulent flow  in human trachea.   J.  Appl.  Physiol.
     16:1060, 1961.

Doershuk,  C.  F.  ,  T. D.   Downs,  L.  W.  Matthews,  and M.  D.   Lough.   A  method  for ventilatory
     measurements in subjects 1 month to 5 years of age:   normal  results and observations in
     disease.  Pediatr. Res.  4:165-174, 1970.

Doershuk,  C.  F. , B.  J. Fisher,  and  L. W.  Matthews.   Pulmonary Physiology of the Young Child.
     In:   Pulmonary  Physiology  of the Fetus, Newborn and Child.   E. M. Scarpelli, ed. ,  Chap.
     77  Mea  and  Febiger, Philadelphia, PA, 1975.

Downs,  W.   L. , H. B. Wilson, G.  Z.  Sylvester,  L. J.  Leach, and E.  A.  Maynard.  Excretion of
     uranium  by  rats  following inhalation  of  uranium dioxide.   Health Phys.  13:445,  1967.

DuBois, A.  B. , and R.  M.  Rogers.   Respiratory factors determining the tissue concentrations of
     inhaled  toxic substances.   Respir.  Physiol.  5_:34, 1968.


SOX11A/C                                      11-63                                   2-9-81

-------
Dunnill, M. S.  Postnatal growth of the  lung.  Thorax 17:329,  1962.

Eatough, D. J. ,  T.  Major, J. Ryder, M.  Hill, N. F. Mangelson, N.  L.  Eatough,  L.  D.  Hansen,  R.
     G.  Meisenheimer,  and J. W.  Fischer.   The formation and  stability of sulfite  species  in
     aerosols.  Atmos. Environ. 12:263,  1978.

Edmunds, L. H. ,  P.  D. Graf,  S.  S.  Sagel,  and R.  H.  Greenspan.   Radiographic  observations  of
     clearance of  tantalum  and barium sulfate particles  from  airways.   Invest.  Radiol.  5:131,
     1970.

Einbrodt,  H.  J.   Experiments on the  elimination of dust from human lungs.  Ann. Occup.  Hyg.
     10:47, 1967.

Engel, L. A., L. D. Wood, G.  Utz, and  P. T. Macklem.  Gas mixing  during inspiration.   J.  Appl.
     Physiol.  35:18, 1973.

Ewert,  G.   On the  mucus flow  rates   in the  human nose.   Acta  Otolaryng. , Suppl.  200,  1965.

Felicetti,  S.  A.,  S.   A.   Silbaugh,  B.  A.   Muggenberg,  and F.  F.  Hahn.    Effect  of ^me
     post-exposure  on  the effectiveness of bronchopulmonary  lavage in removing  inhaled     Ce
     in  fused clay  from  beagle  dogs.   Health Phys.  29:89, 1975.

Ferin, J., G. Urbankova,  and A. Vlckova.   Pulmonary clearance  and the clearance of macrophages.
     Arch. Environ. Health 10:790. 1965.

Ferin,  J.   The mechanism of elimination of deposited  particles  from the  lungs.  Ann.  Occup.
     Hyg.  10:207,  1967.

Ferin, J.  Lung Clearance of Particles.  Jji:  Air  Pollution and The Lung.   E.  F.  Aharonson,  A.
     Ben-David,  and M.  A.   Klingberg, eds.,  Halsted  Press-John  Wiley, Jerusalem,  1976.   pp.
     64-78.

Ferin,   J.    Effect of  particle  content   of   lung on  clearance  pathways.    I_n:   Pulmonary
     Macrophages  and Epithelial Cells.   Proceedings of  the  Sixteenth Annual  Hanford Biology
     Symposium, Energy Research and Development Administration and Battelle Memorial  Institute,
     Richland, Washington, September  27-29, 1976.   C. L.  Sanders  R.  P.  Dagle,  and H.  A.  Ragan,
     eds., ERDA Symposium Series 43,  Energy Research and  Development Administration,  Oak Ridge,
     TN, 1977.  pp. 414-428.

Ferron,  G. A.  The  size  of soluble aerosol particles as a function of the humidity of the air.
     Application to the  human respiratory  tract.   J. Aerosol  Sci.  8:251-267,  1977.

Findeisen,  W.   liber  des Absetzen   Kleiner.   I_n:   der  Luft  suspendieter  teilchen in  der
     menschlichen  lunger bie der atmung.   Pflugers Arch.  J. d.  Physiol. 236:367, 1935.

Fish,  B. R.,  and J. L. Durham.  Diffusion  Coefficient of  SO,  in  air.   Environ Letters 2:13-21,
     1971.                                                  *

Foord,  N. , A.  Black,  and M.  Walsh.   Regional  deposition  of  2.5 -  7.5 mm  diameter inhaled
     particles in  healthy male  non-smokers.  AERE  Harwell,  ML.  76:2892, 1976.

Fowler,  J.  F. , and A.   E.  Young.   The  average  density  of healthy  lung.  Am.  J. RoentgenoV
     Radium Therapy 81:312,  1959.

Frank,  N.  R. , R.  E. Yoder,  E.  Yokoyama, and F. E. Speizer.   The diffusion of S0? from tissue
     fluids into  the  lungs   following  exposure of  dogs  to S02-   Health Physics 13:31-38, 1967.

Frank, N. R., R. E. Yoder, J. D. Brain,  and E. Yokoyama.  S0? absorption by the nose  and mouth
     under conditions of varying  concentration and  flow.   7\rch.  Environ.  Health 18:315^322,
     1969.
SOX11A/C                                     11-64                                    2-9-81

-------
Fraser, D.  A.   The deposition  of  unipolar charged particles  in  the lungs of  animals.   Arch.
     Environ. Health 13:152, 1966.

Fraser, R.  G. ,  and J.  A.  P.  Pare.   Structure and  Function  of the Lung.  W.  B.  Saunders Co. ,
     Philadelphia, PA, 1971.

Friberg.  L. ,  and  B.  Holma.  External  measurement of  lung  clearance.   Arch.  Environ.  Health
     3:56, 1961.

Fry, D.   A  preliminary  model   for  simulating the  aerodynamics  of the bronchial tree.   Comp.
     Biomed. Res.  2:111, 1968.

Fry, F. A.,  and A. Black.   Regional  deposition and clearance of  particles  in the  human nose.
     J. Aerosol Sci. 4:113,  1973.

Fuchs, N.  A.  The  Mechanics  of  Aerosols.   The MacMillan  Company, New York, 1964.

George, A.  C. ,  and A. J.  Breslin.   Deposition of  natural  radon  daughters in  human  subjects.
     Health  Phys.  13:375,  1967.

Giacomelli-Maltoni, G.,  C.  Melandri, V.  Prodi,  and  G. Tarroni.  Deposition efficiency of mono-
     disperse  particles in  human respiratory  tract.   Am.  Ind.  Hy.  Assoc.  J. 3_3:603,  1972.

Gladney,  E.  S. , J. A.  Small, G.  E. Gordon,  and W. H. Zoller.   Composition  and size  distribution
     of in-stack  particulate material  at  a coal-fired  power plant.  Atmos.  Environ.  10:1071,
     1976.

Goldberg,  I.  S.,  and  R.  V.  Lourenco.   Deposition  of  aerosols in pulmonary  disease.   Arch.
     Intern. Med.  131:88-91, 1973.

Goldberg,  I.  S. ,  K.  Y.  Lam,  B.  Bernstein, and H.  0. Hutchens.  Solution  to  the  Fokker-Planck
     equations governing simultaneous diffusion and gravitational  settling of aerosol  particles
     from stationary gas in  a horizontal tube.  J.  Aerosol Sci. 9:209,  1978.

Gordieyeff,  V-  A.   The  adsorption of gases and vapors on  aerosol  particulates.   Am.  Ind.  Hyg.
     Assoc.  Quart. 17:411,  1956.

Gormley,  P.  G. ,  and M.  Kennedy.   Diffusion from a stream flowing through a  cylindrical tube.
     Proc.  Roy. Irish  Acad.  A52:163, 1949.

Grant,  B. J. ,  H.  J.   Jones,  and J. M.  Hughes.  Sequence of  regional  filling during  a tidal
     breath  in man.  J.  Appl. Physiol.  158:  , 1974.

Green,  G. M.   Alveolobronchiolar transport observations  and  hypothesis of  a  pathway.   Chest
     59:15,  1971.

Green, G.  M.  In defense of  the lung.   Am.  Lung Assoc. Bull. 60:4, 1974.

Green,  J. F.   The Pulmonary Circulation.   J_n:   The  Peripheral  Circulations.  R.  Zelis,  ed. ,
     Grune and Straton,  New  York, 1975.  p.  9.

Gunnison, A.  F. ,  and A. W.  Denton.  Sulfur dioxide:  sulfite  interaction  with mammalian serum
     and  plasma.   Arch.  Environ.  Health  22:381, 1971.

Guyton, A.  C.   Measurement of  the respiratory  volumes of  laboratory animals.  Am.  J. Physiol.
     150:20, 1947a.

Guyton, A. C.  Analysis  of respiratory  patterns  in  laboratory  animals.   Am.  J. Physiol. 150:78,
     1947b.

SOX11A/C                                      11-65                                    2-9-81

-------
Harris, R.  L. ,  and D. A.  Fraser.   A model for deposition  of  fibers  in  the  humans respiratory
     system.  Amer. Indus. Hyg. Assoc. J.  37:73,  1976.

Hatch, T.  E., and P. Gross.  Pulmonary Deposition and  Retention  of  Inhaled Aerosols.   Academic
     Press, New York, 1964.

Henderson, R. F. , J. J. Waide, and  R. C. Pfleger.   Replacement time for  alveolar lipid removed
     by pulmonary  lavage:   Effects  of  multiple lavage  on  lung  lipids.   Arch.  Intern,  de
     Physiologie et de Biochemie 83:261, 1975.

Heppleston, A. G.   The fibrogenic action of silica.  Br. Med.  Bull.  25:282,  1969.

Heyder, J.    Conditions  for  the  determination  of aerosol  particle deposition in the  human
     respiratory tract.  Staub-Reinhaldt.  Luft 31:11,  1971.

Heyder, J. ,  and C.  N.  Davies.   The breathing of  half micron  aerosols  -  III dispersion  of
     particles  in the respiratory tract.   J. Aerosol Sci. 2:437,  1971.

Heyder, J.  L. ,  G. J. Armbruster,  and W.   Stahlhofen.    Deposition of aerosol particles  in  the
     human  respiratory  tract.   J.TI:   Aerosol in Physik, Medizin  and Technik,  Proceedings of a
     Conference,  Bod  Soden,  October 17-18, 1973.   V.  Bohlan,  ed. ,   Geselischaft fuer  Aerosol-
     forschung, Bod Soden, West Germany, 1973a.   pp. 122-125.

Heyder, J. ,  J.  Gebhart, G. Heigiver, C. Roth and W. Stahlohofen.   Experimental  studies  of  the
     total  deposition of aerosol  particles in the  human respiratory tract.   J.  Aerosol.  Sci.
     4:191-208, 1973b.

Heyder, J., L.  Arbruster,  J. Gebhart, E. Grein, and W.  Stahlhofen.   Total  deposition of  aerosol
     particles  in  the human respiratory tract for  nose and mouth  breathing.   J.  Aerosol  Sci.
     6:311, 1975.

Heyder, J. ,  and J.  Gebhart.  Gravitational deposition of particles from  laminar aerosol  flow
     through  inclined circular tubes.  J.  Aerosol Sci.  8:289,  1977.

Heyder,  J. ,  J.  Gebhart,  C.  Roth,  W.   Stahlhofen,  B.  Stuck,  G.  Tarroni,  T.   DeZaiacomo,  M.
     Formignani,  C.  Melandri,  and  V.  Prodi.    Intercomparison  of  lung  deposition  data  for
     aerosol  particles.  J. Aerosol.  Sci.  9:147-155, 1978.

Heyder, J. ,  J.  Gebhart, and W. Stahlhofen.   Inhalation of  Aerosols.  Particle Deposition  and
     Retention.   Iji:    Generation  of  Aerosols  and  Facilities  for Exposure Experiments.   K.
     Willeke, ed. , Ann Arbor Science, Ann  Arbor,  MI, 1980.   pp.  65-103.

Higgs,  B.  E. ,  M.  Clode,  G.  J.  R.   McHardy, N.  L.  Jones,  and E.  J.  M.  Campbell.  Changes  in
     ventilation  gas  exchange  and circulation during  exercise in normal  subjects.   Clin.  Sci.
     32:329-337, 1967.

Hollinger,  M.  A.,  0.  G.   Raabe,  S.  N. Giri,  M.  Freywald,  S.  V.  Teague,  and  B.  Tarkington.
     Effect of  aerosolized and dietary zinc on  paraquat toxicity  in  the rat.   Toxicol. Appl.
     Pharmacol., 1979  (In press).

Holma, B.   Lung clearance  of mono-  and di-disperse  aerosols determined by profile scanning and
     whole-body counting.  Acta Medica Scand. Supplement 473,  1967.

Holmes,  T.   H. ,  H.   Goodell,  S.   Wolf,  and  H.  G.   Wolff.   The  Nose.  Charles C.  Thomas,
     Springfield, IL, 1950.
SOX11A/C                                      11-66                                    2-9-81

-------
Horsfield,  K.,  and G.  Gumming.   Angles  of branching and  diameters  of branches in  the  human
     bronchial tree.  Bull. Math. Biophys.  29:245,  1967.

Horsfield,  K.,  and G.  Gumming.   Morphology of the  bronchial  tree in man.  J. Appl.  Physiol.
     24:373, 1968.

Horsfield,  K.,  G.  Dart,  0.  E.   Olson,  G.  F.  Filley,  and  G.  Gumming.   Models  of  the  human
     bronchial tree.  J. Appl. Physiol. 31:207-217,  1971.

Hounam,  R.  F. ,  A. Black,  and M.  Walsh.   Deposition of aerosol  particles  in  the  nasopharyngeal
     region of the human respiratory  tract.   Nature 221:1254-1255,  1969.

Hounam,  R.  F.   The deposition of atmospheric condensation  nuclei  in  the  nasopharyngeal  region
     of  the human respiratory tract.   Health  Physics 20:219,  1971.

Hounam,  R.  F., A. Black, and M.  Walsh.  The deposition of aerosol  particles  in the  nasopharyn-
     geal region  of the human respiratory tract.  J.  Aerosol  Sci.  2:47, 1971a.

Hounam,  R.  F. , A. Black, and M.  Walsh.  The Deposition of Aerosol  Particles  in the  Nasopharyn-
     geal Region  of the Human Respiratory  Tract.   In:   Inhaled Particles III.   W.  H. Walton,
     ed., Unwin Brothers Limited, Surrey  England, 19Tlb.  p.  71.

Hughes,  J.  M. ,  F. G. Hoppin, and J.  Mead.    Effect  of  lung inflation on  bronchial  length and
     diameter in  excised lungs.   J. Appl. Physiol.  32:25, 1972.

Intermountain  Thoracic  Society.  Clinical  Pulmonary Function Testing:   A  manuel  on  uniform
     laboratory  procedures for  the intermountain area.   R. E. Kanner  and A.  H.  Morris,  eds.,
     Salt Lake City,  Utah,  1975.  pp.  VI-1  to 140.

International  Standards Organization,  Draft  Technical  Report  to  ISO TC  146, Dr.  C.  Brosset,
     Chairman, 1980.

Jaffrin, M. Y. ,  and P. Kesic.   Airway  resistance:   a  fluid  mechanical  approach.   J.  Appl.
     Physiol. 36:354-361,  1974.

Johnston, J., B., and D. C.  F. Muir.   Inertial deposition of particles in the lung.   J.  Aerosol
     Sci. 4:269,  1973.

Johnston,   J.  R.,  and  R.   C.  Schroter.   Deposition of  particles  in model  airways.   Resp.
     Environ. Exercise  Physiol.  47:947-953, 1979.

Jones,  N.   L. ,  E. J. M. Campbell,  R. H.  T.  Edwards, and  D. G. Robertson.   Clinical Exercise
     Testing.  W. B.  Saunders, Philadelphia,  PA,  1975.  p.  202.

Kanapilly,  G. M.  Alveolar microenvironment and its relationship to the retention and transport
     into blood  of  aerosols deposited in  the  alveoli.  Health Phys.  32:89, 1977.
                                              239
Kanapilly,  G. M., and J. H.  Diel.   Ultrafine     P 0? aerosol genera-tion, characterization and
     short-term  inhalation study in the rat.   HeaTtn Phys.  39:505-519, 1980.

Kaufman, L.,  and G.  Gamsus.  Fluorescent excitation in the  measurement  of clearance of heavy
     metals  from  the  lungs.   I.E.E.E.  Transaction on Nuclear Science NS-21:1721, 1974.

Kawecki, J.  M.    Emission  of  Sulfur-Bearing Compounds from  Motor Vehicle and Aircraft Engines,
     A  Report to Congress.   EPA-600/9-78-028, U.S. Environmental  Protection Agency, Raleigh,
     NC, August  1978.
 SOX11A/C                                      11-67                                   2-9-81

-------
Klass,  D.  J.   Immunochemical.  studies  of  the protein  fraction of  pulmonary surface  active
     material.  Am. Rev. Resp. Dis. 107:784, 1973.

Knight, G. ,  and K.  Lichti.   Comparison of cyclone  and  horizontal  elutriator  size selectors.
     Am. Ind. Hyg.  Assoc. J.  31:437-441, 1970.

Kott, A. T.,  J.  W. Gardner,  R.  S. Schecter, and W.  DeGroot.   The elasticity of pulmonary lung
     surfactants.  J. Coll. Int. Sci. 47:265,  1974.

Krahl, V-   Microstructure of  the lung.  Arch.  Environ. Health  6:37,  1963.

LaBelle, C.  W. ,  and H.  Brieger.   Patterns  and Mechanisms in  the Elimination of Dust from the
     Lung.    In:   Inhaled  Particles  and Vapours.   C. N.  Davies, ed., Pergamon  Press,  Oxford,
     1961.   p. 356.

LaBelle, C.  W. ,  M. A. Bevilacqua, and  H.  Brieger.  The  influence  of cigarette  smoke  on lung
     clearance.  Arch. Environ.  Health  12:588, 1966.

Landahl, H.,  and S.  Black.   Penetration of air-borne particulates  through the human nose.  J.
      Ind.  Hyg. Toxicol. 29:269, 1947.

Landahl, H. ,  and R.  Herrmann.  On the  retention of air-borne  particulates in the human lung.
      J. Ind.  Hyg.  Toxicol.  30:181, 1948.

Landahl, H.  D.   On the removal of airborne droplets by  the human  respiratory tract.  I.  The
      lung.   Bull.  Math. Biophys. 12:43, 1950.

Landahl,  H. , T. Tracewell, and W.  Lassen.   On the  retention  of airborne  particulates  in the
      human lung:   II.  AMA  Arch Ind.  Health Occ. Med. 3:359, 1951.

Landahl, H.  D., T. N. Tracewell,  and W. H. Lassen.   Retention of airborne particulates in the
      human lung:   III.  AMA Arch.  Indust. Hyg. Occup. Med. 6:508-511,  1952.

Landahl,  H.   Particle  remove!  by the  respiratory system.   Bull.  Math. Biophys.  25:29, 1963.

Larson,  T. V. ,  D.  S. Covert,  R.  Frank,  and  R. J.  Charlson.   Ammonia in  the  Human Airways,
      Neutralization  of  Inspired Acid  Sulfate Aerosol.  Science 197:161-163, 1977.

Lauweryns, J. M.,  and J.  H. Baert.  Alveolar clearance and the role of the pulmonary lymphatics.
      Am. Rev.  Resp.  Dis.  115:625,  1977.

Leach,  L.  J.,  E. A.  Maynard,  H. C. Hodge, J. K.  Scott, C.  L. Yuile, G. E.  Sylvester, and H. G.
      Wilson.   A  five year  inhalation study  with  natural  uranium-dioxide  (U0?)  dust  - I.
      Retention  and biological  effect in  the monkey  dog  and rat.   Health  Phys.  18:599, 1970.

Leach,  L.  J., C.  L.  Yuile, H.  C.  Hodge, G. E. Sylvester,  and  H. B.  Wilson.  A five-year  inha-
      lation  study with  natural  uranium dioxide (U0?) dust  -   II.   Postexposure retention and
      biological  effects  in  the  monkey,  dog, and  rat.  Health Phys.  25:239, 1973.

Leeds,  S.  E.,  S. Reich, H.  N. Uhley,  J. J.  Sampson,  and  M. Friedman.  The pulmonary  lymph  flow
      after irradiation of  the lungs of  dogs.   Chest  59:203,  1971.

Lever,  J. , cited  in  C. N.  Davies.  Deposition of  aerosol  in the human lung.  In:  Aerosole in
      Physik  Medizin  und Technik, Bad-Soden, W. German, Gesellschaft fur AerosoTTorschung,  1974,
      p. 90-99.
SOX11A/C                                      11-68                                    2-9-81

-------
Lippmann,  M. ,  and  R.   Albert.   The  effect  of  particle  size  on the  regional  deposition  of
     inhaled aerosols  in  the human respiratory  tract.   Am.  Ind. Hyg.  Assoc.  J.  30:257,  1969.

Lippmann,  M.   Deposition and  clearance of  inhaled particles  in the  human  nose.  Ann  Otol.
     Rhinol. Laryngol.   79:519-528, 1970.

Lippmann,  M. ,  R.  E.  Albert,  and  H.   T.  Peterson, Jr.   The regional  deposition of  inhaled
     aerosols in man.   In:   Inhaled Particles  III.  W.  H.  Walton, ed.,  Unwin  Brothers  Limited,
     Surrey, England, 1971.  p. 105.

Lippmann,  M. , M.  S.  Mok, and K. Wasserman.  Anaesthetic management  for children  with  alveolar
     proteinosis  using  extracorporeal  circulation:  a  report of two cases.   Brit.  J.  Anaesth.
     49:173-177, 1977.

Lippmann,  M.  Regional  Deposition of  Particles  in the  Human  Respiratory Tract.   J.n:   Handbook
     of  Physiology,  Section 9:   Reactions to  Environmental Agents.   D.  H.  K.  Lee,  H.  L.  Falk,
     and  S. D.   Murphy, eds. , The  American  Physiological  Society,   Bethesda,  MD, 1977.    pp.
     213-232.

Lippmann,  M.   "Respirable"  Dust  Sampling.   I_n:   Air  Sampling  Instruments for  Evaluation  of
     Atmospheric  Contaminants,  5th edition.   American Conference  of  Governmental  Industrial
     Hygienists, Cincinnati, OH, 1978.  pp. G-l, G-23.

Longley, M. Y.   Pulmonary deposition of dust as  affected by electric charges  on the body.   Am.
     Ind.  Hyg. Assoc. J. 21:187, 1960.

Longley, M.  Y. ,  and C. M.  Berry.  Pulmonary deposition of aerosols:  effect  of electrostratic
     charging of the animal  body and the aerosol.   Arch. Environ. Health 2:533, 1961.

Lourenco,  R. V.,  R.  Loddenkemper, and  R. W. Cargon.  Patterns of distribution and clearance of
     aerosols  in  patients  with  bronchiectasis.   Am.  Rev.   Respir. Dis.  106:857-866,  1972.

Luchsinger,  P.   G. ,  B.  LaGarde,  and  J.   E.   Kilfeather.   Particle  clearance  from the  human
     tracheobronchial tree.  Am. Rev.  Resp. Dis. 97:1046,  1968.

Luft, U. C.  Spirometric Methods.  Jji:  Aviation Medicine  - Selected Reviews.   C.  S. White,  W.
     R.  Lovelace,  F. G. Hirsch, eds.,  Pergamon Press, New  York,  1958.   p.  168.

Lynch, J.  R.  Evaluation of size-selective presamplers:  I.   Theoretical cyclone  and elutriator
     relationships.  Amer.  Ind. Hyg. Assoc. J. 31:548-551, 1970.

Martens, A., and W.  Jacobi.  Die In-Vivo Bestimmung der Aerosolteilchen-deposition im  Atemtrakt
     bei Mund-Bzw.   Nasenatmung.   I_n:   Aerosole in Physik, Medizin  und Technik,  Bad Soden, W.
     Germany, Gesellschaft  fur Aerosolforschung, 1973.  pp. 117-121.

Machlin, C.  C.   The alveoli of the  mammalian lung:  an anatomical  study with clinical corre-
     lations.  Proc. Inst.  Med. 18:78,  1950.

Maguire, B. A.,  and  D.  Barker.  A gravimetric  dust sampling instrument  (SIMPEDS):  preliminary
     underground  trials.  Ann. Occup.  Hyg. 12:197-201,  1969.

Marshall,  R. , and W. Holden.  Changes  in calibre of the smaller  airways in man.   Thorax 18:54,
     1963.

Martin,  D. , and  W.  Jacobi.  Diffusion  deposition of  small-sized  particles  in  the bronchial
     tree.  Health Phys. 23j:23-29, 1972.

McEuen,  D. D. ,   and  J.  L.   Abraham.  Particulate concentrations  in  pulmonary alveolar protei-
     nosis.  Environ. Res.  17:334-339,  1978.

SOX11A/C                                      11-69                                   2-9-81

-------
Melandri, C.,  V.  Prodi, G. Tarroni,  M.  Formignani,  T. DeZaiacomo,  G.  R.  Bompane,  G.  Maestri,
     and G.  G.  Giacomelli-Maltoni.   On  the  Deposition of Unipolarly Charged  Particles in the
     Human  Respiratory  Tract.   In:   Inhaled  Particles IV.  W.  H.  Walton,  ed. ,  Pergamon Press,
     New York, 1977.  p. 193.

Melville, G.  N.   Changes in specific airway  conductance  in healthy volunteers  following nasal
     and oral inhalation of S02-  W.  I.  Med.  J.  19:231-235, 1970.

Mercer, T.  T.   On the  role of particle  size  in  the  dissolution of lung burdens.   Health Phys.
     13:1211, 1967.

Mercer, T.  T.   Aerosol  Technology  in Hazard  Evaluation.   Academic Press,  New York, 1973.   pp.
     66-280.

Miller, F.  J. ,  D.  E.  Gardner, J. A. Graham,  R.  E. Lee. Jr.,  W.  E.  Wilson, and  J.  D.  Buchmann.
     Size  considerations  for  establishing   a   standard for   inhalable  particles.   J.   Air
     Pollution Control  Assoc. 29:610-615, 1979.

Morgan, W.  K. C.,  and A. Seaton.  Occupational  lung  diseases.   Philadelphia, PA,  W. B.  Saunders,
     1975.

Morgan,  A.,  J.  C.  Evans, and A. Holmes.  Deposition and  Clearance of Inhaled Fibrous Minerals
     in the  Rat:   Studies Using Radioactive Tracer Techniques.   In:   Inhaled Particles IV.   W.
     H. Walton,  ed.,  Pergamon Press,  1977.  pp.  259-274.

Morrow,  P. ,  E.  Mehrhof,   L.  Casarett,  and  D. Morken.   An  experimental  study  of  aerosol
     deposition  in human subject.   AMA.  Arch.  Ind. Health 18:292,  1958.

Morrow,  P.  E. ,  D.  V.   Pates,  B.   R.  Fish,  T.   F.  Hatch,  and T.  T.   Mercer.   International
     commission  on  radiological  protection  task   group on  lung  dynamics,  deposition  and
     retention  models  for  internal dosimetry  of the  human  respiratory  tract.   Health Phys.
     12:173-207,  1966.

Morrow,  P.  E.,  F.  R.  Gibb,  and  K. M.  Gazioglu.   A study of particulate clearance from the human
      lungs.   Am.  Rev. Resp.  Dis. 96:1209, 1967a.

Morrow,  P.  E. ,  F.   R.  Gibb,   and  K.  M.  Gazioglu.   The Clearance of Dust  from  the  Lower
     Respiratory Tract of  Man:   An  Experimental Study.   _In:   Inhaled Particles  and Vapours.
     S.  C.  N.  Davies, ed.,  Oxford,  Pergamon  Press, 1967b.  p. 351.

Morrow,  P.  E.  Experimental studies  of  inhaled  materials.  Arch.  Intern.  Med.  _126:466, 1970a.

Morrow,  P.  E.  Models  for  the  Study of Particle Retention  and Elimination  in  the Lung.   In:
      Inhalation  Carcinogenesis.   M. G.  Hanna,  P. Nettesheim, J. R.  Gilbert, eds., U.S. Atomic
     Energy Commission, Oak Ridge,  TN,  1970b.   p. 103.

Morrow,  P.  E.   Alveolar clearance of  aerosols.   Arch.  Intern. Med. 131:101, 1973.

Moss,  0.  R. ,  and H.  J. Ettinger.   Respirable Dust  Characteristics  of polydisperse aerosols.
     Amer.  Ind.  Hyg.  Assoc.  J.  31:546-547,  1970.

Muir,  D. C. ,  and C. N.  Davies.  The deposition of 0.5 m diameter aerosols in the lungs of man.
     Ann. Occup.  Hyg. 10:161, 1967.

Nair,  P.  V. N. , and  V.  G.  Vohra.   Growth of Aqueous Sulphuric Acid Droplets as a Function  of
     Relative  Humidity.  J.  Aerosol  Sci.  6:265,  1975.

National Academy of Sciences.   Measurement  and Control of Respirable  Dust  in Mines.   National
     Academy  of  Sciences, Washington,  DC, 1980.   pp. 348-405.

SOX11A/C                                      11-70                                     2-9-81

-------
Natusch, D.  F.  S.,  J. R. Wallace,  and C. A.  Evans,  Jr.   Toxic trace  elements:   preferential
     concentration in respirable particles.   Science  183:202,  1974.

Newhouse, M.  T. ,  M.  Dolovich, G. Obminski,  and R. K.  Wolff.   Effect of TLV levels of SO, and
     H2S04  on bronchial  clearance  in exercising  man.   Arch.  Environ. Health  33:24-32,  1978.

Niinimaa,  V. M.  J.    Oral  nasal  distribution  of respiratory  airflow.   Ph.D.  Dissertation,
     University of Toronto, Canada, 1979.

Olson, D. E., M. F. Sudlow, K. Horsfield,  and G.  F. Filley.  Convective patterns  of flow during
     inspiration.  Arch.  Intern. Med.  131:51-57,  1973.

Orenstein,  A. J. (ed.).   Proceedings  of  the  Pneumonoconiosis Conference 1959,  J & A Churchill,
     Ltd.,  London, 1960.

Owen,  P.  R.  Turbulent Flow  and  Particle  Deposition  in the  Trachea.   In:   Circulatory and
     Respiratory Mass Transport.  G.  E.  W. Wolstenholme and J.  Knight,  eds. , A CIBA Foundation
     Symposium.  Boston,  Little, Brown and Co.,  1969.   pp. 236-252.

Pack,  A.,  M. B. Hooper,  W.  Nixon,  and J. C.  Taylor.   A computational model  of  pulmonary gas
     transport  incorporating  effective diffusion.   Respir. Physio.  29:101-124,  1977.

Paiva, M.   Gas  transport  in the  human lung.   J.  Appl.  Physiol.  35:401,  1973.

Palmes,  E.   D. , and  C.   S.  Wang.    An aerosol  inhalation  apparatus  for human  single  breath
     deposition studies.  Am.  Ind.  Hyg.  Assoc.  J.  32:43,  1971.

Pattle,  R.  E.   The Retention  of  Gases and Particles in  the Human Nose.   In:   Inhaled Particles
     and Vapours.  C. N.  Davies, ed., Pergamon Press,  Oxford,  1961a.   p.  302.

Pattle,  R.   E.  The Lining  Complex  of the Lung  Alveoli.  _In:   Inhaled Particles  and Vapours.
     C.  N.  Davies, ed. , Pergamon Press,  Oxford,  1961b.   p. 70.

Pavia,  D. ,  M. Thomson, and H.  S.  Shannon.   Aerosol  inhalation  and depth of deposition in the
     human  lung.  Arch. Eviron.  Health 32:131,  1977.

Pavlik,  I.   The fate  of  light air ions in the respiratory pathways.   Int. J. Biometeor.  11:175,
     1967.

Pawley,  J.   B.,  and G.  L.   Fisher.   Using  simultaneous  three  colour   X-ray  mapping  and
     digital-scan-stop  for rapid elemental   characterization  of coal  combustion by-products.
     J.  Microscopy 110:87,  1977.

Pedley,  T.  J.  A theory  for  gas mixing  in  a simple  model of  the lung.   In: Fluid Dynamics of
     Blood  Circulation  and  Respiratory Flow, AGARD Conference  Proceedings No.  65, 1970.

Pedley,  T.   J. , R.  C.  Schroter,  and M. F.  Sudlow.  Flow  and pressure  drop  in  systems of
     repeatedly branching tubes.  J.  Fluid Mech.  46:365-383,  1971.

Pfleger, R.  C.,  and H.  G. Thomas.   Beagle dog pulmonary surfactant lipids.   Archs. Intern. Med.
     9:70,  1971.

Phalen,  R.   F.,  and P.  E. Morrow.   Experimental  inhalation  of metallic  silver.   Health  Phys.
     24:509-518, 1973.

Phalen,  R.  F. ,  H.  C.  Yeh,  G.  M. Schum,  and  0.  G.  Raabe.   Application of an idealized model to
     morphometry of the mammalian tracheobronchial tree.   Anat.  Rec.  ^90:167-176, 1978.
 SOX11A/C                                      11-71                                   2-9-81

-------
Polgar, G.,  and T.  R.  Weng.   The functional development  of  the respiratory  system from the
     period of gestation to adulthood.  Am.  Rev.  Resp. Dis.  120:625-695,  1979.

Proctor, D. F., and H. N. Wagner.  Clearance of particles  from the human  nose.   Arch. Environ.
     Health 11:366, 1965.

Proctor, D.  F., and  H.  N.  Wagner.   Mucociliary  Clearance in  the Human  Nose.   In:  Inhaled
     Particles  and Vapours  II.   C.  N.  Davies,   ed. ,  Pergamon  Press,  Oxford,  1967.   p. 25.

Proctor, D. F.,  D.  L. Swift, M.  Quinlan,  S. Salman, Y. Takagi,  and S.  Evering.   The nose and
     man's atmospheric environment.  Arch. Environ.  Health 18:671, 1969.

Proctor, D. F. ,  and D.  Swift.  The Nose - A Defence Against the Atmospheric Environment.  In:
     Inhaled Particles III.  V.   W. H. Walton, ed., Unwin Brothers, Limited, Surrey, EnglanB,
     1971.   p. 59.

Proctor, D. F. ,  I.  Andersen, and G. Lundquist.   Clearance of inhaled particles from the human
     nose.   Arch. Intern. Med.  131:132, 1973.

Pruitt, K. M., M. J.  Cherny, and H. L.  Spitzer.   Physical  and chemical characterization of pig
     lung  surfactant  lippoprotein.  Archs. Intern.  Med.  9:6, 1971.

P-jmp,  K.   K.  The  morphology of the  finer branches of  the bronchial tree  of  the human lung.
     Dis.  Chest 46:379, 1964.

Raabe,  0.  G.  Some  important consideration in use of power function to describe clearance data.
     Health Phys.  13:293,  1967.

Raabe,  0.  G.   Particle size analysis  utilizing grouped data  and the log-normal  distribution.
     Aerosol  Sci.  2:289,  1971.

Raabe,  0.  G.   Aerosol aerodynamic  size conventions for inertial  sampler calibration.  J. Air
     Poll.  Control  Assoc.  26:856,  1976.

Raabe,  0.  G., H. C.  Yen,  G.  M. Schum, and  R.  F. Phalen.    Tracheobronchial Geometry:  Human,
     Dog,  Rat,  Hamster,  LF-53.   Lovelace  Foundation, Albuquerque, 1976.

Raabe,  0.  G.,  H.  C. Yeh,  G.   J.  Newton,  R.  F.  Phalen,  and D.  J.  Velasquez.   Deposition of
     Inhaled  Monodisperse  Aerosols  in  Small  Rodents.  In:   Inhaled Particles IV.   W. H. Walton,
     ed.,  Pergamon  Press,  New York, 1977.  p.  3-22.

Raabe,  0.  G., S. V.  Teague,  N. L. Richardson, and L.  S.  Nelson.  Aerodynamic and  dissolution
     behavior of  fume  aerosols  produced during  the  combustion  of  laser-ignited plutonium
     droplets in  air.  Health Phys. 35:663,  1978.

Raabe,  0.   G.   Deposition  and  Clearance  of  Inhaled Aerosols.    U.S.  Department  of  Energy.
     National Technical  Information Service, UCD-472-503,  Springfield, VA,  1979.

Raabe,  0.  G., and  M.  Goldman.   A predictive  model of early mortality  following acute inhalation
     of Pu02  aerosols.   Radiat.  Res.  78:264-277,  1979.

Ramsden,  D.,  M.  E.  D.  Bains,  and  D.  C.  Fraser.    In  vivo and bioassay  results  from two  con-
     trasting cases  of plutonium-239  inhalation,   rfealth Phys. 19:9,  1970.

Reifenath,  R.   Chemical  analysis  of  the  lung alveolar  surfactant obtained  by alveolar micro-
     puncture.   Resp. Physiol.  19:35,  1973.
 SOX11A/C                                      11-72                                    2-9-81

-------
*

Rudolf, G. ,  and  J.  Heyder.  Deposition  of  Aerosol  Particles  in the Human Nose.   In:   Aerosole
     in Naturwissenschaft,  Medizin und  Technik.  V.  Bb'hlan,  ed.   Proceedings of  a Conference
     held  in Bad  Soden,  October  16-19,  1974.  Bad Soden,  West  Germany:   Gesellschaft  fur
     Aerosolgorschung, 1974.

Saibene, F. , P. Mognoni , C.  L.  LaFortuna, and  R.  Mostardi.  Oronasal  breathing during exercise.
     Pflugers Arch. 378:65-69,  1978.

Sanchis,  J. , M.  Dolovich,  R.  Chalmers, and  M.  Newhouse.    Quantitation of regional  aerosol
     clearance in the normal human lung.  J. Appl.  Physiol. 33:757, 1972.
Sanders,  C.  L. ,  and R.  R. Adee.   Phagocytosis  of  inhaled  plutonium oxide  -     Pu particles  by
     pulmonary macrophages.   Science  162:918, 1968.

Scarpelli,  E.  M.   The Surfactant  System  of the  Lung.   Philadelphia,  Lea and  Febiger,  1968.

Scherer,  P.  W. ,  L. H.  Shendalman,  and  N.  M. Greene.   Simultaneous  diffusion  and convection  in
     a single breath  lung washout.  Bull.  Math.  Biophys. 34:393-412,  1972.

Scherer,  P.  W. ,  L.   H.  Shendalman,  N.   M.  Greene,  and  A.  Bouhuys.   Measurement  of  axial
     diffusivities  in a model of  the bronchial airways.   J. Appl.  Physiol.  38:719-723,  1975.

Scherer,  P.  W. ,  F. R.  Haselton,  L. M.  Hanna, and  D.  R. Stone.   Growth  of  hygroscopic aerosols
     in  a model  of bronchial  airways.  J.  Appl. Physiol.  -  Respir.  Environ.  47:544-550,  1979.

Schlesinger,  R.  B.   Mucociliary interaction in the  tracheobronchial  tree  and  environmental
     pollution.  Bio.  Sci. 23:567,  1973.

Schlesinger,  R.  B. ,  and M.   Lippmann.   Particle  deposition  in the  trachea:  j_n vivo and  in
     hollow casts.  Thorax 31:678,  1976.

Schlesinger, R.  B. , and M. Lippmann.   Selective particle deposition and bponchogenic  carcinoma.
     Environ. Research 15:424, 1978.

Schroter,  R.  C. , and  M.  F.  Sudlow.   Flow patterns  in models of the human bronchial  airways.
     Respir. Physiol.  7:341,  1969.

Shanty,  F.   Deposition of  Ultrafine  Aerosols  in  the Respiratory Tract  of  Human Volunteers.
     Doctoral  Dissertation.   School   of  Hygiene  and  Public   Health   of the  Johns  Hopkins
     University, Baltimore,  1974.

Sherwin,  R. P., M.  L.  Barman,  and  J. L.  Abraham.   Silicate pneumoconiosis  of farm workers.
     Lab  Invest. 40:576-582,  1979.

Sherwood, T. K. , R. L.  Pigford,  and C.  R.  Wilke.   Mass Transfer.  McGraw-Hill, New York,  1975.
     pp.  13, 677.

Silverman,  L. , and C.  E.  Billings.   Pattern of  Airflow in  the Respiratory Tract.  In:  Inhaled
     Particles and Vapours.   C.  N.  Davies, ed. , Pergamon  Press, Oxford, 1961.  p. 9T

Smith,  F.  A. ,  and  E.  A.  Boyden.   An  analysis of the segmental  bronchi  of the right lower lobe
     of  fifty injected lungs.   J.  Thor. Surg. 18:195, 1949.

Snyder, W.  S.  Report  of Task Group on Reference Man, Pergamon Press, Oxford, 1975.

Speizer,  F. E. , and  N.  R.  Frank.   The  uptake and  release  of S0? by  the human nose.   Arch.
     Environ. Health  12:725-728,  1966.
 SOX11A/C                                      11-73                                   2-9-81

-------
if
Spiegelman,  J.  R. ,  G.  D.  Hanson,  A.  Lazarus,  R.  J. Bennett,  M.  Lippman, and  R.  E.  Albert.
     Effect  of  acute  SO, exposure on bronchial  clearance  in the donkey.   Arch.  Environ Health
     17:321-326, 1968.  £

Stahl, W. R.  Scaling of respiratory variables  in mammals.   J.  Appl.  Physiol.  22:453-460, 1967.

Stahlhofen  W.,  J.   Gebhart,  and J.  Heyder.   Experimental  determination  of  the  regional
     deposition of  areosol  particles in the  human  respiratory  tract.  Amer.  Ind.  Hyg.  Assoc.
     J. 41:385-398a, 1980.

Stockham,  J.  D. , and  E. G.  Fochtman,  eds.  Particle Size Analysis.  Ann Arbor Science, Ann
     Arbor,  Michigan, 1979.  pp.  140.

Strandberg,  L.  G.   S0? absorption in the  respiratory tract.   Arch.  Environ.  Health 9:160-166.
     1964.            *

Strecker,  F. J.  Tissue Reactions  in  Rat Lungs after Dust Inhalation with Special  Regard to
     Bronchial  Dust Elimination and to the  Penetration  of Dust  into the Lung Interstices and
     Lymphatic  Nodes.   |n:   Inhaled  Particles  and  Vapours  II.   C.  N.  Davies,  ed. ,  Pergamon
     Press,  Oxford, 1967.  p.  141.

 Swift,  D.  L., F. Stanty, and J.  T. O'Neil.   Human respiratory deposition  patterns of fume-like
     particles.  Presented in  part at the  1977  Amer.  Ind.  Hyg.  Conf. , New Orleans,  LA, May 26,
     1977.

 Taplin,  G.   V.,  N.  D.  Poe,  E.  K. Dore, A.  Greenberg,  and T. Isawa.   Radioaerosol  Inhalation
     Scanning.   In:   Gibson, A.  J. , Pulmonary Investigation with Radionuclides.   W.  M. Smoals,
     ed.,  Springfield,  IL, Charles C. Thomas, 1970.   pp. 296-317.

 Tarroni,  G.,  C. Melandri,  V. Prodi, T. deZaiacomo, M.  Formignani,  and P.  Bassi.   An indication
     on the biological  variability of aerosol total  deposition in humans.  Am.  Ind.  Hyg. Assoc.
     J.  41:826-831, 1980.

 Taulbee,  D. B. , and C.  P. Yu.   A theory  of aerosol  deposition in the human respiratory tract.
     J.  Appl. Physiol.  38:77,  1975.

 Taulbee,  D.,  C. Yu, and J. Heyder.  Aerosol  transport in the human lung from analysis of single
     breaths.   J. Appl.  Physiol.  44:803,  1978.

 Tenney,  S.  M. ,  and J.  E.  Remmers.  Comparative quantitative morphology of the mammalian  lung:
     diffusing  area.  Nature 197:54, 1963.

 Tenney,  S.   M. ,  and D.  Bartlett.  Comparative  quantitative morphology of  the  mammalian  lung:
     trachea.   Resp.  Physiol.  3:130, 1967.

 Thomas,  R.  G.  Transport of relatively  insoluble materials  from  lung to lymph  nodes.  Health
      Phys.  14:111,  1968.

 Thomson,  M.  L.,  and  D. Pavia.   Long-term  tobacco  smoking and  mucociliary  clearance.   Arch.
     Environ. Health  26:86,  1973.

 Threshold   Limits  Committee.   Threshold   Limit Values  of  Air  Borne  Contaminants  for  1968.
     American Conference of  Governmental  Industrial  Hygienists, Cincinnati, OH,  1968.

Thurlbeck,  W. M., and  J.  B. Haines.   Bronchial dimensions and stature.   Am.  Rev.  Resp.  Dis.
     112:142, 1975.

Tuttle,  W.  C. ,  and S.  C. Westerberg.  Alpha-1-globulin  trypsin inhibitor  in canine surfactant
     protein.   Proc.  Soc.  Exp.  Biol. Med.  146:232,  1974.

SOX11A/C                                      11-74                                     2-9-81

-------
Van  As,  A.,  and I.  Webster. .  The  organization of  ciliary  activity and  mucus transport  in
     pulmonary airways.  S. A. Med.  J. 46:347,  1972.

van  Ree, J.  H.  L. , and H. A. E. van Dishoeck.   Some  investigations  on nasal  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. 257:400, 1953.

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.   jtn:   Inhaled Particles and Vapours  II.   C.  N.  Davies,  ed. ,
     Pergamon Press,  Oxford,  1967.   p. 563.

Wang,  C. S.  Gravitational deposition from laminar  flows  in inclined channels.   J.  Aerosol  Sci.
     6:19, 1975.

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.
     444 pp.

Weibel,  E. R.  Morphometry of the  Human  Lung.   Academic Press,  New York, 1963.

West,  J. B.   Observations on Gas  Flow in the Human Bronchial  Tree.   In: Inhaled Particles and
     Vapours.   C.  N.  Davies, ed. ,  Proceedings  of an International  Symposium organized by the
     British  Occupational  Hygiene  Society,   1960.  New York,  Pergamon   Press,  1961.  pp.  3-7.

West,  J. B.   Respiratory  Physiology:   the  Essentials.   Williams and   Wilkins,  Philadelphia,
     1974.

West,  J. B.   Respiration Physiology-the  essentials.  Williams  and Wilkins  Co., Baltimore, MD,
     1977.   185  pp.

Whimster,  W.  F.  The  microanatomy  of the alveolar duct  system.  Thorax  2_5:141,  1970.

Whitby,  K. T.  The  physical characteristics  of  sulfur aerosols.  Atmos.  Environ. 12_:135,  1978.

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,  ed. ,
     Charles  C.  Thomas,  Springfield, IL, 1970.   pp.  5-19.

Wolff,  R.  K. ,  M.  Dolovich,  C.  M.   Rossman,  and M.  T.  Newhouse.   Sulfur dioxide and tracheo-
     bronchial clearance  in man.   Arch.  Environ.  Health 30:521-527,  1975.

Yeh, H.  C.   Use of  a  heat  transfer analogy  for  a mathematical model of  respiratory  tract
     deposition.   Bull.  Math. Biol.  36:105,  1974.

Yeh, H.  C. ,  R.  F.  Phalen,  and 0.  G.  Raabe.   Factors influencing  the deposition of inhaled
     particles.  Environ.  Health  Persp.  15:147, 1976.

Yeh, H.  C. ,  and G.  M.  Schum.   Models of human lung airways  and  their  application to inhaled
     particle deposition.  Bull.  Math.  Biol. 42:461-480,  1980.
 SOX11A/C                                      11-75                                   2-9-81

-------
Yu, C.  P.   An equation of gas transport in the lung.  Resp. Physiol. 2^:257-266,  1975.

Yu, C.  P.   Precipitation of unipolarly charged particles in cylindrical and  spherical  vessels.
     J. Aerosol Sci. 8:237, 1977.

Yu, C.  P.   A two component theory  of  aerosol  deposition  in  human  lung airways.  Bull.  Math.
     Biol. 40:693-706, 1978.

Yu,  C.  P.,  P.  Nicolaides,  and  T.  T.  Soong.    Effect  of  random airway  sizes  on  aerosol
     deposition.  Am. Indus. Hyg. Assoc. J. 40:999-1005, 1979.

Zenz,  C.,  ed.   Occupational  Medicine:   Principles  and  Practical  Applications.   Year  Book
     Medical Publishing, Inc., Chicago, IL, 1975.  pp. 113-115.
SOX11A/C                                     n-76                                    2_9_81

-------
                                  12.  TOXICOLOGICAL STUDIES

12.1  INTRODUCTION
     This chapter describes  the toxicity of sulfur  oxides  and particulate matter in animals.
The health  effects  of  sulfur oxides  and  particles have  also been  reviewed  recently  by the
National Academy of  Sciences (Committee on Sulfur Oxides, 1978; National Academy of Sciences,
Airborne Particles,  1979).   The  toxic effects  of  sulfur oxides and  of atmospheric aerosols
overlap because major  components  of atmospheric aerosols are salts of sulfuric acid (ammonium
sulfate, sodium sulfate, and related compounds) (see Chapters 3 and 5).  The toxicology  of all
forms of sulfur oxides must be considered as a whole.  For example,  in the ambient air,  sulfur
dioxide (S0£) may interact with aerosols, may be absorbed on particles, or may be dissolved in
liquid  aerosols.   To a  lesser degree,  similar  interactions may occur  in the  air  within the
respiratory  tract.   Sulfuric  acid  aerosols may  react  with ammonia  forming  ammonium sulfate
[(NH4)2S04J and ammonium bisulfate (NH4HS04) in the ambient air, in the animal exposure  chamber
atmosphere before inhalation,  or,  to a lesser degree,  in the respiratory tract simultaneously
upon  inhalation  (see Section  12.3).   Biological interaction  can also  occur,  resulting  in a
situation where the effect of a mixture of pollutants has additive,  synergistic, or antagonis-
tic health effects compared to the effects of the single pollutants.
     At the present time, it is clear that the major toxic effects of sulfur oxides are  on the
respiratory  tract.   Discussions  of  the deposition and clearance  of  sulfur oxides are limited
here;  the  reader,  therefore, should be  familiar  with  the content of  Chapter  11  which  covers
this  subject  in  detail.   The  toxic effects of  sulfur  oxides, whether induced by SO™,  H-SO.,
or sulfate salts, include immediate irritation of the respiratory tract.   Most measurements of
this  irritation  have been  through  studies of  the   respiratory mechanics  of  the experimental
animal.  Similar  studies of  respiratory mechanics  have  been undertaken  with human subjects
experimentally  or  environmentally  exposed.  The general  effects of  SO- on  the respiratory
mechanics  of animals and  man are  the same.   The  animal  studies reviewed here  present  some
details  of  the  metabolism  of S0?  and bisulfite,  the  effects  of  S0?  on the biochemistry,
physiology and morphology  of the respiratory tract, and the potential effects on organs other
than the lung.
     A  major problem  area  is  the  diversity  of particulate  matter  in  the  atmosphere.   Any
organic compound whose  local concentration exceeds its vapor pressure will condense and occur
in  the particulate   fraction  when sampled.  Some may  be sorbed  on the  surfaces  of inorganic
particles.    Inorganic particles  can be of a wide chemical variety.   Unfortunately, our knowl-
edge of  the  exact  chemical  nature and  health  effects  of these materials is incomplete.  Pro-
gress  is being made  toward a better understanding  of  the toxicity of these materials associ-
ated with particles,  but at present inadequate data are available.  There is no theoretical or
practical reason why these data should not be attainable; rather, the present deficiency repre-
sents the sophistication of our knowledge.   A more complete treatment of the health effects of

XRD12A/A                                     12-1                                   2-5-81

-------
polycyclic organic matter  is  found in a  recent  review (Environmental Criteria and Assessment
Office, 1978).  Overviews  are  provided for some of  the heavy metals present  in polluted  air.
More  detail  is found in documents dealing specifically with  each  heavy metal (Environmental
Criteria and  Assessment Office,  1979;   Office of Research and Development, 1977; Committee  on
Biologic Effects  of  Atmospheric  Pollutants,  Vanadium, 1974; Committee on Medical and  Biologic
Effects of Environmental  Pollutants, Nickel,  1975;  Committee on Biologic Effects of Atmospheric
Pollutants,  Lead,  1972;  Committee  on  Biologic  Effects  of Atmospheric  Pollutants,  Chromium,
1974;  Committee  on Medical  and  Biologic Effects of  Environmental  Pollutants, Arsenic, 1977;
National  Academy  of Sciences,  Iron,  1979; National  Academy  of  Sciences,  Zinc,  1979).   This
chapter deals  primarily with sulfur oxide-derived aerosols, sulfuric acid, sulfate salts, and
related compounds.   It  is  not intended to represent all of the health effects associated  with
the complex mixture of materials present in atmospheric aerosols.   The reader  should supplement
his knowledge through reference to the additional documents cited above.
      Interactions  between  sulfur  oxides  and  other pollutants  are reviewed briefly because  of
the sparsity  of the data available.  Some of these studies are controversial and have  not  been
duplicated.   Especially controversial  are those studies dealing  with the potential  mutagenic
effects of S02 and the interaction of S02 and HLSO. with known carcinogens.
      Another  difficulty with a current review of the toxicology of sulfur oxides is the spar-
sity  of recent studies.   A hiatus  occurred approximately 10 years ago with few studies  appear-
ing  subsequently.   Work in  progress  is  not  included.   As a  consequence  a  certain  degree  of
sophistication is  lacking  in some of the  intrepretations,  not through a lack of appreciation
of the problem, but simply because insufficient information is available.
12.2   EFFECTS OF  SULFUR DIOXIDE
12.2.1  Biochemistry of Sulfur Dioxide
      Much  of the  discussion under Section 12.2.1  relates to  j_n  vitro  experiments.   J_n vitro
studies are  those in which the potential target (i.e., cells, enzymes, other  molecules, etc.)
is  exposed to the toxicant outside the  body.   In such a system,  some  homeostatic  or repair
mechanisms  are absent.   In  some  cases,  pollutants act by  indirect  mechanisms.   For  example,
the pollutant affects target A which in turn alters target B.  Thus,  if only target B  were pre-
sent,  the effect would not be observed.  In addition, the dosimetric  relationships of  jjn vitro
studies  to jm vivo  studies are  not  defined.   Therefore,  effective  concentrations  cannot  be
extrapolated  directly from HI  vitro to i_n vivo studies.  For  the above reasons, there is  some
controversy as to whether observed i_n vitro reactions can be extrapolated to HI vivo mechanisms
of  toxicity.   Nonetheless,  sound  j_n  vitro investigations can show whether  a given pollutant
has the potential of affecting a given target.   In vitro studies  are  best used to provide  guid-
ance  for  HI  vivo  investigations   or when J_n  vivo  results have been  observed.  In the  latter
case,  the  relatively  simplified jn  vitro  system  can  sometimes  elucidate  the  potential
mechanisms of toxicity.   To these  ends, they can be useful.
XRD12A/A                                     12-2
                                                                                     2-5-81

-------
     Knowledge of  the  chemistry  of  sulfurous acid  and S02  is  necessary to  understand the
physiological  and toxicological properties of SO-.  Sulfur dioxide is the gaseous anhydride of
sulfurous acid.   It  dissolves  readily  in  water;  and  at  physiological pH  near neutrality,
hydrated  S02   readily  dissociates to  form  bisulfite  and  sulfite  ions  as  illustrated  by
Equations 12-1  and 12-2.   The rate of hydration of  SO,, is very rapid;  the  rate constant of
                           6   -1    -1
hydration, k,, is  3.4 x 10  M   sec   ,  and the rate  constant  of  the reverse reaction is 2 x
  8  -1    "I
10  M   sec   at 20°C (Equation 12-1) (Tartar and Garetson, 1941).   The dissociation constants
of sulfurous acid are 1.37 and 6.25 (in dilute salt solutions)  (Tartar and Garetson, 1941), so
at pH  7.4 sulfite  ions are present at about 14 times those of  bisulfite, but in rapid equili-
brium.   Hence, S0» can be treated  as bisulfite/sulfite and conversely.
                               k-,
               S0  + H0   «             HS0                                     12-1
                         PKa = i-37              PKa= 6-
               H2S03     "           H  + HS03    "           H  + S0~3          12~2
     Sulfur  dioxide  reacts  readily with all major  classes  of biomolecules.  Reactions of S02
 or  bisulfite with nucleic  acids, proteins,  lipids,  and other biological components have been
 repeatedly demonstrated j_n vitro.
 12.2.1.1  Chemical Reactions of  Bisulfite with Biological Molecules—There  are three important
 reactions of bisulfite with biological molecules:  sulfonation, autooxidation, and addition to
 cytosine.
     Sulfonation  (Gilbert,  1965) results from the  nucleophilic  attack of  bisulfite on disul-
 fides:
          RSSR1 + HS03           > RSS03  + R'SH                                  12-3

 This  reaction is also  known  as sulf itolysis.   The products  of  the reaction are S-sulfonates
 (RSSO-j  )  and  thiols (R'SH).   Direct evidence for the formation  of  plasma S-sulfonates  i_n  vivo
 has  been found  (Gunnison  and  Benton,  1971;  Gunnison and  Palmes,  1973).   Any plasma  protein
 containing  a  disulfide group  could react  to form  an  S-sulfonate.   Small  molecular weight
 disulfides,  such as  oxidized  glutathione,  can  also be  reactants.   Generally, analyses  of
 plasma  S-sulfonates have been  restricted to diffusable  (dialyzable or small molecular weight
 compounds)  and  nondiffusable  (nondialyzable or  protein)  S-sulfonates.  The exact molecular
 species  has not been determined, and the results of such determinations represent pools of the
 two  groups  of compounds.   S-sulfonates can react with  thiols,  either reduced glutathione  or
 protein  thiol  groups,  to form  sulfite  and  disulfide.   Since this  reverse  reaction  is  facile,
 S-sulfonates  are hypothesized  as  being transportable  forms  of  bisulfite  within  the  body.
 Sulfitolysis  represents a mechanism of toxicity,  a  means  of  detoxification  and  a means  of
 redistribution of a reactive molecule,  bisulfite.
XRD12A/A                                     12-3                                    2-5-81

-------
     Similar  reversible  nucleophilic  addition of  bisulfite  to  j variety  of  biologically
important  molecules has  been reported,  but the  toxicological  importance  of these  chemical
species  is  uncertain.   It  is not  likely,  for example, that the  reactions of bisulfite  with
pyridine nucleotides (NAD or NADP), reducing sugars, or thiamine are  important to  the  toxicity
of bisulfite or S0?.
     Autooxidation of bisulfite occurs through a multistep chain reaction  (Hayon et al., 1972;
Backstrom,  1927;  Fridovich and  Handler,  1958,  1960;  Asada and Kiso,  1973; Peiser and Yang,
1977; Yip and Hadley, 1966; Rotilio et al., 1970; Nakamura, 1970; Klebanoff, 1961;  Yang, 1967,
1970; McCord  and  Fridovich,  1969a,b).  These reactions may  be  important  because  they produce
hydroxyl  (-OH)  and  superoxide  (-0 ~) free  radicals  as well as  singlet oxygen (-02).  These
chemical  species  of oxygen are  highly  reactive and are also produced by ionizing  radiation.
Hydroxyl free radicals are theoretically responsible for the lethal effects  of ionizing radia-
tion.   Autooxidation of  bisulfite  could  lead  to  increased concentrations  of these  reactive
chemical  species  within  the  cell  and  could  hypothetically lead  to similar adverse  effects.
The  reactive  forms  of  oxygen can  also  initiate peroxidation of the lipid bilayer of cells.
Peroxidation  of cellular  lipids,  especially  plasma membrane lipids,  is thought to be highly
deleterious (Kaplan  et al., 1975).   No direct evidence has been presented  to support peroxida-
tion of  cellular  lipids as a mechanism of toxicity of S0?.
     Bisulfite  addition  to  cytosine results  in  the  formation of uracil.   The  reaction of
bisulfite  with nucleic  acids  is  as  follows   (Shapiro  and Weisgras,  1970;  Shapiro  et al.,
1970a,b; Hayatsu, 1976):
                             NH2
                                      HS°3    N^N        H2°
Alteration of cytosine in the genome has not been reported iji vivo.
     Of  these  three reactions,  sulfonation or  sulfitolysis,  is  clearly the most  important.
The  respiratory  effects  of S02  may  be  due  to this  reaction.   Because all  thiols in  the
respiratory tract will undergo  sulfonation, no  single  protein  or small  molecular weight com-
pound can  presently be  identified  as  the  target or  receptor   for  SO-  in  the toxic  lesion.
XRD12A/A                                     12-4                                    2-5-81

-------
*
12.2.1.2  Metabolism of Sulfur Dioxide
12.2.1.2.1  Integrated metabolism.  There are several studies of the metabolism of exogenously
supplied  S02,  sulfite,  or  bisulfite.   Quantitative  differences  exist  between  inhaled  and
ingested  S0? with  regard to the  rate  of clearance of the key intermediary in sulfite metabo-
lism, plasma S-sulfonates (Gunnison and  Palmes, 1973), but no qualitative differences exist in
the  metabolism of  inhaled SO,, and  injected  or  ingested bisulfite or sulfite.  The importance
of the  appearance  of plasma S-sulfonates lies  in  their potential ability to serve as a circu-
 lating  pool  of  sulfite molecules (Gunnison  and Palmes,  1973) as evidenced by the presence of
•\r        ot
  S  from   SO,  in  non-pulmonary tissues  such  as ovaries, for  example  (Frank  et al., 1967).
                                   3
Continuous  inhalation  of 26.2 mg/m  (10 ppm)  SO- resulted in the attainment of 38 ± 15 nmole
of  plasma S-sulfonates/ml  in  rabbits after  about 4 days  (Gunnison and  Palmes,  1973).   The
 clearance of plasma  S-sulfonates  generated by either  inhalation  of SO,, or ingestion of sulfite
 in  the  drinking  water was  exponential,  exhibiting only a single compartment in most rabbits.
 The  half-life  was  4.1 days for  S-sulfonates generated by inhalation vs.  1.3  days for those
 generated by ingestion (Gunnison and  Palmes, 1973).  The mechanism  for this quantitative dif-
 ference in  clearance rates  has  not  yet been  found.
      Inhaled S0? quickly  penetrates the  nasal mucosa  and airways as  shown by the  rapid appear-
 ance of 35S in the  venous blood of  dogs  inhaling  35SO,  (Yokoyama et  al., 1971).   A  significant
                       O t                                                        —
 fraction of the  blood    S  was  probably  in the form  of  plasma  S-sulfonates (RSS03).   Most of
 the inhaled S0?  is  presumed to  be detoxified by the  sulfite oxidase  pathway in the  liver, form-
 ing sulfate which  is excreted  in  the  urine.   The  dominance of this reaction has  been  supported
 by   studies  of sulfite oxidase  inhibition (Cohen, et al.  1972)  which are discussed below and
 by  the  appearance  of about 85  percent  of the inhaled    S02 as urinary sulfate  in dogs  (Yokoyama
 et  al., 1971).   Once oxidized by sulfite oxidase, most of the  inhaled    S derived from   S02
 appears  in  the  urine  as 35S-sulfate  (Yokoyama  et  al.,  1971).  A  small  fraction  (10 to  15
 percent) of the urinary 35S  was  in  the  form of sulfuric  acid esters and ethers (Yokoyama,
 et  al., 1971).   Sulfate  arising  from  the oxidation of sulfite  can  enter  the  sulfate pool and
 could  be incorporated into sulfate macromolecules including glycosaminoglycans  and  glycopro-
 teins.    These  macromolecules  are  actively  synthesized  by  the respiratory  mucosa and  could
 account for the presence of radiolabeled sulfur  in the respiratory  tract  following inhalation
 of   35SO? (Yokoyama  et al.,  1971).   Most of  the  nondialyzable    S detected by  Yokoyama et al.
 (1971)  was  bound to the  orglobulin fraction of  plasma.   The chemical  form of  the   S was not
 determined.  Yokoyama  et al. (1971) speculated  that the 35S  present  in the orglobulin fraction
 was in  the  form  of sulfonated carbohydrates.   The problem is  in need of further clarification.
 According to Gunnison and  Palmes (1973), plasma  S-sulfonated proteins may also have  contained
 the 35S.  They  have suggested  that the slow clearance  of  plasma  S-sulfonates  is an  important
 factor   in  determining  toxicity.  They  have  not reported,  however, intracellular  levels  of
 S-sulfonates or  sulfite.
 XRD12A/A                                     12-5                                   2-5-81

-------
12.2.1.2.2  Sulfite oxidase.  The biochemistry of sulfite oxidase will be discussed because of
its importance as a mechanism of detoxification of sulfite.  A very rare genetic deficiency of
sulfite  oxidase  occurs in  humans  (Mudd  et  al., 1967;  Irreverre et al.,  1967;  Shin et al.,
1977).  Dietary factors can, however, alter the enzymatic activity (Cohen et al., 1973).  Sul-
fite  oxidase  (EC  1.8.3.1)  is  a metallo-hemo  protein with molybdenum  and protoheme  as the
prosthetic groups (Cohen et al., 1972).   It exists in animals (Cohen et al., 1972,1974; Howell
and Fridovich,  1968;   Cohen  and Fridovich,  1971a,b;  Wattiaux-DeConinck and  Wattiaux,  1974),
bacteria  (Lyric  and  Suzuki, 1970),  and  plants (Tager  and  Rautanen, 1955;  Arrigoni, 1959;
Fromageot et al.,  1960).   In both plants  and  animals, the enzyme is located  in the mitochon-
dria.    Purified  sulfite oxidase  can utilize  either  cytochrome  c  or oxygen  as  the electron
acceptor  (Cohen  and Fridovich,  1971a).   When  coupled with cytochrome c  to the mitochondria!
respiratory chain,  sulfite  oxidase  reduces molecular oxygen to water (Equation 12-4), whereas
during oxygen reduction, the product formed is hydrogen peroxide  (Equation  12-5).
                         2 Cyt c (Fe3+)
                           Cyt c (Fe2+)      1/2 02
                                                                               12-4
                S0~2  +  H20  + 02  -»   S0~2+ H202                                   12-5
 Direct reduction of  molecular oxygen  by sulfite oxidase  is prevented  in the presence  of  ferric
 cytochrome c.    In intact  mitochondria, therefore,  sulfite oxidation  occurs through the  inter-
 action of sulfite oxidase with the respiratory chain of the mitochondria, producing  1 mole of
 ATP/mole of sulfite  oxidase.
      Sulfite oxidase  is presumed to  be necessary  for the detoxification  of sulfite.   In three
 reported cases in humans,  a  genetic defect  in  this  enzyme resulted  in severe  neurological  pro-
 blems  (Mudd  et al.,  1967;  Irreverre  et  al.,  1967; Shih et al.,  1977).   Cohen et al.  (1973)
 suggested that  sulfite oxidase is  the principal  mechanism for detoxifying bisulfite and SO-.
 This  is  supported by  a  study  which showed that dogs exposed  to  35SO_ (Yokoyama et al. , 1971)
                                          35
 excreted 80 to 90 percent  of the  inhaled    S as sulfate  in the urine.   Because sulfite oxidase
 requires molybdenum, Cohen et  al.  (1973)  were  able  to deplete  rats  of sulfite oxidase by feed-
 ing them  a  low molybdenum diet and treating them with 100 ppm of sodium  tungstate in drinking
 water.   Tungsten  competes with  molybdenum and essentially  abolishes the activity of sulfite
 oxidase  and  xanthine oxidase  (EC 1.2.3.2),  the  two   major  molybdo-proteins  of rat  liver.
 Similar decreases were observed  in the lung and other organs.  The LD50  for  interperitoneally
 injected  bisulfite  was  found  to  be  181 mg  NaHS03/kg   in the sulfite oxidase deficient rats
 compared to 473 mg/kg  in the nondeficient animals.
 XRD12A/A                                     12-6                                    2-5-81

-------
     The effect  of  inhaled  S02 on  lethality was  more complex  (Cohen  et al.,  1973).   High
levels were used in all  cases and two effects of inhaled S0? were observed.  At 1,546 or 2,424
mg/m  (590  or  925  ppm)  S02 or  less,  the  principal  effect  in  control  rats  was respiratory
insufficiency resulting in  death by asphyxiation.   At  6,157  mg/m3  (2,350 ppm) SOp or greater
(up to 1.3  x 10  mg/m ,  1,310,000 ppm),  the principal  effect appeared  to  be  mediated by the
central  nervous  system  (CNS)  resulting  in  seizures  and prostration  followed  by  death.   A
direct effect of bisulfite  on  the CNS has been suggested (Cohen et al.,  1973).  Mortality was
observed in both the control and tungsten-treated animals exposed to greater than 1,554 mg/m3
(593 ppm)  S02  for  4  hr.   Cohen et  al.   (1973)  suggest that the  shorter survival  times  and
greater mortality of the tungsten-treated rats are due to an inability to detoxify inhaled S02
to sulfate.
     Attempts  to  induce higher  levels of  sulfite oxidase through  pretreatment of  the  rats
with  S02/bisulfite  or phenobarbital  failed (Cohen et al.,  1973).   Since sulfite oxidase is a
mitochondrial enzyme with  a  long  half-life,  it  is not likely  that  phenobarbital  or chronic
exposure to  S02 would result in adaptation through induction of higher  levels of sulfite oxi-
dase.
12.2.1.3  Activation and Inhibition of Enzymes by Bisulfite—Both inhibition and activation of
specific enzymes  have been  reported.  This  may be due to formation  of  S-thiosulfates,  since
disulfide  bonds  often stabilize  the tertiary structure of proteins.  Sulfite ions activated
several  phosphatases including  ATP-ase (Marunouchi and Mori,  1967)  and  2,3-diphosphoglyceric
acid  phosphatase (Harkness  and  Roth, 1969).  The  mechanism  by which activation occurs is not
known.   Inhibition  of   several  enzymes  has  been  reported;  these  include  aryl  sulfatase
(Harkness  and   Roth,  1969), choline  sulfatase (Takebe, 1961),  rhodanase (Lyric  and Suzuki,
1970),  and  hydroxyl  amine  reductase (Zucker and Nason,  1955).   Malic dehydrogenase was inhi-
bited  by micromolar concentrations  of bisulfite  (Ki  = 5 uM)  (Wilson,  1968;  Ziegler, 1974).
Other  dehydrogenases (Oshino  and Chance,  1975)  and flavoprotein  oxidases are  inhibited by
bisulfite.
      Bisulfite  effectively   inhibits  a number  of  other enzymes including potato  and rabbit
muscle  phosphorylase (Kamogawa  and  Fukui,  1973).   Bisulfite  inhibition was  competitive with
respect  to  glucose-1-phosphate  and inorganic phosphate, suggesting that the bisulfite inhibi-
tion  was caused by competition of bisulfite with the phosphate  binding  site of phosphorylase.
Several  important   coenzymes  (such as  pyrodoxylphosphate,  NAD  , NADP  , FMN,  FAD,  and folic
acid) may react with sulfite to  form addition products as discussed above.  As a  result, these
coenzymes  could  theoretically  aid in  inhibition  of a wide variety  of  critical  enzymic reac-
tions.   Pyridine  coenzyme-bisulfite  adduct  (Tuazon  and  Johnson,  1977)  and  flavoenzyme-
bisulfite adduct (Muller and Massey, 1969; Massey  et  al.,  1969) have been studied  in detail;
these adducts have been shown to be biologically inactive.
     Despite all of the  data obtained using  i_n  vitro  systems on the inhibition  of  enzymes by
bisulfite/SO?,   no  inhibition or activation has  been  determined  iji vivo with  S02 exposure.

XRD12A/A                                     12-7                                    2-5-81

-------
Such inhibition may  occur,  but there has been no concerted effort to search  for  inhibition of
specific enzymes during SO- exposure.
12.2.2  Mortality
     The  acute  lethal effects  of S02  have  been examined mostly  in  the older literature  and
have been  reviewed  in the previous Air  Quality  Criteria Document for Sulfur Oxides  (National
Air  Pollution Control  Administration,  1970).  In early  studies,  a number of different  animal
species  was examined  for  susceptibility  to  SO-.   These  data  show that mortality was  not
                                   o             ^
observed  at exposures  of 65.5 mg/m  (25 ppm)  for up to 45  days  in either rats  or mice; this
conclusion  has been confirmed by subsequent studies (Laskin et al., 1970).  Mortality could be
associated  with long-term exposure to S02 at 134 mg/m  (51 ppm) or higher.  The clinical signs
of SO- intoxication appear to vary with the dose rate (Cohen et al., 1973).   At concentrations
below  approximately  1,310 mg/m3 (500 ppm),  mortality  is associated with  respiratory insuffi-
ciency;  above this  concentration, mortality is  ascribed to  central  nervous  disturbances pro-
ducing  seizures  and  paralysis of the extremities.  These  clinical signs  depend  upon the pre-
sence  and activity  of sulfite oxidase as discussed in Section 12.2.1.2.2.  Injections of his-
tamine or  adrenalectomy can increase the lethality of SO- (Leong et al., 1961).
     Matsumura  (1970a,b) examined  the  effect of  a  30-min exposure to  several  air pollut-
ants on  mortality consequent to the anaphylactic response of guinea pigs  to  protein  antigens.
Sensitization to  the  antigen  administered  by  aerosol  was augmented  by  pretreatment  with  786
mg/m   (300  ppm) SO-, but  not with 472 mg/m   (180 ppm).
     On  the basis of mortality due to acute exposure, SO,, is far  less toxic  than ozone  and is
similar  in toxicity  to  nitrogen dioxide.   Concentrations required  to  produce mortality from
S02  are  far in  excess of those  which  occur in the atmosphere  due to pollution  (Table  12-1).
12.2.3   Morphological Alterations
     Because of  the  high solubility of  SO,,  in water,  morphological and physiological effects
occur mostly in the upper airways.  However, changes have also been detected  in the  lower air-
ways  (Table 12-2).   At relatively high  concentrations  of >26.2 mg/m3 (10 ppm)  (used in most
studies  designed  to  detect morphological alterations),  most of the inhaled  SO-  is removed by
the  nasopharyngeal  cavity.   (See Chapter 11, Section 11.2.4 for an expanded  discussion  of  S02
absorption.)  In  rabbits,  the concentration of inspired SO- determines  how much  is removed in
the  nasopharyngeal   cavity  as  opposed  to  the  bronchial  and  alveolar  regions  of  the lung
(Strandberg, 1964).   At high S02 concentrations, greater  than 26.2 mg/m3 (10 ppm),   90 to 95
percent  is  removed  in the nasopharyngeal cavity.  A small part, 3 to 5  percent,  is  removed by
the  bronchiolar-alveolar  region.    So   in  this  concentration  range,   most  of  the dose  is
delivered  to the  nasal  turbinates with  only a small  percentage going to  the lung parenchyma.
At lower  concentrations  of  inspired S02, [such  as  0.13 mg/m3  (0.05  ppm)] which  are  closer to
ambient  levels,  only 40  percent of the dose  is delivered  to  the nasopharyngeal cavity  upon
inspiration, while  another 40  percent  is   removed  by the respiratory  tract  upon expiration.
XRD12A/A                                     12-8                                    2-5-81

-------
TABLE 12-1.   LETHAL EFFECTS OF SO,
SO, Concentration
3
mg/m ppm Duration
26.2
134
275
(See Text)

1,598
2,392
3,086 1,
5,175 1,
9,165 3,
13,236 5,
5,782 2,
6,571 2,
7,205 2,
786
10
51
105


610
913
178
975
498
052
207
508
750
300
6 hr/day x 5 day/wk
x 113 day
113 days
22 day
5 min/day x 5 day/wk
> x lifetime
LT5Q 285.6 min
74.5 min
38.7 min
LT5Q 197.6 min
71.7
41.0
LT5Q 68.2 min
28.7
35.5
30 min
Species Remarks
Rat No mortality in excess of control
No mortality in excess of control
64% mortality (treated-control)
Mice No increased mortality; tumor formation
found
Mice IP injection of 200 to 300 mg histamine/mouse
(Connaught Med. increased toxicity
Res. Lab. Strain)

Rat (Sprague- IP injection of 200 to 300 mg histamine/rat
Dawley) or adrenal ectomy increased toxicity


Guinea Pig

Guinea Pig Increased mortality
Reference
Las kin et al. ,
1970


Peacock and Spence,
1967
Leong et al.
1961

Leong et al.
1961


Leong et al.
1961

Matsumura, 1970a,b,
             due to anaphylaxis
             from antigen challenge
             to sensitized animals

-------
 SOX12C/A   1 2-5-81
                                           TABLE 12-2.  EFFECTS OF SULFUR DIOXIDE ON LUNG MORPHOLOGY
       Concentration
                                      Duration
                                                           Species
                                                                                            Results
                                                                                                                                Reference
0.34. 2.65, or  15.0 mg/m3
 (0.13, 1.01. or 5.72 ppm)
 S02
0.37, 1.7 or 3.35 mg/m3 (0.14.
 0.64 or 1.28 ppm)

12.3 mg/m3 (4.69 ppm) then
 between 524 and 2620 mg/m3
 (200-1000 ppm) then 0 mg/m3
13.4 mg/m3 (5.12 ppm)


13.4 mg/m3 (5.1 ppm)

26.2 mg/m3 (10 ppm)
91.7 mg/m3 (35 ppm) [rose on
occasion to 262 mg/m3(100 ppm)]

1048 mg/m3 (400 ppm)
1048 mg/m3 (400 ppm) S02
1 yr, continuous
78 wk, continuous

30 wk then 1 hr then
 48 wk
18 mo, continuous


21 hr/day, 620 days
72 hr, continuous
1 to 6 wk


3 hr/day, 5 day/wk,
 6 wk
3 hr/day, 5 day/wk,
 3 wk
Guinea pig
Cynomolgus
 monkey
Cynomolgus
 monkey
Cynomolgus
 monkey

Dog

House
Pig

Rat





Rat
Lungs of 15.0 mg/m3 (5.72 ppm)  group,  killed  after
 13 or 52 wk of exposure, showed less  spontaneous
 pulmonary disease than controls.   Controls and 0.34
 and 2.64 mg/m3 (0.13 and 1.01  ppm) animals had
 evidence of lung disease.   Tracheitis present in
 all but 15.0 mg/m3 (5.72 ppm)  group.   Survival
 greater in the latter group
No remarkable morphologic alterations  in the  lung

Persistent changes in lung morphomology including:
 alterations in the respiratory bronchioles,
 alveolar ducts, and alveolar sacs; proteinaceous
 material within the alveoli; thicker  alveolar
 walls infiltrated with histocytes and leucocytes;
 moderate hyperplasia of the epithelium of the
 respiratory bronchioles; bronchiectasis and
 bronchiolectasis; vacuolation  of hepatocytes

No alterations in lung morphology


No alterations in lung morphology
Pathological changes in the nasal mucosa appeared
 after 24 hr of exposure and increased in severity
 after 72 hr.  Mice free of upper respiratory patho-
 gens were significantly less affected than the con-
 ventionally raised animals.  Morphological  altera-
 tions were qualitatively identical in both groups.

Loss of cilia in nasal cavity,  disappearance  of
 goblet cells, metaplasia of the epithelium

Tracheal goblet cells increased in number and size.
 Incorporation of 3SSO.   into mucus increased.
 Sialidase resistant mucus secreting cells were
 found much more distally.  Chemical composition
 of mucus altered
                                                                  Alarie  et  al.,  1970
                  Alarie et al.,  1972,  1973c


                  Alarie et al.,  1972.  1973c
Increased mitosis of goblet cells.
 not lost by 5 wk post-exposure
Alteration
                  Alarie et al.,  1975
                  Lewis et al.,  1973
                  Giddens and Fairchild,
                  1972
                  Martin and Willoughby,
                  1971

                  Reid, 1970
Lamb and Reid, 1968

-------
Thus, at lower concentrations,, the actual percentage of S02 removed in specific regions of the
respiratory tract  is not  known  precisely.   In  the dog,  over 95 percent  was  removed by the
upper airways and  nose  at concentrations between 2.62 and 131 mg/m3 (1 and 50 ppm) S0? (Frank
et al., 1967,  1969).   A more detailed  consideration  of S02 extraction by airways is given in
Section 12.2.4 below.
     Giddens  and  Fairchild  (1972)  pointed out that these differences  in  removal  of inspired
S02 could explain the apparent anomaly of  little damage to the lower respiratory tract at high
S02  concentrations.   They undertook a study of the effects of inhaled S02 on the nasal mucosa
of mice.  Two groups of mice were used; one group that was free of specific upper respiratory
pathogens,  and  an ordinary  laboratory group  that  was presumed  to  be infected or  to have a
latent infection of upper respiratory pathogens.  Mice were exposed continuously to 26.2 mg/m
(10  ppm)  S02  for a maximum  of 72 hr.  Pathological changes in the nasal mucosa appeared after
24  hr of exposure  and increased  in severity after  72 hr of exposure.   Mice  free of upper
respiratory pathogens  had fewer  pathological  findings than the conventionally raised animals.
Giddens  and Fairchild  (1972)  concluded that  resident or acquired  pathogens  exacerbated the
morphological  changes they  nad  observed.   Morphological  alterations  were, however, qualita-
tively  identical  in  both groups of  animals.   Cilia were lost from the nasal mucosa; vacuoli-
zation  appeared;  the mucosa decreased to  about  one half the normal  thickness,  and a watery
fluid  accumulated.   Desquamation of the respiratory and  the  olfactory epithelia was evident.
Alveolar  capillaries were slightly  congested, but edema and  inflammatory  cells were absent.
Martin  and  Willoughby (1971) reported loss of cilia, disappearance of goblet cells, and meta-
plasia  of the epithelium of the nasal cavity  of pigs exposed  to 91.7 mg/m  (35 ppm) S02 for  1
to  6 wk.   This study,  however, was  marred by  difficulties with the control of the SCL, rising
                        3
on  occasion to 262 mg/m  (100 ppm), and with  high  relative humidity occurring during cleaning
of the pig  pens.
      Lamb and Reid  (1968)  and  Reid (1970)  attempted  to  use S02-exposed  rats  in a model of
human  chronic  bronchitis.    They presented  favorable  arguments  that  S0?-induced  bronchial
hyperplasia is analogous  to  human chronic  bronchitis.  Most of their studies have  been carried
out  at high concentrations  of S02  (1,048  mg/m or  400 ppm S02 for 3 hr/day, 5 days/wk) for up
to  6 wk.   Under  these conditions,  the tracheal glands  clearly increased.   The  goblet cell
density  also  increased  in  the  proximal  airways,  main  bronchi,  trachea,  and distal  airways,
with proximal airways  and   main  bronchi  showing the  largest changes.  The  incorporation of
  S-sulfate by goblet  cells into mucus  also increased with  exposure,  reaching a plateau at
approximately  3  wk.   The effects of S02  were concentrated in the central  airways,  again sug-
gesting that  the solubility  of S0?  in water  limits  its accessibility to the periphery.  Mitosis
reached  a maximum  after 2 or 3  exposures  and  declined rapidly as injured cells were replaced.
On repeated exposure  for  periods up  to 6 wk, mitosis remained  elevated  in the proximal airways
compared  to the  distal  airway in which  the mitotic index returned to  the  control level.   The
magnitude  was proportional  to  the  S0?  concentration  up to 524 mg/m   (200 ppm) S02> but  was

XRD12A/A                                     12-11                                        2-5-81

-------
less at 786 mg/m3 (300 ppm).  An elevation of the mitotic index occurred at S02  concentrations
as  low  as  131 mg/m3 (50 ppm) when given for 3 hr/day, 5 days/wk.  Major changes  in  the  goblet
cell type  or  substance produced by  the  goblet  cells were also  detected.   Goblet cells which
produced mucus  resistant  to digestion by sialidase  increased in numbers, and their distribu-
tion extended  distally from the upper bronchioles towards the respiratory bronchioles.  Since
each molecular type of mucin,  sialidase resistant  or susceptible,  could  be produced by one
type of goblet cell, or each goblet cell could produce a different mucin, these  results  can be
interpreted in  two  ways.   The elaboration of a  specific  type of goblet  cell could  occur, or
more goblet cells  could be produced  but with a change in their biochemical  function towards
sialidase  resistant mucins.  These  studies  present an interesting  means  of studying experi-
mental  bronchitis,  but do not provide evidence that ambient  SO- levels cause similar changes.
     Alarie et al.   (1970)  examined the tissues of guinea pigs exposed continuously to 0, 0.34,
2.65, or 15.0  mg/m3 (0, 0.13, 1.01,  or  5.72 ppm) SO, for 1 yr.  The lungs of the guinea pigs
                     3
exposed to 15.0 mg/m  (5.72 ppm) and killed after 13 or 52 wk of exposure showed  less sponta-
neous pulmonary disease than the control group.   The prevalence of pulmonary  disease in the
control groups  which was  not observed prior to exposure suggests that they acquired pulmonary
disease during  the  exposure period.   These  (Alarie  et  al.,  1970) and other  studies by Alarie
and  co-workers  (1972,  1973c,  1975),  were limited to light microscopic observations  of conven-
tional  hematoxylin-eosin stained paraffin sections.  The results are of limited  value compared
to  more recent approaches using  scanning  electron  microscopy of  surfaces  and transmission
electron  microscopy of organelles.   The  control  group,  as  well as  those  exposed to 0.34 and
2.64 mg/m  (0.13 and 1.01 ppm) S0?,  had  evidence of  lung disease as  shown by  histocytic  infiltra-
tion of the alveolar walls.  Tracheitis  was also present in the above three groups,  but  not in
the 15.0 mg/m   (5.72 ppm) group.  Hepatocyte vacuolation was  observed in the  latter  group, but
the pathological  significance of  this change needs  further  investigation.   The survival was
greater (p <0.05)   in  the 15.0 mg/m   (5.72  ppm)  group than in  the  other groups  including the
air-exposed  control group.   The authors do  not address the significance of  the  hepatocyte
vacuolation.   The  possible effects  of  S02  in  this  study  cannot   be  accurately  determined
because of the disease in the control animals.
     Subsequently  these researchers  (Alarie  et al., 1972, 1973c)  exposed cynomolgus monkeys
continuously  to 0.37,  1.7 or 3.35 mg/m   (0.14,  0.64 or 1.28 ppm)  SO-  for 78 wk  but found no
remarkable morphological  alterations.   Another  group exposed to 12.3 mg/m3 (4.69  ppm) S02 for
30  wk was accidentally exposed to  concentrations  of SO- not  higher than 2,620 mg/m3  (1,000
                            3
                                                         2
 ppm)  or lower than 524 mg/m   (200  ppm)  for 1 hr, after which  they were  placed in a clean  air
 chamber and  held  for 48 more wk.  Persistent changes were noted in this group.   Alterations in
 the  respiratory  bronchioles,  alveolar  ducts,  and  alveolar sacs were  found.   Proteinaceous
 material  was found within the  alveoli.   The  distribution of such  lesions was  focal,  but  was
 observed  within  all   lobes  of  the  lung.   Alveoli  containing proteinaceous material were
 generally those which arose directly from  respiratory  bronchioles.  Alveolar walls were

 XRD12A/A                                     12-12                                        2-5-81

-------
thicker and were  infiltrated with histocytes and leukocytes.  Macrophages were present within
these foci.  Moderate  hyperplasia of the epithelia  of  the respiratory bronchioles was found,
and  frequently  the  lumina  of  the  respiratory bronchioles  were plugged  with proteinaceous
material, macrophages, and leukocytes.   Bronchiectasis and bronchiolectasis were present in 8
of 9  monkeys.   Vacuolation  of  hepatocytes  was also observed,  as with  the  guinea pig group
exposed to 15.0 mg/m  (5.72 ppm) SCL in the prior study (Alarie et al., 1970).
                                                                                  3
     In a  replication  of this study, cynomolgus monkeys were exposed to 13.4 mg/m  (5.12 ppm)
S02  continuously  for 18  mo.  (Alarie et  al., 1975).  No  alterations  in  lung morphology were
reported to be due to S02>  The morphological alterations  reported in the control group includ-
ed lung mite infections and associated "slight  subacute bronchiolitis, alveolitis, and bronchi-
tis."  Pulmonary function  measurements were made in  the above mentioned studies (Alarie et al.,
1970, 1972, 1973c, 1975) and are described in Section 12.2.4.
     The absence  of  S02-induced morphological  alterations as reported by Alarie et al. (1970,
1972, 1973c, 1975)  and Lewis et  al.  (1973)  who exposed dogs for 620 days (21 hr/day) to 13.4
mg/m  (5.1 ppm) S02 is not in conflict with the bronchoconstriction induced by acute S02 expo-
sure  reported  by Amdur  and co-workers  (1973)  at lower  concentrations  (see  Section 12.2.4).
Alarie et al.  (1970) pointed out, "As recent  literature attests, there is also an obvious lack
of knowledge about the correlation between subtle microscopic alterations in the lung and con-
comitant  changes  in this  physiological  parameter  (lung  function)."  Further,  the transient
nature of  the  pulmonary function effects observed during  short-term exposures would be diffi-
cult  to  detect  morphologically  unless the lungs were fixed during the time of exposure.  Even
then,  if the  cause of the increased pulmonary resistance were a  subtle  alteration of smooth
muscle tone as has been hypothesized, it might  be morphologically undetectable.
     Most  of the  studies  in which the  lungs of S0?-exposed animals have been examined center
around tracheitis,  bronchitis,  ulceration,  and mucosal hyperplasia  (Table  12-2).   The lowest
concentrations of  SO,  at which these alterations  have  been reported have been  in  the rat at
                "\                                                                         3
131  to 134 mg/m  (50 to 51 ppm)  for 30 to 113  days.  At higher concentrations (1,048 mg/m  or
400  ppm  S02 for  3  hr/day, 5 days/wk for  3  wk),  recovery to normal  morphology did not occur
after 5  wk post-exposure.   The possibility  of  recovery from lower concentrations and shorter
durations of exposure is not known (Lamb and  Reid, 1968; Reid, 1970).  Discounting their first
study (Alarie, et al., 1970) where the control  group of guinea pigs had a higher level of pul-
monary infection  than  the exposed groups, Alarie  et al.   (1973c)  reported  no effect from S02
exposure  up to 5 ppm.   These  observations were,  however,  restricted  to  light microscopy and
did  not  include  scanning  or transmission electron  microscopic  observations.   This group also
reported  no observable  effects  at 0.37,  1.7 or 3.35  mg/m3 (0.14,  0.64,  and  1.28  ppm) S0?
                                                                    o                         '-
(Alarie  et al.,  1975).   The group of monkeys  exposed  to 12.3 mg/m   (4.69 ppm) must also be
disregarded due  to  the accidental exposure  to  high  levels of SO.-  (Alarie  et al.,  1975).  No
effects  were  reported for monkeys exposed  to  13.5  or  13.7 mg/m  (5.15  or  5.23 ppm) S0? and
                                   33
sulfuric acid aerosols at  0.10 mg/m  or fly  ash at 0.44 mg/m  (Alarie et  al.,  1975).

XRD12A/A                                      12-13                                       2-5-81

-------
12.2.4  Alterations in Pulmonary Function
     Changes in breathing mechanics have been among the most sensitive parameters  of  S02  toxi-
city.  They have likewise been useful in studying the effects of aerosols alone  or in combina-
tion with  S02  (Sections  12.3.3.1 and 12.4.1.1).  A variety of methods have been used,  some of
which have  been  applied  to human exposures.  A method for measuring  increases in  flow resist-
ance due  to bronchoconstriction in guinea  pigs  has been developed by  Amdur  (Amdur  and  Mead,
1955,  1958).   Animals  are  not  anesthetized  and  breathe  spontaneously,  allowing  sensitive
measurements of pulmonary  function.   Another method by Alarie and co-workers (1973d) measures
changes in  respiratory  rate.   S0? also initiates bronchoconstriction in man, and  is  also more
closely related to human health effects.
     Several investigators  (Nadel et al. 1965a;  Corn et al., 1972;  Frank and  Speizer,  1965;
Balchum et  al.,  1960;  Nadel et al.,  1965b) found that bronchoconstriction resulted  from both
head-only  and  lung-only exposures  in cats  and  dogs.  When  corrected for  the  amount of SCL
hypothesized to  reach  the  lung, Amdur's study  (1966)  with guinea pigs has  shown  that S02 is
highly  effective  in producing  bronchoconstriction through direct exposure  of  the lung.   Two
sets of  receptors  are  involved in the  response  of animals to SCL.   At high concentrations of
S0?  or following  long  durations  of  exposure, the  nasopharyngeal  receptors  fatigue  or become
unresponsive, whereas the bronchial receptors do not.  Widdicombe (1954a) originally  described
the  receptors  responsible  for the S02-initiated bronchoconstriction.  The bronchoconstriction
is  initiated through the activation of a bronchial  epithelial chemoreceptor whose  efferent and
afferent  pathways  are through the vagus nerves (Nadel et al., 1965a,b; Grunstein et al.,  1977;
Tomori  and Widdicombe, 1969).  Chilling the  vagus prevents conduction of nervous impulses pro-
duced  on inhalation of SO,,.  Other  receptors  located in the same regions of the  lung respond
to  mechanical  stimulation  and  particles  such as talc (Widdicombe,  1954b;  Widdicombe et al.,
1962).    Intravenous injection  of atropine blocks the  efferent impulses, presumably at the
cholinergic preganglionic synapse (Grunstein et al., 1977).  Sulfur dioxide-initiated broncho-
constriction  involves  smooth muscle  contraction since p-adrenergic  agonists,  such as  isopro-
terenol,   reverse  the  SOp-bronchoconstriction  (Nadel  et  al.,  1965a,b).   Histamine  may be
 involved  in this response as  implied by other studies of hyperreactive airways (Boushey,  et al.
1980),  but no definitive proof of histamine  involvement is available.  Release of  acetylcholine
could  also cause increased mucus secretion  as noted during S0?  exposure.  Chronic exposure to
S02  could lead  to mucus hypersecretion and altered airway caliber.   Cholinomimetic  drugs and
histamine applied  as aerosols mimic the S02-initiated bronchoconstriction  (Islam et al.,  1972).
Cholinomimetic  drugs  act through  either the  same autonomic reflex  arc  or directly upon the
cholinergic receptors on smooth muscles and  mucus secreting cells and glands.  As  discussed in
Chapter 13, S02 also produces bronchoconstriction  in man through the  same  autonomic reflex arc.
XRD12A/A                                     12-14                                        2-5-81

-------
*
     Exposure to S02 evokes  an increased resistance  to  air flow in guinea  pigs  which can be
repeated by  several  exposures over a period  of hours and  exhibits  none  of  the tachyphylaxis
found with  other species  (Corn  et al.,  1972; Frank and  Speizer,  1965).   However, different
techniques  were  used  for  these different  species.  Amdur  (1973),  in  a  review of  her data,
reported that  for  a 1-hr  exposure, a  mean of  0.68 mg/m  or 0.26 ppm  (range  of  0.08  to 1.57
mg/m  or 0.03  to 0.6 ppm) was the  lowest concentration of SOp that increased flow resistance
in guinea pigs.  The  response, a 12.8 percent increase  (p < .001)  at these (Amdur, 1973) low
levels of S02, was  the average of 71 guinea pigs; the individual data points were reported in
other publications (Amdur  and Underhill, 1968, 1970; Amdur,  1974).   For a 1 hr exposure, the
lowest concentration these researchers tested which caused an increase (p <0.01) in resistance
was  0.42 mg/m   (0.16 ppm) SO, (Amdur and Underhill,  1970).  In a more recent study, Amdur et
                             '                                    o
al.  (1978) showed that a 1 hr exposure of guinea pigs to 0.84 mg/m  (0.32 ppm) S0? caused a 12
percent increase in resistance (p <0.02) and a  non-statistically  significant decrease in com-
pliance.  Investigations of the interaction of  oil mists and SOp showed that 2.62 mg/m  (1 ppm)
S09,  the  lowest concentration  used,  significantly  increased  resistance  (Costa  and Amdur,
                                                       3
1979a,b).    At  concentrations  of  SOp  below  2.62  mg/m   (1  ppm),  the  response  of individual
animals varied considerably (Amdur, 1964, 1973, 1974).  Of 1,028 guinea pigs, 135 were "suscep-
tible", responding  to low concentrations  of  S02  with greater changes  in  resistance than the
predicted mean.  Amdur cites comparative data for other  species, including man, to suggest that
a  certain fraction of all  subjects may exhibit  this phenomenon (Amdur, 1973, 1974; Horvath and
Folinsbee,  1977).  On  the other hand, Amdur  et al.  (1978) also point out that some groups of
animals may by  chance  not have a "susceptible"   individual.   In this study,  3  groups of 10
                                                                               o
animals each or  a  total of 30  guinea  pigs exposed to 0.52,  1.05,  or 2.1 mg/m  (0.2, 0.4, or
0.8  ppm) S02 had no significant increase  in airway resistance above the control values.  Based
on data from earlier work (Amdur  and Underhill,  1968),  Amdur concluded that 10 to 13 percent
of the guinea  pig population  is  more  responsive  than the  average (Amdur,  1974).   In cats
 (Corn  et  al.,  1972)  and dogs  (Frank and Speizer,  1965), on the other  hand, few were  found to
                                                            3                                 3
be sensitive to  short-term (< 1 hr) exposure to  52.4 mg/m  (20 ppm) S02 (cats) or 18.3 mg/m
 (7 ppm)  SOp (dogs).   Even with the  relatively small  sample sizes  used,  some  cats and dogs
 responded and others did not.
     Some M the problem  of "susceptible" vs. "non-susceptible"  members  of the  experimental
population  can  be  understood  by considering  a simple  hypothesis.   If one  assumes that the
 response to  a given toxicant, such as SOp, is the result of a number of different  genes within
the  population  and  not  just a single gene,  then  a single  individual  could have a number of
recessive or dominant genes  which could  contribute  to  either  the "susceptibility" or "non-
susceptibility"  of that  individual.   Since experimental  animals  and human  subjects are drawn
on as  random a basis as is  possible  (in most  experimental  designs),  there will  be a maximum
chance  of  getting  some  "susceptible"   responders  in each  experiment.  The  total  number of
"susceptible"  responders  will  be  small  and variable   because  of  the  low  incidence  of
"susceptible" responders  in  the general  animal population.   A  small,  but variable, number of
XRD12A/A                                      12-15                                       2-5-81

-------
"susceptible" responders will  tend to shift the  dose-  or concentration-response  curve  toward
lower concentrations and to decrease the slope of the curve (e.g., when the data are  expressed
as the log-probit transformation).  Such phenomena have been studied in detail  for "resistant"
insects which have  different  genomes responsible for increased detoxification  mechanisms.  In
the case  of  SO-,  the matter  is  further  complicated by comparisons  between  groups of animals
and between  different  strains or species.   Even with guinea pigs, the total number of animals
examined  to  date  (about 1,000  to 2,000) is too  small  to give more than  a  crude  estimate of
those animals  having a "sensitive"  genome.   The incidence of  "susceptibility" in the  guinea
pigs (about 13 percent) is too low to have been detected clearly in the 100 or  so  cats and dogs
used in S0?  experiments.   Here only 1 or  2  "susceptible" animals would have been encountered
in each experiment.   Further,  the small number of animals has been studied in different  labora-
tories and at different times, and the animals have come from different genetic stocks.  It is
fortuitous that  Amdur's laboratory has  persisted in  these studies with  the  same  animal,  the
guinea pig, using the same general methodology so this  low incidence of "susceptibility" could
be detected.  While the mechanism(s) responsible for "susceptibility" is not known,  the ques-
tion of "susceptibility"  is  an important aspect deserving further study.  A similar  incidence
of  some  10  percent "susceptible" individuals  in man  would  present a  major  health problem.
                                                                                              3
Adverse reactions might occur among "susceptible" individuals at exposures less than  2.62 mg/m
(1 ppm) (Amdur, 1964,  1973,  1974).  These concentrations  of  less  than 2.62 mg/m   (1 ppm) are
encountered  in  ambient air.   Neither the  frequency  of susceptibility to  S0?  in  man, nor the
physiological or biochemical basis, is known.
     A  broad dose-response curve has been noted also for histamine initiated bronchoconstric-
tion  in man  (Habib  et al., 1979),  guinea pigs (Douglas  et al., 1973, 1977; Brink et al., 1980),
dogs  (Loring et al., 1978; Snapper et al., 1978), and monkeys (Michoud, 1978).  Among 12 normal
human  subjects  a 38-fold  range  of  inhaled  histamine  in both the  threshold  and  median doses
causing bronchoconstriction was observed (Habib et al., 1979).  The dose required  to  produce a
50  percent change  in dynamic  lung compliance in 131 female guinea pigs varied  over a 100-fold
range  of  concentrations (Douglas  et al., 1973).  While  the interindividual dose varied consid-
erably,  the values  were  log  normally distributed indicating a  single population  (Douglas et
al.,  1973,  1977).  Dogs showed  a 40-fold  variation in the histamine  dose needed  to initiate
changes  in airway diameter (Snapper et  al.,  1978).   These values were also log  normally dis-
tributed  indicating a  single  population amongst  the 102 mongrel dogs examined.   A wide  inter-
individual  variation for  histamine  and  methacholine  initiated bronchoconstriction  was found
amongst  8 rhesus monkeys,  some  of  which  were  sensitive  to  Ascaris  suum allergen  (Michoud,
1978).  No differences  in  sensitivity to histamine or methacholine could be found  with Ascaris
sensitivity,  however.   While  genetic differences in  histamine  sensitivity have been found in
quinea pigs, naturally  occurring  or acquired allergic reactions are, thus, not  likely to cause
the  large interindividual differences  in  sensitivity  in either  guinea pigs  (Takino et  al.,
1971)  or  monkeys  (Michoud et al., 1978).  A further complicating  factor  is the age-dependence

XRD12A/A                                     12-16                                        2-5-81

-------
of histamine and other drug initiated bronchoconstriction (Brink et al., 1980).  Younger guinea
pigs were  more  sensitive to histamine  than were older animals,  for  example.   The decreasing
bronchial  reactivity to  histamine  with age in the guinea pig has been suggested as a model of
human juvenile asthma.   However, human bronchial hyperreactivity does not seem to decrease with
age in the same manner (Boushey et al., 1980).  While large interindividual differences appar-
ently occur  with  a wide variety of  chemical  agents causing bronchial  reactivity  in  both man
and animals, the  response  of the same individual is quite reproducible regardless of species.
The  variability in  the threshold  dose of  SO^ needed to  evoke a  given  bronchoconstriction
(measured for example as an increased resistance to flow by the studies of Amdur) is apparently
an inherent part of the bronchial response to a broad range of chemicals and is not an artifact
of the method.   Similar variations in threshold doses for S0? are likely to occur in man, judg-
ing from the variability to inhaled histamine.  The general observation that asthmatic patients
are hypersensitive to a broad range of chemical and physical agents initiating bronchoconstric-
tion (Boushey et  al.,  1980) supports the  contention  that the most susceptible animal species
should be  used  as  a surrogate  for man.   A major difference in pharmacology may exist between
the guinea  pig  and man.   Autonomic mediators  interact  with histamine in bronchial reactivity
in guinea  pigs  but not in man.  Beta  adrenergic blockade by propranolol causes no difference
in  bronchial  reactivity in man  (Habib  et al., 1979) but potentiates  histamine  reactivity in
the guinea pig (Douglas et al., 1973).   Insufficient numbers of animals and subjects have been
examined to predict the general shape of the dose-response curve for the human population, even
excluding  the  hypersensitive asthmatic population.  These  variations  in interindividual dose
needed to  evoke a specific amount of increased resistance to flow in guinea pigs by SO- like-
wise apply  to  the measurement of increased resistance to flow evoked by aerosols as discussed
below in Section 12.3.3.
     Using  Strandberg's  (1964) data from  the rabbit to correct  for  the concentration of SO™
hypothesized to  reach  the  lung, Amdur (1966) was able to normalize the concentration-response
curve for S09-induced bronchoconstriction  in the guinea pig resulting from nose-only exposures.
                                                                       3
A  break occurs  in the concentration-response  curve  at  about 52.4 mg/m  (20 ppm) S0?, perhaps
due to the  poorer extraction of gaseous S0? by the upper airways at low concentrations.  How-
ever, it should be recognized that S0? extraction data for rabbits (Strandberg, 1964) and dogs
(Frank et  al.,  1967;  Balchum et al.,  1960;  Frank et al., 1969) are in some conflict and that
the data  for rabbits  are not clear with respect to the site of S02 removal.  Thus, use of the
rabbit data for guinea pig studies can be  done only hypothetically.  Sulfur dioxide introduced
directly  into  the  lung by a tracheal  cannula was much more  effective  in producing bronchial
constriction.  Amdur (1966)  suggests  that at concentrations of 1.05 to 1.31 mg/m  (0.4 to 0.5
ppm) very  little  removal  of S0? occurs  in the upper airways.   These  data contrast with the
radiotracer  studies  in dogs  (Frank  et al.,  1967, 1969;  Balchum  et  al.,  1960).   Others have
required concentrations  greater than  18.3 mg/m  (7 ppm) to evoke  increases in flow resistance
in anesthetized cats  (Corn et al., 1972)  and dogs (Frank and Speizer,  1965).  Differences in

XRD12A/A                                     12-17                                       2-5-81

-------
the sensitivity of  the  two models may  lie  in the use of  anesthesia,  in the  use  of  different
species, or in a different incidence of "susceptible" individuals.
     Using anesthetized,  intubated,  spontaneously breathing dogs exposed to 2.62,  5.24,  13.1,
or  26.2  mg/m3 (1,  2,  5,  or  10 ppm)  S02  for  1  hr, Islam  et al.  (1972)  found an  increased
bronchial  reactivity  to  aerosols  of  acetylcholine,   a  potent  bronchoconstrictive agent.
Acetylcholine  is  also  the endogenous neuromuscular  transmitter which causes  bronchoconstric-
tion.   Greatest  response  occurred  at  5.24 mg/m   (2 ppm),  although 2.62  mg/m  (1 ppm) also
caused an effect.   The effect at 26.2 mg/m  (10 ppm) was less than  that at  2.62, 5.24, and 13.1
mg/m3  (1,  2,  and  5 ppm).  These  results  suggest  that  S02 may modify bronchial  reactivity.
     Animals  chronically  exposed  to SO,, have also  been  examined for alterations  in pulmonary
function.  Guinea  pigs  exposed continuously  to 0.34, 2.64,  or  15  mg/m   (0.13, 1.01, or 5.72
ppm) S02 for  up to 1 yr showed no changes in pulmonary function;  however, spontaneous  pulmonary
disease  was  present in all animals  (including  controls) except  those  exposed to  the highest
concentration  (Alarie et  al.,  1970).  Dogs exposed  for  21 hr/day  to 13.4  mg/m (5.1  ppm) S02
for up to 225  days demonstrated increased pulmonary flow resistance and decreased  lung compli-
ance  (Lewis  et al., 1969).  After 620 days' exposure, the mean  nitrogen washouts of dogs were
increased  (Lewis  et al.,  1969).   Alarie and co-workers  (Alarie et al.,  1972, 1973c,  1975)
exposed  cynomologus  monkeys  continuously to 0.37,  1.7,  3.4,  or 13.4 mg/m  (0.14,  0.64,  1.28,
or  5.12  ppm)  S02.   The  latter concentration was used in an 18-mo  study, whereas the others were
used  for 78  wk exposures.  Pulmonary function was unchanged in  all of these groups.   After 30
wk  of  exposure to 12.3 mg/m  (4.69 ppm) SO,, monkeys were inadvertently exposed to concentra-
                                  3
tions  between 524  and  2,620  mg/m   (200 and  1000 ppm)  for 1  hr.   This  treatment  resulted in
pulmonary  function alterations which  persisted  for  the remaining 48 wk  of  the study during
which the animals were  exposed to clean air.  Morphological alterations were also  seen in this
group (see Section 12.2.3).
     In  summary,  there  are at least two sets of  receptors responsible for  changes  in  respira-
tory  function in  animals acutely exposed to  SO,,.   Decreases in  respiratory rate  or  increased
resistance to  flow are  reproducible end points.    Increased resistance to flow  results  from SO,
                                     3
concentrations  as  low  as 0.42 mg/m  (0.16 ppm)  using  guinea  pigs.   Of  the  animals so far
examined, guinea pigs are  the most sensitive to S0«.  The reason  for this is not known; poten-
tial factors  include species,  strains, and experimental  technique used.   Large interindividual
differences  in dose-response  curves for changes  in  pulmonary  resistance to air flow  exist in
all  species.   A single population of  animals for this  trait  appears  likely for guinea  pigs,
dogs, and cats.   The exact number of  animals responding to a  given dose will  depend  upon the
shape of the  dose-response curve.   The nature of  the  dose-response curve  at low  levels is
poorly understood  and has not been  investigated  directly.   While  pulmonary function  measure-
ments in guinea pigs appear to be highly sensitive to acute S0? exposures,  chronic S02 exposure
has not  been  proven to  have a similar  effect.   Chronic studies  with guinea pigs  are unclear,
however, because of disease in the control  group.    In other chronic studies, pulmonary

XRD12A/A                                      12-18                                        2-5-81

-------
*
function of  monkeys was  unchanged at  S02  concentrations  up  to 13.4  mg/m3 (5.12 ppm); dogs
were affected by  225,  but not 620, days  of exposure to 13.4 mg/m3 (5.1 ppm).  High  levels of
S02 likely to initiate airway narrowing and hypersecretion  of mucus do alter several  parameters
of pulmonary function.   These results are not contradictory in view of the physiology of S0»-
initiated bronchoconstriction.   Sulfur dioxide  appears to  cause bronchoconstriction through
action on the  smooth muscles surrounding the airways.  Since smooth muscles fatigue  or become
adjusted to altered tone over time, chronic exposure to SO. is not likely to cause a  permanent
alteration in bronchial  tone.   Unfortunately, investigations of  the reactivity of the airways
after chronic exposure  to S02 have not appeared.   We do not know  if  chronic exposure to SCL
causes  an  alteration in  response  to  SO-  itself, since only direct  measurements  of  pulmonary
function were  made  on  the animals after chronic exposure.  It  would  be  very informative to
learn if chronically exposed monkeys, for example,  were  more  or less sensitive to S02 (Table
12-3).
     The respiratory rate of  mice has been  used  as  an indication of sensory irritation by
Alarie  et al.  (1973d).   Mice were exposed for 10 min to 0, 44.5, 83.8, 162, 233, 322, 519, or
781  mg/m  (0,  17, 32, 62, 89, 123, 198,  or 298 ppm) SO,.   About  a 12 percent decrease in res-
                                        3
piratory rate was observed at 44.5 mg/m   (17 ppm).  The respiratory rate decreased  inversely
to the  logarithm  of  the concentration of  inspired S0?.  The decrease in respiratory rate, how-
ever, was transient, returning to  nearly  control levels within 10 min at all S02 concentrations.
Complete  recovery to control  values  occurred within 30 min following  all  exposures to S02-
The  time  for maximum response was  inversely  related to the logarithm of the concentration of
 S0?, being shortest  at highest concentrations.  Mice exposed to 262 mg/m  (100 ppm) S0? for 10
min  were allowed  to  recover in clean air  prior to a  subsequent 10 min exposure to the same con-
 centration.   As  the length of the  recovery period  was decreased (from 12  min to 3  min), the
 effect  of  the subsequent SO- exposure on  respiratory  rate was  lessened.    "Desensitization,"
 thus,  appeared  to occur  during  the course of exposures.   When  another irritant, aerosols of
 chlorobenzilidene malononitrile  (CBM), was  used during  the refractory period  following SO-
 exposure, the  respiratory rate  decreased at  a rate comparable  to  that following exposure to
 CBM  alone.  Thus, the refractory period associated  with S0» exposures appeared specific to S0?
                                      7
 and  not to  CBM.   When 262 to 328  mg/m  (100  to 125  ppm) S02 was  provided repeatedly  for dura-
 tions  of 90 sec, with each  exposure separated  by a  60-sec  recovery period, the refractory
period was cumulative.  Ten such exposures eventually abolished all respiratory rate  responses
 to S02.  Breathing clean  air  for 60 min resulted  in a return of the response to initial  levels.
When mice were  exposed to SO- by  means of a tracheal  cannula,  no changes  in the  respiratory
 rate were observed,  indicating that the  decrease in  respiratory  rate was mediated  by a  reflex
 arc.   This  hypothesis has  been  developed  in considerable  detail  in  an  extensive  review by
Alarie  (1973)  who  suggests  that stimulation and desensitization occur via cholinergic nerve
endings  of  the  afferent  trigeminal nerve.   Alarie et  al. (1973d) also  suggest that S02  is
 XRD12A/A                                      12-19                                        2-5-81

-------
 SOX12C/A  2 2-5-81
                                           TABLE  12-3.   EFFECTS OF SULFUR DIOXIDE ON PULMONARY FUNCTION
          Concentration
                                         Duration
                          Species
                                                                                             Results
                                                                                                                                 Reference
 0.37,  1.7,  3.4,  or 13.4 mg/m3     72-78 wk,  continuous
  (0.14.  0.64.  1.28.  or 5.12 ppm)
  S02

 0.42 or  0.84 mg/m3 (0.16 or       1  hr
  0.32  ppm)  S02

 0.52.  1.04.  or 2.1 mg/m3 (0.2.     1  hr
  0.4,  or 0.8 ppm)  S02

 2.62.  5.24,  13.1.  or 26.2 mg/m3    1  hr
  (1, 2,  5, or 10 ppm)  S02
13.4 mg/m3  (5.1 ppm) S02
18 to 45 mg/m3 (7 to 17 ppm)
 S02

0, 44.5, 83.8, 162. 233, 322,     10 min
 519, or 781 mg/m3 (0, 17, 32,
 62. 89, 123, 198, or 298 ppm)
 S02
21 hr/day. 225 and
620 days


1 hr
>50 mg/m3 (>19 ppm) S02
1 hr
                        Cynomologus  No change
                         monkey
                        Guinea pig   Increase in resistance
                        Guinea pig   No significant increase in airway resistance.
Dog


Dog



Guinea pig


Mouse





Guinea pig
Increased bronchial reactivity to aerosols of
 acetylcholine, a potent bronchoconstrictive agent

Increased pulmonary flow resistance and decreased
 lung compliance at 225 days; increased nitrogen
 washout at 620 days

General decrease in tidal volume and an increase in
 respiratory rate
                                                                   Alarie et al.,  1972,
                                                                    1973c, 1975
                                                                   Amdur et al.,  1970,  1978a
                                                                   Amdur et al.,  1978c
                                                                                           Islam et al.,  1972
Lewis et al.,  1969
Lee and Danner,  1966
Respiratory rate decreased proportionally to the log  Alarie et al.,  1973d
 of the concentration; complete recovery within 30
 min following all exposures.   The time for maximum
 response was inversely related to the log of the con-
 centration, being shortest at highest concentrations

Increase in tidal volume and a decrease In respiratory Lee and Danner,  1966
 rate

-------
*
hydrated to bisulfite and sulfite which react with a receptor protein to form an S-thiosulfate
and a thiol, cleaving  an existing disulfide bond.  The receptor protein slowly regenerates to
its original disulfide configuration by the oxidation of S-thiosulfide and free thiol moieties
of  the  receptor  protein  to disulfide.   No  direct  evidence  for this  hypothesis  has  been
presented.
12.2.5  Effects on Host Defenses
     Because alterations  in  the  ability  to  remove  particles  from the  lung could  lead to
increased susceptibility to airborne microorganisms or increased residence times of other non-
viable  particles,  the  effects  of S02  on particle  removal  and  engulfment,  as  well  as on
integrated defenses against respiratory infection, have been studied.   Cilia function does not
appear  to  be affected  by exposure.  No  changes  were  observed in  the cilia  beat  frequency or
the  relative number  of alveolar macrophages  laden  with  particles in rats exposed  to 2.62 or
7.86 mg/m   (1  or  3 ppm) S02  and graphite  dust (mean diameter  1.5 urn,  1 mg/m ) for up to 119
consecutive days  (Fraser  et  al.,  1968).   Donkeys  (Spiegelman et al.,  1968)  were  exposed by
                                       3                                                 3
nasal catheters to 68.1 to 1,868  mg/m  (26 to 713 ppm) SO, for 30 min.  Below 786 mg/m  (300
                                                                               3
ppm) clearance was not affected,  but  at high concentrations (786  to 1,868 mg/m  or 376 to 713
ppm)  clearance  was depressed.   Increased  mucus  flow and  nasal  irritation  have been observed
with as little as 26.2 mg/m   (10 ppm)  SO,  for 24 hr.
                                                                     o
     Ferin and Leach (1973) exposed rats to 0.26, 2.62, and 52.4 mg/m  (0.1, 1, or 20 ppm) S02
 for  7 hr/day,  5  days/wk,  for  a  total  of 10 to  15  days  and then  measured the clearance of an
aerosol of  titanium  oxide  (TiO?).   The aerosol  was  generated at  about 15 mg/m  (1.5 pm MMAD,
a  3.3).   These  investigators took the amount of TiO, retained at 10 to 25 days as a measure
  "                                                                              3
of  the  "integrated alveolar  clearance".    Low concentrations  of  SO, (0.26  mg/m   or 0.1 ppm)
                                                            3
accelerated clearance after 10 and 23  days, as did 2.62 mg/m  (1 ppm) at 10 days but not after-
wards until 25 days when clearance was decreased.  Hirsch  et al. (1975) found that the trachea!
mucus flow was reduced in  beagles  exposed  for 1 yr to 2.62 mg/m  (1 ppm) S02 for 1.5 hr/day, 5
days/wk.   No differences in pulmonary function were reported.  Confirmation of this study and
determination of the persistence of the decreased mucus flow at this low level of S02 would be
 important to confirm in  light of other data available.
     S02 may have  more of an  effect on  anti-viral  than on anti-bacterial defense mechanisms.
Bacterial  clearance was  not depressed or  altered in guinea pigs exposed to 13.1 or 26.2 mg/m
 (5 or 10 ppm) S02 for 6 hr/day for 20  days  (Rylander, 1969; Rylander et al., 1970).  Using the
 infectivity model  (see  Section 12.3.4.3),   Ehrlich  (1978)  found that short (3 hr/day for  1 to
15 days) or long (24 hr/day for 1  to 3 mo)  exposures to 13.1 mg/m  (5 ppm) S02 did not increase
mortality  subsequent to  a  pulmonary streptococcal  infection.   Virus  infections,  however, are
augmented  by  simultaneous or subsequent  SO,  exposure.   Mice  were  exposed to concentrations
                              o              ^
varying from  0 to 52.4 mg/m   (0  to  20 ppm)  S02 continuously for 7  days  (Fairchild et  al.,
1972).  Mice breathing 18.3 to 26.2 mg/m3  (7 to 10 ppm) S02 began  to experience an  increase in
XRD12A/A                                     12-21                                        2-5-81

-------
*                                                          3
pneumonia.  Lung consolidation. was significant at 65.5 mg/m  (25 ppm). but not at 26.2 or 39.3
mg/m3  (10  or  15 ppm).   The rate  of  growth  of the virus within the lung was unaffected by S02
exposure.  Further  analysis  of  the data (Lebowitz and Fairchild, 1973) indicated that S02 and
virus exposure produced weight loss at concentrations as low as 9.43 mg/m  (3.6 ppm).  Exposure
to S02,  whether alone  or in combination with  a  viral  agent, had more  of an effect on weight
reduction than on pneumonia.   Since Giddens and Fairchild (1972) showed that mice with apparent
respiratory infection  were more  susceptible to S02  (Section  12.2.3),  a rebound effect may be
possible in which S02 and microbial agents each potentiate the effect of the other.
     Several   studies of  the  effects  of S02 on alveolar macrophages have been conducted, since
these cells participate in clearance of viable and non-viable particles in the gaseous exchange
regions  of the  lung.   Alveolar  macrophages from  rats  exposed for 24 hr  to  2.62,  13.1, 26.2,
and 52.4 mg/m3  (1,  5,  10, and 20 ppm) S02 were investigated by Katz and Laskin (1976).  Expo-
sure to  the 2 highest  concentrations increased rn  vitro phagocytosis of latex spheres for up
to 4 days in  culture.   At 13.1 mg/m  (5 ppm) S02, phagocytosis was increased after 3 or 4 days
in culture, but not after 1 or  2 days.   Histochemical  studies  of  pulmonary macrophages from
rats exposed  to  786 mg/m  (300 ppm) S02 for 6 hr/day on 10 consecutive days showed no changes
in  the  lysosomal  enzymes,  p-glucuronidase,  p-galactosidase,  and  N-acetyl-p-glucosaminidase
(Barry and Mawdesley-Thomas, 1970).   Acid phosphatase activity  was  markedly increased.  This
is in  agreement  with  Rylander's  observation (Rylander,  1969) which suggests that S0? exposure
           3                                                                         '
(26.2  mg/m ,  10  ppm,  for 6  hr/day, 5  days/wk  for  4 wk)  does not affect  the bactericidal
activity of the lung.  (Table 12-4)
12.3  EFFECTS OF PARTICULATE MATTER
     Sulfur dioxide  is oxidized  to sulfuric acid  in the atmosphere.  Sulfuric acid can react
with atmospheric ammonia to produce ammonium sulfate and bisulfate.  Similar reactions can also
occur  in the  animal exposure chamber and confound the experiment.  Ambient particulate matter
may be composed of  sulfur compounds and definition of the effects of ambient aerosols  indepen-
dent of  sulfur compounds may be  impossible.  Sulfur dioxide is often present in polluted atmo-
spheres  with  complex  mixtures  of other compounds including heavy metals, which may be present
as oxides  or  as  sulfate or nitrate salts.   In addition,  organic  compounds present  in the atmo-
sphere in  the gaseous  phase can  be associated with the particulate fraction or become  adsorbed
on  particles  either i_n  situ or  during collection.  The diversity  of these organic compounds
simply precludes any  rational  discussion of  their toxicity at  this  time,  since little or no
inhalation data  is  available.  The details  of the composition of atmospheric aerosols  are dealt
with elsewhere  (Chapter 5).  The  deposition and transport of  particles are also  discussed else-
where  (Chapter  11).
     Since very few studies  have appeared  on the  toxicity  of complex atmospheric particles
themselves,  this section will  deal  primarily  with the toxicity  of the  components  of  these
particles  and the toxicology of  those compounds  which have been identified  as constituents of
atmospheric particles.  Therefore, these discussions,  no matter  how  sophisticated  for  a single
component, are  inherently simplistic.   For aerosols other than  H2SO.,  (NH  ) SO.,  and  NH.HSO,,
XRD12A/A                                    12-22                                        2-5-81

-------
     SOX12C/A  4 1-30-81
                                                    TABLE 12-4.  EFFECTS OF SULFUR DIOXIDE ON HOST DEFENSES
           Concentration S02
                                            Duration
                                                                 Species
                                                          Results
                                                                                                                                         Reference
    0.26, 2.62, or 52.4 mg/m3
     (0.1, 1, or 20 ppm)
    2.62. 13.1, 26.2, and 52.4 mg/m3
     (1, 5, 10, and 20 ppm)
    2.62 mg/m3 (1 ppm)

£  2.62 or 7.86 mg/m3 (1 or 3 ppm)
^   S02 + graphite dust (mean
«"•   diameter 1.5 urn, 1 mg/m3)

    9.43 to 52.4 mg/m3 (3.6 to 20
     ppm)

    13.1 or 26.2 mg/m3 (5 or 10 ppm)

    13.1 mg/m3 (5 ppm)
    Varying from 0 to 52.4 mg/m3
     (0 to 20 ppm)

    26.2 mg/m3 (10 ppm)

    65.5 to 1868 mg/m3 (25 to 713
     ppm)
    786 mg/m3 (300 ppm)
7 hr/day, 5 day wk      Rat
24 hr
7 days continuous
6 hr/day, 20 day
                        Rat
1.5 hr/day, 5 day/wk    Dog

Up to 119 days          Rat
Mouse
Low concentrations (0.26 mg/m3 or 0.1 ppm)
 accelerated clearance of Ti02 aerosol after 10
 and 23 days, as did 2.62 mg/m3 (1 ppm) at 10
 days but not afterwards until 25 days when
 clearance was decreased.

Exposure to the 2 higher concentrations increased
 HI vitro phagocytosis of latex spheres for up to
 4 days in culture.   At 13.1 mg/m3 (5 ppm) phago-
 cytosis was increased after 3 or 4 days in culture,
 but not 1 or 2 days.

Trachea! mucous flow was reduced.

No changes in the cilia beat frequency or the
 relative number of  alveolar macrophages laden
 with particles.

Exposure to S02 and  a virus produced weight loss.
Guinea pig   Bacterial clearance was not altered.
3 hr/day, 1-15 days     Mouse
 and 24 hr/day, 1-3 mo

7 days, continuous      Mouse


6 hr/day for 20 days    Rat

30 min                  Donkey
6 hr/day, 10 days       Rat
 continuous
             Did not increase mortality subsequent to a pulmonary
              streptococcal  infection.

             Increase in viral  pneumonia at 18.3 to 26.2 mg/m3
              (7 to 10 ppm).   Rate of growth of virus unaffected.

             Did not affect  the bactericidal activity of the  lung.

             Below 786 mg/m3 (300 ppm)  clearance was not affected,
              but at high concentrations (786 to 1868 mg/m3 or  376
              to 713 ppm) clearance was depressed.

             No changes in selected lysosomal enzymes.
                                                                     Ferin and Leach, 1973
                                                                     Katz and Laskin,  1976
Hirsch et al., 1975

Fraser et al., 1968



Lebowitz and
 Fair-child, 1973

Rylander, 1969, 1970

Ehrlich, 1979


Fairchild et al., 1972


Rylander, 1969

Spiegelman et al., 1968



Barry et al., 1970

-------
*
no attempt  will  be  made to  be  as inclusive  as  separate  documents would be  for  some of the
individual components.   Rather,  an attempt will be made to  integrate this information in the
perspective of the potential biological effects of atmospheric particles.
     As will  be  apparent from the discussion of the toxicity of sulfate aerosols in this sec-
tion, the chemical  composition of the atmospheric particulates will determine the toxicity of
the  aerosol.   Atmospheric  particles  are  likely to  have direct toxic  effects in themselves,
indirect toxic effects through interactions with other pollutants,  and chronic effects through
cell  transformation  or  chronic  alteration in  cell  function.   Direct  toxic  effects are best
substantiated by studies of cytotoxicity.   Those reviewed here are for some specific compounds
which are known  to  occur in the particulate fraction.  The studies cited are by no means com-
plete and could be expanded by including a number of other investigations carried out i_n vitro
or by exposures  other than inhalation.  The  review was  purposefully restricted to those most
applicable to the inhalation route of exposure.  Major exceptions to this policy have been made
for silica and the limited data on compounds in the so-called "coarse-mode" particles fraction.
Most of  the  effects  through interaction with  other pollutants  have previously been discussed
for  S0?.  Some  additional  data implicating interactions between SO- and particulate material,
between  S0?  and  ozone, and between H?SO. and ozone are included here.  One should recall that
a  large  fraction of the mass of atmospheric particles is composed of sulfate and nitrate com-
pounds.
     Almost  all  of  the studies (and  all of  the inhalation studies) discussed in this section
involve  the  health effects  of particles in the "fine mode"  size range and composition.  Within
the  category of  fine mode  particles, several investigators examined the influence of particle
size for a  given chemical.  For coarse mode  particles,  only a few i_n vitro and intratracheal
instillation  studies  could  be found.  This work is discussed separately-
12.3.1   Mortality
     The  susceptibility  of laboratory animals to sulfuric acid  aerosols varies considerably.
Amdur  (1971)  has reviewed the toxicity of sulfuric acid aerosols and pointed out that, of the
commonly  used experimental  animals, guinea pigs are the most sensitive and most similar to man
in  their bronchoconstrictive  response to  sulfuric  acid.    The  lethal  concentration  (LC)  of
                                                           3                                 3
sulfuric  acid depends upon the age of  the  animal  (18 mg/m  for 1 to 2 mo-old versus 50 mg/m
for  18 mo-old animals),  the particle  size (those near 2 urn being more toxic), and the tempera-
ture  (extreme cold  increasing toxicity).   In  a recent study (Wolff  et al.,  1979b), the LC50
(the concentration at which 50 percent of the animals die) in guinea pigs for an 0.8 pm (MMAD)
                    3                                                                   3
aerosol  was  30  mg/m , whereas for  a  0.4  pm (MMAD) aerosol, the LC50 was above 109 mg/m  .  In
determining acute toxicity, the concentration of the aerosol appears to  be more important than
the  length   of  exposure  (Amdur  et al.,  1952).   The animals  that died  did so within  4 hr.
Chronic  studies have  only recently  been  undertaken, and they  support  this  conclusion that
mortality rarely occurs  at  moderate concentrations of sulfuric acid.
XRD12A/A                                     12-24                                        2-5-81

-------
*
     Sulfun'c acid aerosol  appears to have two actions.  Laryngeal and/or bronchial spasm are
the predominant causes  of death at high  concentrations.   When lower concentrations are used,
bronchostenosis and  laryngeal  spasm can still occur.  Pathological lesions in the latter case
include capillary engorgement  and hemorrhage.  Such findings are in accord with anoxia as the
prime cause of death.
12.3.2  Morphological Alterations
     Alarie  et  al.   (1973a)  investigated  the  effects of chronic H2SO.  exposure.   Guinea pigs
were exposed  continuously for  52 wk to 0.1 mg/m3 H^SO. (2.78 urn,  HMD) or to 0.08 mg/m3 H2$04
(0.84  urn,  HMD).   Monkeys  were exposed continuously for  78 wk to 4.79 mg/m3  (0.73  urn,  MMD),
2.43 mg/m3  (3.6 |jm,  MMD), 0.48  mg/m3  (0.54  urn,  MMD),  or 0.38 mg/m3  H2$04,  (1.15  urn,  MMD).
Sulfuric acid had no  significant hematological  effects  in either species.   No  light micro-
scopic lung alterations resulting  from KLSO.  exposure were observed in guinea pigs after 12 or
52  wk  of exposure in  this study (Alarie et  al.,  1973a)  or in a  later study  (Alarie  et al.,
1975).   Morphological  changes  were evident in the  lungs  of monkeys.   At the two highest con-
centrations,  there were changes (more prevalent  in  the  4.79 mg/m   H?SO, group) regardless of
the particle  size.   Major findings included  bronchiolar epithelial hyperplasia and thickening
of the walls  of the  respiratory bronchioles.  Alveolar walls were thickened in monkeys exposed
             3                      3
to  2.43  mg/m ,  but  not to 4.79  mg/m  ,  H9SO...  However, particle  size  had  an  impact at lower
                                                                                          3
HpSO.  concentrations.   No significant  alterations  were seen after exposure to 0.48 mg/m  of
the smaller particle size  (0.54 urn).  However, bronchiolar epithelial  hyperplasia and thicken-
ing of the  walls  of the  respiratory  bronchioles  were  seen after exposure  to  the  larger size
(1.15  urn)  and lower concentration (0.38  mg/m ).   These results are  not  those predicted from
strict  considerations  of  particle deposition within  the  lung.   The  larger  particles should
have been  deposited mostly  in the upper airways,  with less deposition  in  the  lower airways
(See  Chapter 11).   Pulmonary  function  changes  followed  a  slightly  different  pattern (See
Section 12.3.4.2).   In these studies, the cynomolgus  monkey  was much more sensitive than the
guinea pig.   Dogs also appear to be relatively insensitive to H~SO. alone as judged by morpho-
logical changes.  Lewis et al. (1973) found  no  morphological  changes after the dogs had been
exposed for  21  hr/day for 620 days to  0.89 mg/m  H-SO. aerosol (90  percent  of the particles
were <0.5 urn  in di"meter)
     Recently,  Co<: rell  and Busey (1978)  and Ketels et al.  (1977)  studied the morphological
changes resulting from sulfuric acid aerosols.  Cockrell and Busey (1978) examined the effects
of  25  mg/m   H?SO.  (1 urn, MMD,  o  1.6)  for  6  hr/day for 2 days  in guinea  pigs.   Segmented
alveolar hemorrhage, type 1 pneumocyte hyperplasia, and proliferation of pulmonary macrophages
were reported.  Ketels et al. (1977) examined the response of mice to 100 mg/m  sulfuric acid;
these  exposures produced  injury to the top and  middle of the trachea, but none  to the lower
trachea and  distal  airways.   In an attempt to  investigate the dose-response relationship for
sulfuric acid, mice received either 5 daily 3 hr exposures to 200 mg/m  , 10 daily exposures to
100 mg/m ,  20 daily exposures  to 50  mg/m ,  or  any one of these  doses combined  with 5 mg/m
carbon particles.   The damage was judged to be proportional to the concentration (C) of H-SO^,
XRD12A/A                                      12-25                                       2-5-81

-------
*
but not to  the  integrated dosp (C x T) or to the time of exposure (T).   (All of the exposures
had the same C x T and therefore their equivalence might have been hypothesized.)
     A number of  other studies of the morphological effects of H2$04 when combined with other
pollutants have been conducted.  (See Section 12.4.1.2.  and Table 12-5)
     Inhalation of  Si  results  in silicosis which is characterized by morphological changes of
the lungs.   Because the extensive information on  the  health effects of Si  has  been reviewed
elsewhere (Ziskind et al., 1976; NIOSH, 1974; Reiser and Last, 1979; Singh, 1978), it will not
be discussed  in detail  in this document.  Due to  the  toxicity of  Si  a  Threshold Limit Value
(American Conference of Governmental  Hygenists, 1979) has been set.   Because of the involvement
of alveolar macrophages  in  its toxicity and its presence  in ambient particles,  however, some
of the  effects  of  Si  will  be  summarized  briefly  here.   All the information  given  below for
silicon is derived from reviews by Ziskind et al.  (1976) and NIOSH (1974).
     Silicon is ubiquitous in the earth's crust.   Silicon dioxide (Si02), which is responsible
for the disease silicosis, is found in 3 crystalline forms (quartz,  cristobalite, and tridymite)
As a generalization, the ranking of toxicity is tridymite >cristobalite > quartz.  These uncom-
bined  forms  of SiO,,  are generally called  "free  silica."   SiCL  is also  found  combined with
cations,  in which case the  term silicates is  applied.   Very few animal  toxicological studies
of silicates  exist.   Several  hypotheses of the etiology of silicosis have been developed, but
no single one has been proven definitively.  One widely accepted hypothesis was developed from
both animal and human studies.   According to this theory, alveolar macrophages ingest the par-
ticles, die,  and  release their intracellular contents,  including  lysosomal  enzymes  and SiO?.
This  is  followed by  a recycling  of  particle  ingestion by macrophages  and  their death, slow
accumulation of other macrophage cells, increased collagen synthesis in response to macrophage
lysosomal enzymes, hyalinization, and perhaps complicating factors.   Since the alveolar macro-
phage  hypothesis  does  not explain completely the etiology and pathogenesis of the disease, it
is likely that additional factors contribute to the disease.  These might include auto immunity,
co-existing  tuberculosis or other  infections,  and/or  alterations  of lung  lipid content and
metabolism.
     Many animal  toxicological  studies of Si02 exist.   Unfortunately, comparisons are diffi-
cult because of the species and strain of animal  used, accidental infections, the size of SiCL
particle  used, and the crystalline form of SiO? used.
     Silicosis, similar  to  that observed in man, has been produced in animals exposed to high
concentrations  of quartz and  other  Si02  dusts  via intratracheal  instillation  (30-50 mg) or
chronic  inhalation.   Chronic   exposures   (2.5  yr)  of  dogs  to earth  containing 61 percent
cristobalite produced fibrotic nodules in hilar lymph nodes, but not the lungs.
     Several studies of the hemolysis of red blood cell by particles have been reported.  This
model may correlate  with the ability of mineral  dusts to cause lung fibrosis  ui  vivo and thus
is used  for screening.   Ottery and Gormley  (1978) studied the  influence  of particle size of
quartz (Min-u-sil) and other materials on red cell hemolysis.  The  particle  size  of  the  quartz

XRD12A/A                                     12-26                                        2-5-81

-------
 SOX12C/A  5 2-5-81
                                             TABLE 12-5.   EFFECTS OF PARTICIPATE MATTER ON LUNG MORPHOLOGY
       Concentration
                                        Duration
                                                             Species
                                                          Results
                                                                                                                                     Reference
0.08 mg/m3 H,S04 (0.84 MID, MHO),
 or 0.1 mg/m5 H2S04 (2.78 M".
 HMD)

0.38 mg/m3 (1.15 urn, MMO).
 0.48 mg/m3 (0.54 um, MMO),
 2.43 mg/m3 (3.6 um, MMO), or
 4.79 mg/m3 (0.73 um. MMO)
0.89 mg/m3 (90X <0.5 MID in
 diameter) H2S04 aerosol

25 mg/m3 (1 um. MMD, o  1.6)
 H2S04 aerosol        9
50 mg/m3 H2S04, or
 100 mg/m3 H2S04, or
 200 mg/m3 H2S04, or any of
 of these doses combined with
 5 mg/m3 carbon particles
 (at all three duration schedules)
52 wk, continuous
78 wk, continuous
Guinea pig



Monkey
21 hr/day, 620 days     Dog


6 hr/day, 2 days        Guinea pig
3 hr/day, 20 days; or   Mouse
 3 hr/day, 10 days; or
 3 hr/day, 5 days
No significant hematological effect.  No microscopic
 lung alterations after 12 or 52 weeks exposure.
No significant hematological effect.  Morphological
 changes in the lungs.   At the two highest concentra-
 tions there were changes, regardless of the particle
 size.  Major findings included bronchiolar epithelia
 hyperplasia and thickening of the respiratory bron-
 chioles.  Alveolar walls were thickened with 2.43
 mg/m3, but not 4.79 mg/m3.  No alterations with
 0.48 mg/m3 (0.54 urn),  but with larger size (1.15 um,
 0.38 mg/m3) hyperplasia and bronchiole thickening.

No morphological changes.
             Segmented alveolar hemorrhage, type 1 pneumocyte
              hyperplasia, and proliferation of pulmonary
              macrophages.

             Damage was proportional  to the concentration.
Alarie et al.,
 1973a, 1975
Alarie et al., 1973a
                                                                     Lewis et al.,  1973
                                                        Cockrell et al.,
                                                         1978
                                                        Ketels et al.,  1977

-------
was from  2.7  to 6.8 urn  (mean  volume  diameter,  MVD).   At lower concentrations (0.025 to about
0.15 mg/ml),  there  was a linear dose-response increase in hemolysis for quartz (1.35 and 3.55
urn, MVD), kaolin (4.7 urn, MVD), cristobalite (3.05 urn, MVD), and bentonite (5 urn MVD).  In this
experiment, the effectiveness for increasing hemolysis was ranked as bentonite >kaolin > quartz
>  cristobalite.   Even though  this  test  is  typically used to predict  fibrotic  potential,  it
should be  noted that usually cristobalite is more fibrogenic than quartz.  In another experi-
ment,   kaolin  and quartz  were  additive when  mixed.   Linear increases  in hemolysis were also
observed  with  increasing  numbers  of  particles.  When  the various  sizes of Min-u-sil  were
directly compared,  as  particle size decreased from 6.8  urn to  2.7 urn, a  smaller concentration
was required  to produce  5% hemolysis.   For example,  at the largest size  tested,  2.7 mg/ml was
required, whereas at the smallest size tested, 0.21 mg/ml was needed.
12.3.3  Alterations in Pulmonary Function
12.3.3.1  Acute Exposure Effects—On short-term exposure, respiratory mechanics are very sensitiv
to inhaled H?SO. and some other compounds.  Amdur (1971) has cautioned that her method for mea-
suring airway resistance (Amdur and Mead, 1955,  1958)  should  not be used as an indication of
chronic  toxicity  and should be considered only  for  very short-term toxicity.  As pointed out
above, the  Mead-Amdur method uses unanesthetized guinea pigs in which a  transpleural catheter
has been implanted.   Amdur suggests (1971) that, if anything,  this procedure increases rather
than decreases  the  sensitivity of the guinea pigs to inhaled irritants.
     Using  this method,  Amdur  and  co-workers (Amdur and Underhill,  1968,  1970;  Amdur, 1954;
1958,  1959,  1961;  Amdur and Corn, 1963; Amdur et al., 1978a,b,c,) have studied the effects of
aerosols  alone  (see Table  12-6)  or in  combination  with  S0?.   The combination  studies are
described  in  Section 12.4.1.1.   In all of their studies, exposures were  for 1 hr.  The method
 records  resistance  to air flow in  and  out of the lungs and airways, compliance (a measure of
 lung distensibility),  tidal volume (the volume of air moved during normal breathing), respira-
tory frequency,  and  minute volume.  While  increased flow resistance is often the most striking
 feature  of  the  response  to aerosols, calculations of the elastic, resistive, and total work of
breathing  can also be made.   The method  is,  therefore,  nearly  as  elaborate  and inclusive an
evaluation  of  pulmonary  mechanics  as  could  be  made in  small   laboratory  animals  until very
recently (Drazen, 1976).
     The  importance  of  particle size  on the  site  of  pulmonary deposition  is  described in
Chapter  11.   The impact  of these factors on the effects on human  health is clear from an early
study  (Amdur, 1958).   Sulfuric acid aerosols of concentrations  ranging from 1.9 to 43.6 mg/m
were generated  in three particle sizes:   0.8  urn (a  , 1.32 urn),  2.5 urn (a  , 1.38 urn),  or 7 urn
(a , 2.03 urn) MMD.   Particles of the  largest size (7 urn, at 30  mg/m ) produced a  significant
increase  in  flow  resistance  but no other detectable changes in respiration.   At the  lowest
concentration tested, 1.9 mg/m , the 0.8 urn particles produced  an  increase  in  resistance to
flow and in elastic, resistive, and total work  of breathing;  but they produced a  decrease in
compliance.   The 2.5  urn particles also  increased the  resistance to  flow at concentrations
from 2.3 to 43.6 mg/m .  The  relative  efficacy  of the 0.8 and  2.5 urn particles differed.  At
XRD12A/A                                     12-28                                        2-5-81

-------
    SOX12C/A  15 2-5-81
ro
vo
                             TABLE 12-6.   RESPIRATORY RESPONSE OF GUINEA PIGS EXPOSED FOR 1 HR TO PARTICLES

                                                       IN THE AMDUR et al.  STUDIES
Concentration
Compound mg/m3
H2S04 0.10

0.51
1.00
1.90

5.30
15.40
26.1
42.00
0.11
0.40
0.69
0.85
2.30
8.90
15.40
43.60
30.50
(NH4)9S04 0.50
* 2.14
1.02


9.54
NH4HS04 0.93
2.60
10.98
Particle
size, urn, HMD
0.3

0.3
0.3
0.8

0.8
0.8
0.8
0.8
1.0
1.0
1.0
1.0
2.5
2.5
2.5
2.5
7.0
0.13
0.20
0.30


0.81
0.13
0.52
0.77
Resistance
cm H20/ml/sec
% difference
from control
+41*

+60*
+78*
+51*

+54*
+69*
+89*
+120*
+14*
+30*
+47*
+60*
+39*
+61*
+96*
+317*
+42*
+23*
-4
+29*


0
+15*
+28*
+23*
Compliance
ml/cm H20
% difference
from control
-27*

-33*
-40*
-35*

-40*
-24*
-38*
-26*
-13
-8
-25*
-28*
-16
-26*
-43*
-76*
-17
-27*
-13*
-23*


-12*
-15*
-30*
-19*
Reference
Amdur et al . ,
Amdur, 1975
Amdur et al . ,
Amdur et al . ,

1978b;

1978b
1978b
Amdur, 1969; Amdur,
1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur et al . ,
Amdur et al . ,
Amdur and Corn
Amdur et al . ,
Amdur, 1974
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,





1978b
1978b
1978b
1978b





1978a
1978a
, 1963;
1978a;

1978a
1978a
1978a
1978a

-------
  SOX12C/A  16 2-5-81
CO
O
      NaV04


      FeS04
                                                  TABLE 12-6. (continued).
Compound
Na2S04
ZnS04

ZnS04-

(NH4)2S04













CuS04


Concentration
mg/m3
0.90
0.91

0.25

0.50
1.10

1.80

1.50

2.48
1.40


1.10

3.60
0.43
2.05
2.41
Particle
size, M"I» MMD**
0.11
1.4

0.29

0.29
0.29

0.29

0.51

0.51
0.74


1.4

1.4
0.11
0.13
0.33
Resistance
cm H20/ml/sec
% difference
from control
+2
+41*

+22*

+40*
+81*

+129*

+43*

+68*
+29*


+6

+32*
+9
+25*
+14*
Compliance
ml/cm H20
% difference
from control Reference
-7 Amdur et al. , 1978a
Amdur and Corn, 1963;
Amdur, 1974
Amdur and Corn, 1963;
Amdur, 1975
Amdur and Corn, 1963
Amdur and Corn, 1963;
Amdur, 1974
Amdur, 1969; Amdur and
Corn, 1963
Amdur and Corn, 1963;
Amdur, 1975
Amdur and Corn, 1963
Amdur, 1969; Amdur and
Corn, 1963; Amdur,
1975
Amdur and Corn, 1963;
Amdur, 1975
Amdur and Corn, 1963
-11* Amdur et al. , 1978a
-15* Amdur et al. , 1978a
-11* Amdur et al. , 1978a
0.70
1.00
+2
Amdur and Underbill,
 1968

Amdur and Underbill,
 1968

-------
SOX12C/A  17 1-30-81
                                                TABLE 12-6.  (continued)
Compound
Fe203 (2hr)
(Fumes)
MnCl2
Mn02
HnS04
Open hearth
dust
Activated
carbon
Spectographic
carbon
Concentration
mg/m3
11.70
21.00
1.00
9.70
4.00
0.16
7.00
8.70
2.00
8.00
Resistance
cm H20/ml/sec
Particle % difference
size, urn, MHO from control
0.076 (GMD) -9
0.076 (GMD) 0
+4
-6
-1
0.037 (GMO) +9
0.037 (GMO) +6
-3
+7
+17
Compliance
ml /cm H20
% difference
from control Reference
5 Amdur and Underbill,
1968; 1970
0 Amdur and Underbill,
1968; 1970
Amdur and Underhill,
1968
Amdur and Underhill,
1968
Amdur, 1974
0 Amdur and Underhill,
1968; 1970
-16 Amdur and Underhill,
1968; 1970
Amdur and Underhi 1 1 ,
1968
Amdur and Underhi 1 1 ,
1968
Amdur and Underhi 1 1 ,
1968
    *p <  0.05
    **Diameters  are provided as mass median diameter (MMO)  unless  specified  as geometric median
      diameter by count (GMD).

-------
concentrations of 2 mg/m3, the. 0.8 |jm particles were more effective than the 2.5 |jm particles.
The time course of the response also varied with the particle size, since the 2.5 urn particles
did not evoke their major effects until the last 15 to 20 min of the 1 hr exposure.  These dif-
ferences in response were probably associated with the degree and site of obstruction within the
bronchi.  The 2.5  urn particles  affected the larger bronchi producing obstruction, whereas the
0.8 urn particles caused narrowing of the smaller bronchi.  While the results of the experiments
are reported  in  a straightforward concentration-response  curve,  the  physiological mechanisms
producing the measurable effects are obviously highly complex.   Detailed understanding is lack-
ing.
     In a  more  recent  investigation,  Amdur et  al.  (1978b) exposed  guinea pigs  for  1  hr to
                                                                            3
either 0.3 or 1  urn (MMD) H?SO.  in concentrations ranging from 0.1 to 1 mg/m .   The concentra-
tion-response for  percent  change  in resistance was  linear for  both particle sizes.  However,
the smaller particle  caused  a greater response, particularly at 0.1 mg/m  where a 26 percent
increase in airway resistance was observed.  Except for exposure to 0.11 mg/m  HpSO^ (1 urn),
all increases  in  resistance  were statistically significant.  The  smaller  particle size also
decreased compliance  at  all  concentrations tested.  However, for the 1 urn particle the lowest
effective concentration  tested  was  0.69 mg/m .  For equivalent concentrations,  the 0.3 urn par-
ticle  decreased  compliance more  than  the  1 urn particle.   Animals were also  examined 30 min
after  exposure  ceased.   At this  time, after exposure  to 0.1 mg/m  H-SO.  (0.3 urn) resistance
was still  elevated above  control in  guinea  pigs; but  for the  1  urn particle,  recovery had
occurred.  These  exposures caused  no  alterations of tidal  volume,  respiratory frequency, or
minute volume.  In comparing these results to earlier work with S0? (Amdur, 1966), Amdur et al.
(1978b) describe  how the same amount  of  sulfur  when given as H?SO. produces 6 to 8 times the
response observed  than when given as S0?.
     Silbaugh et  al.  (1980)  exposed Hartley guinea pigs for 1 hr to 1 urn (MMAD) sulfuric acid
aerosols at concentrations and relative humidities of 0 mg/m  (control group) (40 or 80 percent
RH), 1.2  mg/m3  (40 percent RH),  1.3 mg/m3 (80  percent RH), 14.6  mg/m3  (80 percent RH), 24.3
mg/m   (80 percent  RH), or 48.3 mg/m  (80 percent RH).  Ten animals were exposed at each concen-
tration except for the 24.3 and 48.3 mg/m  groups, which consisted of 9 and 8 animals, respec-
tively.   Measurements of  tidal  volume,  breathing frequency, minute  volume,  peak  inspiratory
and expiratory  flow,  tidal transpulmonary pressure excursions,  total pulmonary resistance and
dynamic  lung  compliance were obtained every 15  min  during (1)  a  30  min  baseline period, (2)
the 60 min exposure period,  and  (3) a 30 min recovery period.   Pulmonary function changes in
sulfuric acid-exposed guinea pigs did  not  differ from controls,  except for 1 animal exposed to
          3                                  3                                     ^
14.6 mg/m  ,  3 animals exposed to 24.3 mg/m ,  and 4 animals exposed to 48.3 mg/m  .  Pulmonary
function  changes  in  these 8 responsive animals included  marked  increases  in  total pulmonary
resistance and marked decreases in dynamic compliance.    Four of these 8 guinea*pigs died  during
exposure.   The  proportion  of  responsive to  non-responsive animals  increased  with  exposure
concentration, but the  magnitude of pulmonary  function  change  was similar for all responsive
animals.   Compared to  non-responders,  responsive animals  tended  to  have higher  pre-exposure
XRD12A/A                                     12-32                                        2-5-81

-------
values of  total  pulmonary resistance  and lower  pre-exposure  values of  dynamic compliance.
Authors suggested that  guinea pigs react  to  acute sulfuric acid exposure with an essentially
all-or-none airway constrictive  response.   The finding that resistance and compliance changes
are important components of the guinea pig's airway response to sulfuric acid aerosols is con-
sistent with  results published  by Amdur  et  al.   (1978b).  The  presence  of  high pre-exposure
pulmonary  resistance  values  in responsive animals is similar to the  finding  by Amdur (1964)
that  guinea  pigs with  high pre-exposure  resistance values were  those most  severely affected
during irritant  aerosol exposure.   However,  the   lack of effects at  lower concentrations  and
the essentially  all-or-none  airway  constrictive   response  observed  in these  studies  differs
markedly  from the  graded  response  observed  by   Amdur  et al.  (1958, 1978b)  during  similar
exposures.   The  bifurcating  and declining  airway  diameter  of the  lung  make  all-or-none
responses  as  measured  by changes  in airflow  unlikely.   The graded  response observed by Amdur
et al. (1958,  1978b) seems more  reasonable.   The  reasons for the differences in experimental
results are  unclear, but may  be  at  least partially related to  differences  in animal  strains
and techniques.   These  results indicate that  changes  in  respiratory  function do not occur at
environmental  concentrations  of  sulfuric  acid in most animals,  but  suggest that susceptible
subpopulations might exist.   (See  discussion above about susceptible individuals.)
     Sackner et al.  (1978)  evaluated pulmonary function in anesthetized dogs immediately after
                                                 3                                3
or 2  hr  after exposure to  approximately 18 mg/m   H?SO. for 7.5 min or to 4 mg/m  H,,S04 for 4
hr.   The  MMAD was  < 0.2  urn.   There were no significant  changes  in respiratory resistance,
specific  respiratory conductance, specific lung compliance,  or  functional residual  capacity.
At the higher concentration,  cardiovascular parameters (e.g., blood pressure, cardiac output,
heart  rate,  and  stroke volume) and arterial blood gas tensions were also  studied, but no sig-
nificant changes were observed.  The pulmonary function (pulmonary resistance and dynamic com-
pliance)  of  donkeys was  not affected by  HUSO, exposure  (1.51  mg/m , 0.3 to  0.6 MMAD,  1 hr)
(Schlesinger et al., 1979).
     Studies of the irritant  potential of  sulfate  salts have shown that these aerosols are not
innocuous  but  evoke  increased flow resistance similar  to sulfuric  acid aerosols.  The influ-
ence  of particle  size on the  effects of zinc ammonium sulfate  has also  been investigated by
Amdur and  Corn (1963).   They  showed, in guinea  pigs  exposed for 1 hr,  that zinc sulfate had
about half the potency of zinc ammonium  sulfate, with ammonium sulfate being one-third to one-
fourth as potent as zinc ammonium  sulfate.  Zinc ammonium sulfate was  chosen for  study because
it had been  reported as a  major  component of the aerosol from the Donora,  PA episode of 1948
(Hemeon,  1955).  Zinc ammonium sulfate is  not a common species found  in urban  air.   Four sizes
of aerosols  were  administered:  0.29, 0.51,  0.74,  and 1.4 |jm (particle mean  size by weight).
When  the  aerosol concentration was  held constant at 1 mg/m  ,  the  smaller particles produced
greater  increased resistance to  flow.    This response was  thought  to  be the  result  of the
number of  particles  rather than of differential sites of deposition.  The dose-response curve
also  became  steeper with  decreasing  particle size.  These data should  be carefully compared
with  those from similar human exposures (Chapter 13, pp.  26-29) where  no response occurred.
XRD12A/A                                     12-33                                       2-5-81

-------
     Amdur  et  al.   (1978a)  recently compared the  effects of  (NH4)2S04,  NH4HS04>  CuS04,  and
Na2S04.   Although particle  sizes  and concentrations were not precisely matched throughout the
study, statistical  analyses for ranking were not applied, and the degree of response increased
with decreased size  (size  range,  0.1 to 0.8 urn, MMD),  the authors suggest that  the order of
irritant  potency was  (NH4)2$04 >  NH4HS04  > CuS04-   Sodium sulfate  (0.11  mg/m ,  0.11  MMD)
caused no significant effects on either resistance  or compliance.   At the lowest concentrations
used, (NH4)2S04  (0.5  mg/m3,  0.13  urn MMD), NH4HS04  (9.93 mg/m3,  0.13 urn MMD),  and CuS04 (0.43
mg/m3, 0.11 |jm MMD)  decreased compliance.   These concentrations of (NH4)2$04 and NH4HS04 also
increased resistance.  For  CuSOA,  the  lowest concentration tested which caused an increase in
                        o       ^
resistance was 2.05 mg/m  (0.13 urn MMD).   All of these compounds are less potent than H2$04 in
the Amdur studies.
     Comparisons  between sulfuric acid  and sulfate  salt aerosols are difficult to make because
of  the  marked dependence  of  the  efficacy  on  the aerosol  size.   If  the  particles  are  of
identical size,  sulfuric acid  is  more  efficacious  than zinc ammonium sulfate;  but if the zinc
ammonium sulfate  were present as a submicron aerosol and the sulfuric acid as a large aerosol,
then zinc ammonium  sulfate  would  be more efficacious at the same concentration (Amdur, 1971).
Regardless of the  particle  size,  the equivalent amount  of sulfur present as S02 is much less
efficacious than if  it were present as a sulfate salt or sulfuric acid.  When present as S02,
         •3                                      O
2.62 mg/m  (1 ppm) S02 is equivalent to 1.3 mg/m  S and produces a 15 percent increase in flow
resistance.   If  this  amount of sulfur were  present as  a 0.7 urn  aerosol  of  sulfuric acid, it
would evoke a 60 percent increase in flow resistance or be about 4 times more efficacious.   If
the  sulfur  were  present  as zinc ammonium sulfate  as  a  0.3 urn aerosol,  the  increase in flow
resistance  would be about 300  percent or  a 20-fold increase in  efficacy.   Some  sulfate salt
aerosols are not irritating.  For example, though ferrous sulfate and manganous sulfate do not
cause an increase  in flow resistance, ferric sulfate  does cause this response.  A summary of
irritant potency is presented below.

                       Relative Irritant Potency of Sulfates In Guinea Pigs
                             Exposed  for One Hour3 (Amdur et al., 1978a)

                             Sulfuric acid                      100
                             Zinc ammonium sulfate               33
                             Ferric  sulfate                      26
                             Zinc sulfate                        19
                             Ammonium sulfate                    10
                             Ammonium bisulfate                   3
                             Cupric  sulfate                       2
                             Ferrous sulfate                    0.7
                             Sodium  sulfate  (at 0.1 urn)         0.7
                             Manganous sulfate                 -0.9
          aData are  for 0.3  pm  (MMD)  particles.  Increases  in airway  resistance  were
          related  to  sulfuric  acid  (0.41%  increase  in resistance  per ug  of sulfate
          as  sulfuric acid)  which was assigned a value of  100.

XRD12A/A                                    12-34                                        2-5-81

-------
*
     Nadel   et al.  (1967)  faund  that  zinc  ammonium  sulfate  (no  concentration  given)  and
histamine aerosols produced similar increases in resistance to flow and decreases in pulmonary
compliance in the cat.  Histamine was more potent than zinc ammonium sulfate.  The increase in
flow resistance  could not  be  blocked by intravenous administration of  atropine sulfate,  but
was blocked by either intravenous or inhaled isoproterenol.   The increased flow resistance was
suggested to be due to an increase in bronchial smooth muscle tone.  Histamine appears to be a
likely  mediator  of  the  bronchoconstriction  following  inhalation of  sulfate  salt aerosols.
Charles and Menzel (1975a)  investigated the release of histamine from guinea pig lung fragments
incubated with  varying concentrations  of sulfate  salts.   Almost complete  release of tissue
histamine occurred with  100 mM ammonium sulfate.   Intratracheal injection of ammonium sulfate
also released all of  the  histamine  from perfused and ventilated rat lungs  (Charles  et al.,
1977a).  The  potency  ranking of different sulfate salts in the release of histamine from lung
fragments  (Charles  and Menzel, 1975a;  Charles  et al.,  1977a) was equivalent  to that causing
increased resistance  to  flow (Amdur et al., 1978a).  Bronchoconstriction of the perfused lung
occurred on  intratracheal  injection  of sulfate  salts  or histamine (Charles  et al.,  1977a).
About 80 percent of the constriction could be blocked by prior treatment of the isolated lungs
with an H-l antihistamine.  These experiments, as well as the original  observations of Nadel et
al. (1967) and Amdur et al. (1978a), support the concept that an intermediary release of hista-
mine or some other vasoactive hormone is involved in the irritant  response of sulfate aerosols.
An ammonium sulfate particle is calculated to reach a concentration of about 275 mM at equilib-
ration  with  the  99.5  percent relative  humidity of  the  respiratory tract (Committee on Sulfur
Oxides, MAS,  1978).   Thus, the concentration of  the  hydrated particle on striking the mucosa
would be within the range  found to cause release of histamine in guinea pig and rat lung frag-
ments (Charles and Menzel,  1975a; Charles et al., 1977a).  A recently published estimate of the
dose  of  inhaled  ammonium  sulfate  needed  to  release  histamine in  the   lung  is  in  error
(Committee on Sulfur Oxides, MAS, 1978).  Complete release of histamine (100 percent) occurred
with 1  umole  of ammonium  sulfate/lung  and  not  1  uM solution  for  the  entire lung (Charles et
al., 1977a).   Further, total  release  of  all  histamine  stores  of a  tissue rarely,  if ever,
occurs  under physiological  conditions.   Only  about  10 percent  of  the  total  histamine is
released  during degranulation  reactions  i_n  vivo,  producing anaphylactic  shock  and death.
Therefore,  even  if  the  calculations   were  correct,  only  a  small  fraction  of  the  ammonium
sulfate  dose  would be required to  produce the far less  violent increases  in flow resistance
reported by  Amdur et  al.  (1978a)  for ammonium bisulfate and  ammonium sulfate.   Assuming  the
calculation of ammonium sulfate to be correct, a 4 hr, not a 2 day, inhalation would produce a
marked  increase in resistance to flow.  Additionally, Charles et al. (1977b) found  the rate of
           35   -2
removal of    SO.    from the rat lung both in vivo and in vitro  to be  a function of the cation
               4
associated with  the  salt  and  to  follow the same  order of potency as  reported by Amdur  and
co-workers (1978a)  in the guinea pig  irritancy test.   Especially noteworthy  is the  fact  that
manganous  sulfate  was removed at essentially  the same rate as  sodium sulfate,  both of which
did not produce increased  resistance to flow in the guinea pig.
XRD12A/A                                     12-35                                       2-5-81

-------
     Hackney  (1978)  has presented a  preliminary  summary  of the effects of  aerosols of H2$04
and  nitrate  and sulfate  salts  on squirrel  monkeys (Saimiri sciurens).  Monkeys were exposed
(head-only) to  aerosols  at 2.5 mg/m3 of  the  respective  salts  or sulfuric acid, 40 or 85 per-
cent  RH  at 25°C.   The exposure  system  was designed  to  reduce stress  on the  unanesthetized
monkey.  A non-invasive  method of pulmonary function measurement was used in which total res-
piratory resistance  was measured  by the forced  pressure oscillation technique at sine wave
frequencies  of either  10  or  20 Hz.   The  measurement of  pulmonary resistance included  the
resistance of  the  chest wall which was  assumed  to be irrelevant to pollutant response and to
be constant throughout  the experiments.   To correct  for  stress,  control values were taken as
those  for  a  given  monkey exposed on the previous day to an aerosol of distilled water (for
aerosol experiments).
     Hackney  (1978)  reports  that the  measurement of respiratory  resistance  was frequency-
dependent,  with changes in resistance appearing greater in the 10 Hz than the 20 Hz measurement
frequency.   (The  measurement frequency  is  net to be  confused with  the  breathing frequency.)
The exposure period  in the experiments was either 1  or 2 hr.  Some aerosols were studied at
only 40 percent RH.   No attempt was  made at  a dose-response curve  for  aerosols and all expo-
                              o
sures were at or near 2.5 mg/m .  At  low relative  humidity (40 percent RH; MMAD  0.3 urn, °a 2.0),
there were no differences between (NH.^SO.-exposed and control values, while at high relative
humidity (85  percent RH,  MMAD 0.6 urn, o  2.3), 3  of 5 monkeys had increased airway resistance
by 1 hr.   Zinc  ammonium sulfate aerosols produced  increased resistance at  low humidity (40 per-
cent RH; MMAD 0.3 urn, o  2.5) but no  consistent increases over control values at high humidity
(85 percent RH; MMAD 0.6 urn, a  1.6).  Ammonium bisulfate (40 percent RH; MMAD 0.4 urn, o  1.8)
                              9                o                                         9
also produced  increased resistance at 2.7 mg/m .
     Data (Hackney,  1978)  from exposures  to sulfuric acid and NH.NO., aerosols were analyzed by
computer  and  differed  quantitatively from  the data reported above  for  those exposures which
were  reduced by hand.  Differences were probably due to a systematic error in the  hand reduced
data  which  required a judgement  in  selection  of  raw  data points.    The  biological interpreta-
tion  does  not appear to be  altered by these two approaches, but it  does point out the experi-
mental  difficulties in  interpretation  of pulmonary  function  data from  experimental animals.
While  H2S04  aerosols (40 percent RH; MMAD 0.4 urn, o   2.0) caused no statistically significant
increases,  there was  a  trend toward increased  resistance after 60 min which then tended to
decline.  Ammonium  nitrate  exposures  produced  no changes.
      Multiple  contrast analysis of the above  data (Hackney,  1978) showed that  no significant
differences  between baseline  or  control values  could be  found  for any  exposure using data
collected  at the 20 Hz  measurement  frequency.  At the 10  Hz  measurement  frequency, the data
were  more variable,  but  significant differences indicative of increased  airway  resistance could
be  found for animals  exposed  to  2nS04,  (NH4)2$04 and H2$04 at  40 percent relative  humidity.
Several  procedural   aspects  should be recognized.   First, data were  analyzed on a group mean
basis,  even though  large differences between individual  monkeys  existed  in both  variability
 XRD12A/A                                      12-36
                                                                                          2-5-81

-------
*
and absolute  magnitude.   Second,  the time  course of exposure  to  the aerosols illustrated a
trend  indicative of  a  transient response  on  the  part of  monkeys  to  sulfate,  nitrate,  or
sulfuric acid aerosols.  The use  of group means  tended to reduce the magnitude of the response
and flatten  the response-time  curve.   This  is certainly true  for  the S02 exposures.   Third,
there were  major differences  in the  response measured at  either 10 or 20  Hz.   Fourth, the
response estimated  by both manual and  computer reduction  differed by as much  as  40 percent.
However, compared to  the data  reported for guinea pigs, these experiments support the general
trends originally proposed from the guinea pig  data.
     Sackner  and  co-workers   (1976,  1977a,b,c,  1978b)  have  noted  that  neither  ammonium
sulfate  or  sulfuric  acid  aerosols alters  cardiovascular  and  pulmonary  function  in  dogs  or
tracheal mucus  velocity  in sheep.  Some  of  these reports  are at variance with the previously
cited published experiments.   No significant  alterations in  pulmonary resistance  and dynamic
compliance were  observed in donkeys exposed to  0.4 to 2.1 mg/m   (NH.)2S04  (0.3 to 0.6 urn MMAD)
for 1  hr (Schlesinger et al.,  1978).   The  small size of the particles may be responsible for
the lack of an  effect.   Larger  particles  in other  studies may be more potent.
     Larson and co-workers  (1977) have proposed  that breath ammonia is important in neutrali-
zing  inhaled  sulfuric  acid.    Ammonia   is  released  in the  breath   from blood  ammonia and
bacterial  decay  products  in  the buccal  cavity.   Ammonia  in  the breath  could  react  with
sulfuric acid  to produce ammonium bisulfate or ammonium sulfate, depending upon the amount of
ammonia and sulfuric  acid present in  the  aerosol  droplet.  Complete neutralization of sulfuric
acid would produce ammonium sulfate.  This theory  has been discussed at some length (Committee
on  Sulfur  Oxides, NAS,  1978).    Much  of  the  data has not yet  been published,  so a critical
review  of the  model   given for  the neutralization  of sulfuric acid aerosol droplets by gaseous
ammonia is not  available.  Calculation of the  relationship between inhaled sulfuric acid aerosol
and  neutralization  by breath  ammonia  is not  simple,  and the  model  needs to  be validated.
     The biological effects of  sulfuric acid aerosols could be due to a combination of several
factors.  First,  the  pH of the  particle  could be very  important.  Larson et  al.  (1977) have
calculated the  neutralization capacity of the  breath  ammonia.   Once  the  neutralization  capa-
city of the ammonia present in  the breath is exceeded, the pH of the aerosol reaching the lung
may fall  rapidly.   Under low pH, the physical  properties of the mucous layer lining the  upper
airways may  be  altered (Holma  et al.,  1977)  or the permeability of the  lung may be increased
(Charles,  1976).  Second,  the  chemical  composition  of the  sulfate  aerosol,  if  other than
sulfuric acid,  may  also alter  the permeability of the lung to  sulfate (Charles et al., 1977b;
Charles,  1976;   Charles  and  Menzel,  1975b).   Third, the  cation associated with  the sulfate
compound  may have  pharmacological  properties  in  itself.   The  permeability of  the  lung to
sulfate ion presented as various  sulfate  salts  (Charles  et al.,  1977b) is in the same  relative
order as the  irritant potential  found  for  aerosols  of the same  sulfate  salts (Amdur et al.,
1978a).
XRD12A/A                                      12-37                                        2-5-81

-------
     It  is  likely that  ammonia  functions within pulmonary  tissue  as a source  of protons to
increase the  flux  of  sulfate to the site  of  action.   Ammonia can diffuse readily across cell
membranes  as  unionized  ammonia  to  react  with protons  forming  ammonium  ion.   Intracellular
transport  of   negatively charged  sulfate would  result  in  the  concomitant accumulation  of
positively  charged protons  to  preserve  electrochemical  neutrality.   At  physiological  pH
values, a  significant  fraction  of  ammonium salts  is present as ammonia.   Ammonium salts could
augment the local ammonia concentration and thus increase the uptake of sulfate ions and result
in release of  histamine.   Ammonia increased the uptake of sulfate by the lung (Charles et al.,
1977a; Charles, 1976),  possibly by  this mechanism.
     In relation to sulfuric  acid,  ammonium sulfate and  bisulfate  are less  irritating to the
lung  because  of  their  higher  pH  values  once dissolved  in  the milieu  of  the  lung.   Thus,
neutralization of  sulfuric acid  aerosols  by breath ammonia  could  be an important detoxifica-
tion  step.  The  concept  of  breath  ammonia  does  not negate the  histamine release hypothesis
since  ammonium  sulfate  is active  in  the  release  of  histamine  in  guinea pig  lung fragments
(Charles, 1976) and in  rat lungs (Charles  and Menzel,  1975b).
     An important problem is  the relation  of these  observations to human effects.  Unfortunate-
ly,  histamine release  by non-immune  mediate  reactions,  such as  the apparent  ion  exchange
process due to  sulfate interaction with mast  cell  granules  (Charles, 1976), is poorly under-
stood.  Metabolism of  histamine by  man and rodents could have  important  differences.   Also,
not  all  of the  pharmacological  action of  ammonium sulfate instilled  intratracheally  in the
perfused rat  lung  could  be blocked by an  H-l antihistamine (Charles et al.,  1977a).  A number
of  other  inflammatory  hormones, aside from  histamine,  mediate  bronchial tone  in man.   Slow
reacting  substance of  anaphylaxis  (SRS-A or  leukotrienes), prostaglandins, and kinins would
not  be blocked  by an H-l antihistamine.   Thus, species differences are not unanticipated, but
should be clarified so the potential applicability of these data to man is understood.
     The biological effect of sulfate compounds is  highly dependent upon the  chemical  composi-
tion  of  the compound.   For example, for  pulmonary  function  sulfuric acid is much more potent
than  any  sulfate  salt,  but  the  sulfate  salts also  are  of  differing potency.   The cations
associated  with  the sulfate  ion may  promote  the  transport of the  sulfate  ion and,  thereby,
increase  the  biological   response.    The cation has  biological effects  by  itself as discussed
here.   It  is  not possible, then, to predict the potential toxicity of a sulfate aerosol based
solely on the sulfate content.  Clearly, the acidity of the aerosol plays an important role in
the  toxicity  as  do particle size and other physical  properties.
     An  important experimental  problem is raised  by  the ammonia  neutralization of sulfuric
acid.  Ammonia is  produced in all animal experimental exposure systems through the  accumulation
of  urine and feces.   This is  particularly so in whole-body  chronic exposures.   Few exposure
systems provide  a  rapid  turnover of  the chamber air, e.g., 1 chamber  volume/min, and  given the
technological problems in monitoring NH3,  even this rate of air flow  may be  insufficient.  The
XRD12A/A                                     12-38                                        2-5-81

-------
usual  turnover rate  is  10 to 15 chamber  volumes of air/hr or  less.   Under these conditions,
animals  exposed  to  sulfuric acid  aerosols may,  in fact, be  inhaling ammonium  sulfate  and
ammonium bisulfate aerosols as well.  The high concentrations of sulfuric acid aerosols needed
to produce significant  pathological effects on  chronic  exposure  may be due to these chemical
conversions.    Since  human exposure chambers would  not be expected to have  comparably  high
levels of ammonia, there  could be  difficulty in comparing results of human and animal studies
of H2$04-   The  level  of ammonia in the  breath  of animals is also unknown and is sure to vary
with the diet  of  the animals.  Some  commercial  animal  diets  are low in protein, while others
are high.   The  blood ammonia will   depend, in part, on the total amount of protein and quality
of the  protein as well  as on the  kidney  function  of  the animal.   What effects,  if  any,  the
buccal flora have  on the exhalation of ammonia  in animals is totally unknown.   Certainly,  the
propensity  of   S02~  and  sulfuric   acid-exposed  animals  to  develop  nasal   infections  raises
disturbing questions.   The buccal  flora of  animals  may  be very different from that of man in
its ability to  produce  ammonia.   This technical problem of ammonia  in the exposure atmosphere
should  be  addressed  and  solved  before  further reliance  can be  placed  on  these  data  for
sulfuric acid (Table 12-7).
12.3.3.2  Chronic Exposure Effects—The  influence  of chronic  exposure  to  HpSO.  on pulmonary
function was investigated by Alarie et al. (1973a, 1975).  Guinea pigs exposed continuously to
either 0.9 mg/m3 (0.49 urn, MMD) (Alarie et al.,  1975), 0.1 mg/m3 (2.78 urn, MMD) (Alarie et al.,
1973a), or  0.08 mg/m3  (0.84 urn, MMD)  (Alarie  et  al.,  1973a) for  52 wk  had no significant
changes  of  pulmonary  mechanics   (including  measurements of flow resistance,  respiratory
rate,  lung  volumes,  and  work  of  breathing)  that  could be  attributed to  H-SO..   However,
cynomolgus monkeys exposed continuously and tested periodically during 78 wk were affected by
some treatment  regimens (Alarie  et al., 1973a).  Monkeys exposed to 0.48 mg/m  (0.54 urn, MMD)
experienced  an  altered  distribution of  ventilation  (increased  N? washout)  early  in  the
exposure period,  but recovery  occurred during  exposure.   Animals  exposed  to a similar con-
centration  (0.38  mg/m  )  but  a  larger  particle size  (2.15  urn,  MMD)  had  no change  in  this
parameter.    Higher  concentrations  altered  distribution  of  ventilation, with  the  lesser
concentration (2.43  mg/m  ) and larger particle  size (3.6 urn, MMD) causing an onset sooner (at
17 wk compared  to 49 wk)  in monkeys exposed to  4.79 mg/m  H9SO. (0.73 urn, MMD).  Beginning at
                                                3                          3
approximatey 8  to  12 wk of  exposure, 0.38 mg/m  (2.15 urn, MMD), 2.43 mg/m  (3.6 urn, MMD) and
4.79 mg/m3 (0.73  pm,  MMD) H2S04 increased  respiratory  rate.   The only alteration in arterial
partial  pressure  of  0?  was a decrease  observed  in monkeys exposed  to 2.43 mg/m .  Except for
respiratory rate  as  described above, mechanical properties (including resistance, compliance,
tidal volume,  minute volume,  and   work  of breathing) were  not significantly  altered  by the
chronic H?S04  exposures.   Morphological  studies  of these animals  are described  in Section
12.3.2.
     Chronic studies  of dogs were  performed by  Lewis et  al.  (1969, 1973).   The animals were
exposed for 21 hr/day for 225 or 620 days to 0.89 mg/m  H2S04 (90 percent <  0.5 um in

XRD12A/A                                     12-39                                       2-5-81

-------
       SOX12C/A  6 1-30-81
                                       TABLE 12-7.   EFFECTS OF ACUTE  EXPOSURE  TO PARTICULATE  MATTER ON PULMONARY FUNCTION*
             Concentration
                                              Duration
 Species
                                                                                                    Results
                                                                                                                                           Reference
      0 mg/ro3 (40 or 80% RH) 1.2 mg/ms    1 hr
       (40% RH),  1.3 mg/ma (80% RH),
       14.6 mg/m3 (80% RH). 24.3 mg/ms
       (80% RH),  and 48.3 mg/m3 (80%  RH)
       1 pm (MMAO) H2S04 aerosol

      0.8 - 1.51  mg/m3 H2S04              1 hr
       (0.3 - 0.6 M">,  MMAD) or
       0.4 - 2.1  mg/m3 (NH4)2S04
       (0.3 - 0.6 M">,  MMAO)

      2.5 mg/m3 (NH4)2S04.                1 hr
       ZnS04,(NH4)2S04,  H2S04,
       and NH4N03; 2.7 mg/m3
       NH4HS04
Guinea pig   Pulmonary function changes observed in one animal
              (out of 10) exposed to 14.6 mg/m3, three animals
              (out of 9) exposed to 24.3 mg/m3, and four animals
              (out of 8) exposed to 48.3 mg/m3
Donkey       No significant alterations in pulmonary resistance
              and dynamic compliance
Monkey       Increased airway resistance at high relative humidity
              for (NH4)2S04, and low relative humidity for
              ZnS04 (NH4)2S04.  NH4HS04 also increased resistance.
              No significant effects with H2S04 or NH4N03
Silbaugh et al.,  1980
Schlesinger et al.,
 1978
Hackney, 1978
K3


O
      •See  Table  12-6  for  the  Amdur  et  al.  studies  on  pulmonary  function  effects  in  guinea  pigs.

-------
*
diameter) alone  and in combination  with S02 (see  Section  12.4.1.2 for expanded discussion).
After 225 days  (Lewis  et  al., 1969), dogs receiving H2$04  had a significantly lower diffusing
capacity for CO  than  animals that did not receive  H2$04.   After 620 days of exposure, CO dif-
fusing capacity  was still decreased  (p  <  0.05) (Lewis et  al.,  1973).   In addition, residual
volume and  net  lung  volume  (inflated)  were decreased  (p  < 0.05),  and  total  expiratory re-
sistance was increased  (p <  0.05).  Total lung capacity, inspiratory capacity, and functional
residual capacity were  also  decreased (p =  0.1).   Other pulmonary function measurements were
not significantly affected (see Table 12-8).
12.3.4  Alteration  in Host Defenses
     To  protect  itself against  inhaled microorganisms and  inanimate particles,  the host has
several mechanisms  of defense.  Microbes reaching the gaseous exchange regions of the lung can
be phagocytized  and killed by alveolar  macrophages.   Later these  macrophages can move to the
ciliated airways where they  are cleared  from  the lung, along with  other particles that are
deposited on the airways, by the mucociliary escalator.   Inanimate particles can also be en-
 gulfed and  removed  from the  lung by this means (See Chapter 11).   Mucociliary clearance is an
 important defense against both microorganisms and inanimate particles.  It is likely then that
 an  impairment  of mucociliary clearance  might not be expressed as increased infections.   These
 and other means  of  defense against microbes  are discussed here.
 12.3.4.1  Mucociliary C1earance--Fairchi1d et al. (1975b) investigated the influence of a 1 hr
 exposure to  H^SO.  on deposition of  inhaled  nonviable bacteria (Streptococcus pyogenes, 2.6 urn
 MMAD)  in guinea  pigs.  All exposure  regimens used caused no significant alterations of breath-
 ing frequency, tidal volume, or minute ventilation.  After  exposure to 3.02 mg/m  (1.8 urn CMD),
 a 60  percent increase (p < 0.01) in  total pulmonary bacterial deposition  and a proximal shift
 in  the deposition  pattern to the  nasopharynx were observed.  No alteration in deposition was
 observed in  the trachea or  lung.  After exposure to 0.32  mg/m  (0.6 urn  CMD),  no significant
 effect on total  or  regional deposition was seen.  However,  at a lower concentration and parti-
 cle  size (0.03 mg/m3, 0.25 urn CMD),  the deposition pattern did shift (p <  .05) to the trachea
 but without a  significant change in  total pulmonary deposition.
     After studying effects of HpSO.  on  deposition  of bacteria, these investigators  (Fairchild
 et al.,  1975a) turned their attention to effects  on clearance of bacteria.  They  showed that  4
 hr exposures to  15  mg/m3  H2S04 (3.2  urn,  CMD) after  exposure to a nonviable radiolabeled strep-
 tococcal aerosol reduced  the rate  of  ciliary  clearance  of the bacteria from the lungs and
 noses  of mice.   When mice received  a 90 min exposure  to  15 mg/m   H2$04  (3.2 urn, CMD) 4 days
 prior  to the bacterial aerosol, clearance  of nonviable bacteria was reduced in the nose but
 not  in the  lungs.   Neither  regimen  affected clearance  of  viable streptococci.  No significant
                                                O
 effects were seen at concentrations  of 1.5 mg/m  H2$04  (0.6 urn,  CMD).
     Schlesinger et al. (1978) demonstrated  that  1  hr exposures  to  0.3  to  0.6 |jm  H2S04  mist  at
concentrations  in   the  range  of 0.19  to 1.36  mg/m  produced transient  slowing of  bronchial
mucociliary  particle clearance  in  3 of 4  donkeys tested.  In addition, 2 of  the 4  donkeys

XRD12B/A                                 12-41                                         2-5-81

-------
       SOX12C/A  7 1-30-81
ro

ro
                                       TABLE  12-8.   EFFECTS  OF  CHRONIC  EXPOSURE TO PARTICULATE MATTER ON  PULMONARY  FUNCTION
Concentration
Duration Species Results Reference
0.08 mg/m3 HoS04 (0.84 pm, MMD) 52 wk, continuous Guinea pig No effects on pulmonary function. Alarie et al., 1975,
or 0.1 mg/ms H2S04 (2.78 u». MHO) 1973
0.38 mg/m3 (1.15 urn, MHO)
78 wk, continuous Monkey Exposure to 0.48 mg/m3 altered distribution of Alarie et al., 1973
       .. .. mg/m3 (0.54 urn,  HMO)
       2.43 mg/m3 (3.6 pm. MMD)
       4.79 mg/m3 (0.73 jim.  MMD)
       HaS04
      0.89 mg/m3  HZS04  (90X
       
-------
developed persistently  slowed, clearance  after about  6 exposures.   Similar  exposures had no
effects on regional  particle deposition or respiratory mechanics, and corresponding exposures
to (NH4)2S04 up  to  2 mg/m  had no measurable  effects.  In subsequent experiments (Schlesinger
et al.,  1979),  the 2  animals showing  only  transient  responses  and 2  previously unexposed
animals were given  daily 1 hr exposures,  5  days/wk, to H2$04 at  0.1 mg/m3.  Within the first
few wk  of exposure,  all 4  donkeys  developed erratic clearance rates,  i.e.,  rates which, on
specific test  days,  were either significantly slower  than  or significantly faster than those
in  their pre-exposure   period.   However,  the degree  and  the  direction  of  change  in  rate
differed  to   some  extent   in  the different   animals.   These changes  may herald  subsequent
alterations and,  like  many other toxicant effects,  may represent  important low level signals
at  the  detection  limit   of  the  method.    The  2  previously unexposed animals  developed
persistently slowed  bronchial  clearance during the  second 3 mo of exposure and during 4 mo of
follow-up  clearance  measurements,  while  the  2  previously  exposed animals  adapted  to  the
exposures  in  the sense  that  their  clearance  times  consistently fell within  the  normal range
after the  first  few wk  of  exposure.   The sustained, progressive slowing of clearance observed
in 2  initially  healthy  and previously unexposed animals is  a  significant observation, since
any persistent alteration  of  normal  mucociliary  clearance  can have  important implications.
Lippmann et al.  (1980) have conducted similar  experiments in human subjects which are reviewed
in Chapter 13.
     Tracheal  mucociliary  transport  rates have been measured in several other animal studies.
Sackner et al. (1978a) failed to find significant changes in tracheal mucus velocity following
short-term exposures to 14 mg/m  (0.12  urn)   H-SO.  in  sheep.   Similarly,  Schlesinger et al.
(1978)  saw no  effect on tracheal transport  in donkeys after 1-hr exposures to concentrations
up to  1.4 mg/m3  (0.3 to 0.6 ^m MMAD) H9SO..   On the other hand, Wolff et  al.  (1979a) reported
                                                                                             3
a  depression  in  tracheal  transport  rate  in  anesthesized  dogs  exposed for 1  hr  to 1.0 mg/m
(0.9 urn,  MMAD, a  1.4)  which  persisted  at 1  wk postexposure.  Recovery had occurred when the
                 9                                                                           3
animals  were  examined again  at 5 wk post  exposure.  Following a 1  hr  exposure  to 0.5 mg/m
H-SO.,  there were slight increases (p  >0.05)  in  tracheal  mucous  velocities immediately and 1
day after exposure.  However,  1 wk after exposure, clearance was significantly decreased.  The
latter  results are  quite similar to those observed  in the bronchi of individual humans in the
Lippmann et al.  (1980) study (see Chapter 13), although they recorded no significant change in
the mean tracheal mucociliary transport rates.
     Clearly,  the results  of  the donkey  studies  support the  human experiments  (Chapter 13)
which  indicate  that  H2S04  aerosol  affects   mucociliary clearance  in  the distal  conductive
airways.  Mucociliary  clearance  is  dependent  upon  both  the  physicochemical properties of the
mucus  and the coordinated  beat of  the underlying  cilia.   Mucus  is excreted into the airway
lumen  in  an  alkaline  form which  is  then acidified by C02  (Holma  et  al.,  1977).   In vitro
studies  have  shown  that mucus is a  sol  in  high  pH solutions, while  at  lower pH it  becomes
viscous (Breuninger,  1964).   The H+ supplied  by  the H2S04 may stiffen  the mucus and  increase

XRD12B/A                                12-43                                         2-5-81

-------
the efficiency of  removal.   This is consistent with  the  increase  in bronchial clearance rate
observed in  humans  following exposure  to 0.1 mg/m3.  Major changes  in  mucous viscosity could
also  impair  clearance by  making the mucus  so stiff that  ciliary movement  is  not possible.
Other studies  (Grose  et  al., 1980;  Schiff et  al.,  1979)  have shown that exposures to 0.9 to
1.1 mg/m3  H2$04  can cause a depression  of  tracheal  ciliary beat frequency  in hamsters which
may lead to a depression in overall bronchial  clearance.   See  Sections 12.4.1.1 and 12.4.2 for
more details on these latter studies (Grose et al.,  1980;  Schiff et al., 1979) which were con-
ducted with pollutant mixtures.
     Based on  the  results  summarized  above,   it  is possible  that chronic H^SO^  exposures  at
concentrations of  about  0.1 mg/m   could produce persistent changes  in mucociliary clearance
and exacerbate preexisting respiratory  disease (see  Table  12-9).
     Cadmium and nickel  chlorides also  disrupt the activity of the  ciliated epithelium (Adalis
et al., 1977,  1978).  Tracheal  rings have been  isolated  from hamsters  and the beat frequency
and morphology of  the ciliated  epithelium have been observed.   Concentrations of CdCl« as low
as  6  uM   i_n  vitro  resulted in  decreased beat  frequency and  degradation  of  the  ciliated
epithelium architecture  (Adalis  et al.,  1977).   A prior  2-hr exposure i_n vivo to 2 urn aerosols
of  CdCl9   at  0.05  to  1.42  mg/m    caused  a  significant  decrease  in  cilia beat  frequency
                                                                                    3
proportional  to the  aerosol  concentration.   When hamsters were exposed  to 1.33 mg/m  Cd for 2
hr/day  for 2  days,  the  beat  frequency did  not return to  control  values  until  6  wk after
exposure.   Nickel  chloride aerosols or  solutions had similar,  but less marked, effects (Adalis
et al., 1978).  The beat frequency decreased by 60 beats/min on exposure to 0.1 mg/m  Ni for 2
hr.   The  decrement in beat  frequency was  proportional  to  the concentration  of  Ni  aerosol  or
solution.   A  single  2 hr exposure to 0.1  mg/m  Ni  depressed  cilia beat frequency 24 hr after
exposure,  but the frequency returned to near normal  values after 72 hr.   After exposure to 0.1
ng/m  ,  Cd  was about  20  percent more effective than Ni  in slowing  cilia beat (Table 12-10).
12.3.4.2   Alveolar Macrophages—Cytotoxicity  of components of  atmospheric aerosols  has been
studied with alveolar macrophages  (AM).   The  physiological  role  of AM  in  the  prevention  of
infection  and  in the defense of the lung  through  removal  of  inhaled particles has been amply
demonstrated (Green, 1970).
     The viability  of guinea pig alveolar macrophages was decreased by Min-u-sil silica (6.8,
4.5,  and   2.7  urn  MVD),  with the  effect  increasing as particle  size  decreased  (Ottery and
Gormley, 1978).
     Aranyi  et al.  (1979) reported cytotoxic effects to AM with fly ash particles coated with
PbO,  NiO,  or Mn02-   The percentage of  metal adsorbed on the fly ash was fairly similar across
particle size  for  a given metal.  The  fly  ash particles  were of three size  ranges:  <2, 2 to
5,  or 5 to  8 urn  in  diameter.   All of  the  particles,  regardless of the coating or particle
size,  decreased  cell  viability and were phagocytized by  the  AM.   Within  a given chemical
series of coated particles, the  effects were both concentration and size related, with  smaller
particles  and  greater concentrations producing greater  effects.  The  greater surface  area of

XRD12B/A                                12-44                                         2-5-81

-------
 SOX12C/A  8 2-5-81
                                            TABLE 12-9.  EFFECTS OF SULFURIC ACID ON MUCOCIL1ARY CLEARANCE
       Concentration
                                        Duration
                         Species
                                                                                              Results
                                                                                                                                     Reference
0.1 mg/ra3 H2S04
0.19 to 1.4 mg/m3 H2S04 (0.3
 to 0.6 MI". MMAD)

0.5 mg/m3 H2S04
1.0 mg/m3 H2S04 (0.9 urn, MMAD,
 o  1.4)
  9
1.4 mg/m3 H2S04 (0.3 to 0.6 urn.
 MMAD)

1.5 mg/m3 H2S04 (0.6 urn, CMO)

14 mg/m3 H2S04 (0.12 UB HMAD)


15 mg/m3 H2SO« (3.2 urn, CHO)        4 hr
 15 mg/m3  H2S04  (3.2 urn. CMD)
1 hr/day, 5 day wk,
 several mo
1 hr


1 hr



1 hr


1 hr


90 min

Short-term
90 min
Donkey       Within the first few wk, all 4 animals developed
              erratic bronchial mucociliary clearance rates,
              either slower than or faster than those before
              exposure.  Those animals never pre-exposed before
              the 0.1 mg/m3 H2S04 had slowed clearance during
              the second 3 mo of exposure.

Donkey       Bronchial mucociliary clearance was slowed.
Dog          Slight increases in tracheal mucociliary transport
              velocities immediately and 1 day after exposure.
              One wk later clearance was significantly decreased.

Dog          Depression in tracheal mucociliary transport rate
              persisted at 1 wk post-exposure.

Donkey       No effect on tracheal  transport..
House        No significant effects.

Sheep        No significant changes In tracheal  mucociliary
              transport rate.

House        Exposure to H2S04 after  exposure  to a  nonviable
              streptococcal  aerosol reduced the  rate  of  ciliary
              clearance of the bacteria from the lungs and  nose.

House        Exposure to H2S04 4 days prior to bacterial  aerosol.
              Clearance of nonviable  bacteria  reduced in nose,
              but not lungs.
 Schlesinger et al.,
  1979
                                                                                             Schlesinger et al.,
                                                                                              1978

                                                                                             Wolff et al., 1979a
Wolff et  al.,  1979a


Schlesinger et al.,
 1978

Fairchild et al.,  1975a

Sackner et al., 1978a


Fairchild et al., 1975a



Fairchild et al., 1975a

-------
  SOX12C/A   9  2-5-81
                                    TABLE 12-10.  EFFECTS OF METALS AND OTHER PARTICLES ON HOST DEFENSE MECHANISMS
Concentration
0.01 or 0.15 mg/m3 Pb20s
(0.18 um, MMAD)
Duration Species
3 mo Rat
Results
Decreased the number of alveolar macrophages/lung.
Reference
Bingham et al. ,

1968
 0.01 mg/m3  (0.17  urn, MMAD)  PbCl2
 or 0.11 mg/m3  (0.32 urn, MMAD)
 NiCl2  or 0.15  mg/m3 (0.15  urn.
 MMAD)  Pb203  or 0.12 mg/m3  (0.17
 pm, MMAD)  NiO
0.05 to  1.42 ng/m3 CdCl2

0.1 mg/3 NiCl2

Graded concentrations:
 0.075 to 1.94 mg/m3 CdCl2
 0.1 to 0.67 mg/m3 NiCl2, or
 0.5 to 5 mg/m3 Mn304;
 all aerosols (94-99%) <1.4 um
 in diameter

109 mg/m3 Mn02 (0.70 um, mean
 diameter)
0.2 mg/m3 CdS04, 0.6 mg/m3 CuS04.
 1.5 mg/m3 2nS04, 2.2 mg/m3
 A12(S04)3, or 3.6 mg/m5 MgS04

Ammonium sulfate at 5.3 mg/m3
 S04. NH4HS04, at,6.7 mg/m  S04,
 N02S04 at 4 mg/mj S04, Fe2(S04)2
 at 2.9  mg/in3 S04, or
 Fe(NH4)2S04 at 2.5 mg/m3 S0«
12 hr/day, 6 day/wk,
 2 mo with PbCl2,
 NiCl2, or NiO; con-
 tinuously for 2 mo
 with Pb203
2 hr

2 hr

2 hr
Rat
Hamster

Hamster

Mouse
3 hr/day
Mouse
3 hr
3 hr
                        Mouse
                        Mouse
Exposure to Pb20,, but not PbCl2, resulted in a
 depression of the number of alveolar macrophages
 (AM) for up to 3 mo but returned to control  levels
 within 3 days after discontinuation.   NiO produced
 a marked AM elevation, while NiCl2 did not.   NiCl2
 resulted In marked increases in mucus secretion and
 bronchial hyperplasia.  No morphological  alterations
 with PbCl2 or Pb203.

Decreased ciliary beating frequency in trachea.

Decreased ciliary beating frequency in trachea.

The aerosols increased the mortality from the sub-
 sequent standard airborne streptococcal infection:
 CdCl2 affect the response at 0.1 mg/m3 Cd, NiCl2 at
 0.5 mg/m3 Ni. and Mn304 at 1.55 mg/m3 Mn.
Increased mortality after 3 or 4 days exposure when
 mice received bacterial aerosol immediately after
 exposure.   When the bacteria were administered 5 hr
 post pollutant exposure, a single 3 hr exposure
 increased mortality.   In mice exposed to aerosols
 of virus 1 or 2 days prior to Mn02, there were also
 increased mortality and pulmonary viral lesions.

Estimated concentrations which caused a 20% enhance-
 ment of bacterial-induced mortality over controls.
             No significant alterations of host defense
              mechanisms.
                                                                     Bingham et al.,  1972
Adalis et al.,  1977

Adalis et al.,  1978

Gardner et al., 1977b
Adkins et al.,  1979,
 1980C
                                                                     Mai getter
                                                                      et al.,  1976
                                                                                             Ehrlich et al.
                                                                                              1978, 1979
                                                                                             Ehrlich et al.
                                                                                              1978, 1979
5.0 mg/m3 carbon black or 2.5       2 hr
 mg/m5 iron oxide

0.19 mg/m3 CdCl2                    2 hr
0.25 mg/m3 NiCl2
                        Mouse        No significant increases in mortality resulted on       Gardner,  1981
                                     subsequent exposure to airborne infection.

                        Mouse        Decreased number of antibody-producing spleen cells.    Graham et al.,  1978

-------
*
the smaller particles was suggested as being  responsible  for  the  greater  toxicity of the small
particles.   Total  cellular  protein and  lactic  acid dehydrogenase also decreased after treat-
ment, probably  as  a non-specific  result of the death of  the cultured AM.   For each particle
size, Pb-coated particles  were  most toxic,  NiO-  and  MnCycoated  particles had intermediate
effects, and  the  untreated  fly ash was  least toxic.  The  toxicity  did not appear related to
the  solubility  of  the metal oxide coating, since  no soluble  metal could  be  found using the AM
themselves  as  a  bioassay.   The  toxicity appeared  to  be  associated  with  the  uptake  of  the
intact  particle.   No changes  were observed  in the  total  lysosomal  enzyme  content,  but the
latency  or  intactness   of   the   lysosomal  membrane  was  not  examined.   Toxicity  could  have
resulted from the  disruption of the intracellular  lysosomal membrane,  which  in turn could have
released intracellular  lysosomal   enzymes.  Lysosomal enzyme  release has  been proposed as one
potential  mechanism  for the  toxicity   of  asbestos and  silica  particles (Heppleston,  1962).
These  results  support  the  concept  that the  surface  activity  of  particles  determines  the
toxicity of the particle  (Allison and Morgan, 1979).
     Camner  et  al.  (1974)  exposed  rabbit  alveolar  macrophages   HI vitro to 5  pm  Teflon
particles  coated  with Al,  Be, C,  Pb, Mn, Ag, and  U.   All  particles were phagocytized by the
 cells,  but only Be caused a decrease  in  viability.
     Although  White and  Kohn  (1980) did not consider  particle  size  in their  investigation,
 they did conduct i_n  vitro alveolar macrophage studies with  iron carbonyl  (0.5-5  |jm, diameter),
 SiO? (size not given),  crocidolite  and  crysotile  asbestos (size not  given), kaolinite (size
 not  given),  and polystyrene latex beads (1.1 urn,  diameter).   Although particle  to cell ratios
were roughly equivalent  (10-15 particles/cell),  the particle concentration differed markedly
 for  each chemical.   Enzyme release  was measured.   Compared  to  a  no  particle  control group,
 iron carbonyl,  SiO?,  both forms of asbestos and  latex beads,  but  not kaolinite,  increased (p  <
 0.02) the percent  of extracellular p-glucuronidase (a lysosomal enzyme).  Similar results were
 obtained  for % extracellular  LDH, except for this  parameter,  latex beads  had  no significant
 effect.   All   particles,   except crocidile  asbestos   and  latex   beads  increased  elastase
 secretion.
     Allison  and   Morgan  (1979)   have summarized  the evidence  that  AM ingest  both toxic and
 non-toxic  particles  in  the  same  manner.    In  the  case  of  fibers,   ingestion  appears  more
 dependent  upon the  length  of the fiber (Allison,  1973).    Short fibers of >5 urn are almost
 always  ingested, while  fibers  >30 pm  are seldom  ingested  completely  and remain  in contact with
 the  plasma  as well  as with the  lysosomal surface.   Intermediate sized particles (5 to 20 urn)
are  sometimes  completely  ingested   and sometimes  not.    Once  ingested, particles  have two
effects.   An  immediate  cytotoxicity  appears  which is apparently  due to the  interaction of the
particle with  the  plasma membrane (Allison and  Morgan,  1979).  This interaction is  similar  to
the  hemolytic effects  described   for silica particles.   The  second  effect  results  in  delayed
cytotoxicity and occurs  after  the particle  has  been ingested  into a  primary  phagocytic  vacuole
which  then  combines with  a primary lysosome  to  yield  a secondary  lysosome   containing the

XRD12B/A                                 12-47                                        2-5-81

-------
particle  (Allison  and  Morgan,  1979).    Here  toxic  particles  exert  an  effect  upon  the
permeability of the lysosomal membrane, resulting in the release of lysosomal enzymes into the
cell and  into the external  medium.   These  proteolytic enzymes have the  potential  of causing
tissue damage.
     Hatch et al.  (1980) examined the influence of iji vitro exposure to a variety of particles
on AM  oxidant production  (0~ and H?0?) and  found  the response to be chemical specific.  All
the particles studied stimulated the chemiluminescence, with amphibole asbestos being the most
active.  Silica,  chrysotile  asbestos,  and  metal oxide  (Pb,  Ni,  Mn)-coated fly ash had inter-
mediate activity.   Fugitive dusts and fly ash had the lowest activity.
     Waters  et al.  (1974)  found  that  AM  cultured  with particulate  forms of  vanadium  had
decreased  cell  viability,  indicating  a   direct  cytotoxicity.   Alveolar  macrophages  were
cultured in medium containing vanadium pentoxide (VpOr), vanadium trixoide (V^,), or vanadium
dioxide  (V0?).    Cytotoxicity  was  directly  proportional   to the  solubility of  the  vanadium
compound:    V20&   >  V203 >  V02-   The  concentration  of  V  required to  produce a  50  percent
decrease in  viability  after  20 hr of culture was found to be:   13 ug V/ml as VpOr, 21 ug V/ml
as V203%  and  33  ug  V/ml  as  V0?.  When  V?05  was  dissolved in the medium  prior to incubation
with the  AM,  only about  9  (jg  V/ml  were  required  to  reduce viability  by  50  percent,  thus
indicating  that  the soluble  V was  responsible for toxicity.   Phagocytosis, an  essential
function for the defense of the lung, was decreased  by 50 percent  with 6 ug  V/ml as dissolved
VpOr.   Acid  phosphatase,  a   lysosomal degradation  enzyme necessary  for digestion of  phago-
cytized bacteria,  was  inhibited by 1  ug V/ml  as VpOr, while the  lysosomal  enzymes,  lysozyme
and p-glucuronidase, were not inhibited by  concentrations as high as 50 ug V/ml.
     The effects  of Fe?0- on AM have also been investigated.   Rabbits were exposed for 3 hr to
186-222 mg/m3 Fe203 (0.17-0.31  um,  MMAD),  and  AM  were  removed  0, 12,  18, and  24  hr later
(Grant et  al.,  1979).   When  selected lysosomal enzyme activites were determined for the first
three  post-exposure times,  there  were  no  significant  differences  from control.   However,
since  an  increased  (p  < 0.02) number of cells were  recovered 12, 18, and 24  hr post-exposure,
the  total  amount  of some of the lysosomal  enzymes in the lung was increased.   It appears that
the  increased  number of cells was due to the influx  of smaller cells into the lung.
     Alveolar  macrophages  exposed  J_n vitro for  20  hr to metallic salts  were  also studied by
Graham et  al.  (1975b)  using  a  technique to  determine phagocytosis of viable cells only.  The
chlorides  of Cd  (2.2  x 10~5M), Cr  (3.1 x  10~3M),  Mn (1.8 x 10~3M),  and  Ni  (5.1  x 10~4M)
significantly  inhibited  phagocytosis.   Ammonium vanadate  (6.9  x  10  M)  had no effect  on
phagocytosis,  but did   lyse  and kill  cells.   Nickel, which caused  the  greatest reduction in
phagocytosis,  had very little  effect on viability  or  cell  lysis.   Antibody-mediated rosette
formation of  AM was also inhibited iji vitro  by low concentrations of  CdClp (2.2 x 10~5M) or
NiCl2  (10   M) (Hadley   et  al.,  1977).   Inhibition  was proportional to the  Mi"*"*" or Cd++ con-
centration  and reached its  maximum  within 20  min.   These  studies showed  that the antibody
dependent  recognition  system of AM  was inhibited  by  trace  concentrations  of  NT"*"*"  and Cd++

XRD12B/A                                12-48                                        2-5-81

-------
almost immediately after contact with the metal.  Such  an effect  implies that these metals may
affect  receptors  for  phagocytosis  of  the opsonized  bacteria.   Depression of  AM viability,
phagocytosis, and  receptors  for  phagocytosis may  be  a mechanism  by  which these heavy metal
salts  increase  the  susceptibility  to  airborne   infections  as  discussed  later  (Section
12.3.4.3).
     Bingham and co-workers (1968, 1972) have examined the effects of Pb and Ni  inhalation on
the number  and  type of AM  present in the lungs  of  rats.  In a preliminary report, Bingham et
al. (1968)  showed  that a 3 mo  exposure to 0.01  or  0.15 mg/m3 Pb,0, (0.18 |jm, MMAD) decreased
                                                                  c.  <3
the  number  of AM/lung.   The specificity  of  this  response  was  investigated  in a subsequent
study  (Bingham  et  al.  1972) using  soluble  PbCl2  (0.1 mg/m3,  0.17 urn  MMD) and NiCl- (0.11
mg/m  , 0.32 \m MMD) and insoluble  Pb203 (0.15 mg/m3, 0.15 urn MMD) and NiO (0.12 mg/m3, 0.25 ^m
MMD) aerosols.  Rats were exposed  for 12 hr/day,  6 days/wk for 2  mo.  The only exceptions were
those exposed to Pb203 continuously.  Exposure to Pb203, but not  PbCl2, aerosols  resulted in a
depression  of  the  number of  AM which persisted  throughout the experiment.  The number of AM
was depressed on inhalation of  0.15  mg/m  Pt>2°3 for  UP  to 3 mo> but returned to control levels
within  3 days  after discontinuation  of the  exposure.   The solubility of the Ni  compound also
had  marked  effects on the  biological response.   Nickel oxide produced  a  marked elevation in
the  number  of AM/lung,  while  NiCl2 did  not.  The  most  significant  effects in  NiCl2-exposed
rats  were  marked  increases in mucus  secretion   and  bronchial  hyperplasia.  No  morphological
alterations were observed in  those rats exposed to PbCl,, or Pb?0^.  Isolated AM also varied in
diameter with  the  exposure,  but  the  biological  significance of this size variation  is not
known  at  present.   Perhaps  different cell  populations were recruited into the  lung with the
differing exposure  conditions.
      Cadmium chloride aerosols  also  altered the number  and kind of  cells recoverable by lavage
following exposure  (Gardner,  1977b, 1981).   The  total  number of  AM isolated from exposed rats
decreased following exposure to 1.5  mg/m  Cd (99 percent <3 urn  in diameter)  but returned to
normal  values  within  24  hr.    The viability of  the  isolated cells decreased  by 11.2 percent
immediately  after  exposure and  was still  depressed  24  hr later.   There was  an  influx of
polymorphonuclear  leukocytes,  especially  24 hr post-exposure, but  no  increase in lymphocytes.
These  effects  were not observed  at  0.5 mg/m  Cd,  indicating that  the minimum effective dose
may  lie somewhere between these two  concentrations.
      Nickel  chloride  aerosols  (Adkins et al., 1979; Gardner 1981) produced neither an effect
on the  number of AM isolated  by lavage  of rats the  day  following  a  2 hr exposure  to 0.65 mg/m
Ni nor  an  influx of polymorphonuclear  leukocytes.   The phagocytic  capacity of the isolated AM
was,  however,  depressed.   A 2-hr  exposure of mice to 0.9 mg/m  Mn304  reduced the number of AM
which  could be  recovered  by  lavage,  but  did not  result  in an influx of other cell types
(Adkins et  al.,  1980a).   The AM  had a  reduced concentration of ATP and  total protein and acid
phosphatase activity.  Viability  and phagocytic activity of AM were normal.
XRD12B/A                                 12-49                                        2-5-81

-------
     The number, function and kind of cells isolated from the lung by lavage are influenced by
the prior  exposure  to  heavy metal aerosols.  Not  all  metals produced the same effect but Cd,
Ni, and Mn also enhanced the susceptibility of mice to subsequent airborne infections (Gardner,
1981).  The  observations  of two independent laboratories (Bingham et  al.,  1968, 1972; Adkins
et al., 1979) on NiCl? aerosols are essentially in agreement (Table 12-10).
12.3.4.3   Interaction with  Infectious Agents—Gardner  (1981)  and  Ehrlich (1978) have reviewed
their groups' studies and presented new data on the effects  of aerosols on host defense mecha-
nisms against  infectious  pulmonary  disease in mice.   In  all  of  the  Gardner studies, 94 to 99
percent of the aerosols  was  less than  1.4 urn  in diameter (Gardner et  al.,  1977b; Gardner,
1981).  Animals were placed in a head-only exposure system for 2  hr and were given graded con-
centrations  ranging  from 0.075  to  1.94 mg/m   Cd (Gardner  et  al.,  1977b), from  0.1  to 0.67
mg/m  Ni (Adkins  et  al.,  1979), or from 0.5  to 5 mg/m  Mn  (Adkins et al.,  1980c).   In mice,
these exposures to  Cd  and Ni  chlorides and Mn,0. resulted in the deposition of 0.002 to 0.026
mg Cd  (Gardner  et al.,  1977b), 0.001 to 0.012  mg Ni  (Adkins et  al., 1979), or 0.005 to 0.042
mg Mn  (Adkins  et  al.,  1980b)  per g dry weight of lung respectively.   Nickel clearance (Graham
et al.,  1978)  from the  lungs  of mice had a half-life of 3.4 days;  while Mn  (Adkins  et al.,
1980b) clearance  was  rapid, with a half-life of  only  4.6 hr.   None  of the  exposures appeared
to be  edematogenic as  judged  by the  ratio of dry weight  to wet weight of the lung.   After
metal exposure, mice were challenged  with an aerosol  of Streptococcus pyogenes (S. pyogenes).
The aerosols of CdCl2 (Gardner et al., 1977b), NiCl2 (Adkins et al.,  1979),  or  MnCl2 (Gardner,
1981)  increased  the mortality  from  the subsequent standard airborne  infection.   Cadmium was
more toxic  than  Ni,  which was more toxic than Mn.  Exposure to Cd and Mn resulted in a signi-
ficant linear  concentration response.   The lowest concentration  tested at which a significant
increase in mortality was  detected  was 0.1  mg/m  Cd or 0.5 mg/m  Ni.  Manganese, as Mn^O^
(Adkins et al.,  1980c),  was statistically estimated to  produce  a 10 percent increase in mor-
tality at  1.55 mg/m  Mn, while MnCl_  (Gardner,  1981)  required a higher concentration to pro-
duce  a measurable increase in  mortality.   Using a different infectivity model  (Maigetter et
al. , 1976), 3 or 4 days (3  hr/day) of exposure to 109 mg/m  MnO?  (0.70 urn, mean diameter) were
required to increase mortality  consequent to  Klebsiella pneumoniae infection  when the mice
received the bacterial aerosol immediately after exposure.
     The toxicity of  NiCl2 was complex (Adkins et al.,  1979).   Nickel exposure had no effect
on the  S.  pyogenes  infection  if the bacteria was given immediately after Ni aerosol exposure.
When  the  bacterial exposure  was delayed  by 24 hr,  Ni aerosols   increased  the  mortality in a
concentration-related fashion.   In  contrast,  effects  of  CdC1? (Gardner  et  al., 19J7b) and Mn
(Gardner,  1981) were observed when the bacterial challenge immediately followed  exposure.  The
concentration-response  curve  of Ni was very  steep compared to  those of Cd and Mn exposures
(Gardner,  1981).   No  explanation has  been offered for the delay in effect of Ni.  Perhaps the
delayed effects  represent  either  redistribution of Ni  to   the  site of  action or  some  major
change in  the  lung such as  death of a specific cell type.  The delayed toxicity  does raise the
possibility of carry-over of effects from  a single exposure  to a second.
XRD12B/A                                12-50                                        2-5-81

-------
     The  influence  of  a  variety  of  sulfate  species  on  host  defense  mechanisms  against
infectious  respiratory disease  has  been  investigated  by  Ehrlich  (1979)  and Ehrlich  et al.
(1978)  using  the  infectivity  model  with  S.   pyogenes.   Mice  were  exposed  for 3  hr.   The
estimated  concentrations  of  the  compounds  which  caused  a  20  percent  enhancement  of
bacterial-induced  mortality  over controls  were 0.2  itig/m3  CdS04>  0.6  mg/m3  CuSO.,  1.5 mg/m3
ZnS04, 2.2  mg/m   A12(S04)3,  2.5 mg/m   Zn(NH4)2(S04)2,  and  3.6 mg/m3 MgS04-  Ammonium sulfate
at 5.3 mg/m  S04, NH4HS04 at  6.7 mg/m3  S04> Na2S04 at 4 mg/m3 S04,  Fe2(S04)3 at 2.9 mg/m3 S04>
and Fe(NH4)2S04  at 2.5 mg/m  S04 did  not cause significant alterations.  The nitrates of Pb,
Ca, Na,  K,  and  NH4 did  not  cause  an effect at concentrations of 2 mg/m3 or higher.   However,
Zn(N03)2 caused effects similar to ZnS04-  From this body of work,  it appears that the NH4 ion
rendered the compound  less toxic,  and  that the toxicity is primarily due to the cation.  With
the infectivity model, ZnS04  and Zn(NH4)2(S04)2 ranked differently than with airway resistance
experiments  (Amdur et  al.,   1978a).    This  is  not  unexpected as airway  resistance  primarily
detects  alterations of  the  medium to  large  conducting airways, while the infectivity model
(Gardner and Graham, 1977) is hypothesized to reflect alveolar level changes.
     When  mice  were exposed  for 2 hr  to  5.0  mg/m   carbon  black or 2.5 mg/m3  iron  oxide,  no
significant  increases   in  mortality  resulted  on  subsequent  exposure  to  airborne  infection
(Gardner, 1981).
     Death  from  S.  pyogenes   exposure  in  this  infectivity model  is due to septicemia (Gardner
et  al.,  1977b).    Septicemia  occurs  when  the bacteria have grown to  10   organisms  per lung.
Removal and killing of the inhaled organisms will reduce the growth of  the bacteria within the
host and prevent the occurrence of septicemia.  For these reasons,  the  infectivity model is an
integrative  assessment  of  toxicity  for host  defense  systems  against  infectious  pulmonary
disease.  As reported  above,  the number,  kind,  function and viability of the cells isolated by
lavage  from the  lungs  of animals  exposed to  heavy metal aerosols are  different from those of
control  animals.   Studies  of   trachea!  rings  isolated from aerosol-exposed  hamsters  also
indicate  depression of  mucociliary  clearance.   Both mucocilary and AM clearance of bacteria
are depressed by aerosols of  these heavy  metals (Gardner, 1981)  (Table  12-10).
12.3.4.4  Immune Suppression--Antibodies  play a significant role in the ability of macrophages
to  recognize and engulf pathogenic bacteria.   The functioning of the  immune system interlocks
with  the macrophage system   in other  ways also.   In  mice,  intramuscular  injections  of NiCl2
depressed the number of antibody-producing cells in the spleen  (Graham et al., 1975a).  Using
the  Jerne  plaque  assay,  a   negative  linear  dose-response curve  was found  with injections
ranging from 9.26  to 12.34 ug Ni/g body weight.  No effect  was observed with a dose of  3.09 ug
Ni/g body  weight.   The inhalation of  NiCl2  aerosols  (99 percent less  than  3 urn in diameter)
was  more  effective  in  suppressing  the primary  immune  response.   Graham  et al.  (1978)
calculated  that  exposure  to  an aerosol of 0.25 mg/m3  Ni  for 2 hr  would  result in a  maximum
deposition  of 0.98 ug  Ni,  assuming  complete  retention and  a  minute volume  of 1.45 ml/g body
weight.   This  concentration  was  found to  be the lowest tested which produced a significant

XRD12B/A                                12-51                                        2-5-81

-------
*
depression  in  the  immune  response.   The  lowest dose  found  to produce  a similar  effect by
injection was  208 ug  Mi/mouse  (Graham et  a!.,  1975a).  The inhalation  dose  was, therefore,
approximately 200 times more potent.   Ni was found to follow first order removal kinetics from
the lung, but measurable elevations remained in the lung up to 4 days after exposure.  Similar
kinetics  of  removal  have  been  found using  the  isolated,  ventilated,  and perfused  rat lung
(Williams et  al., 1980) and  human,   rat,  and cat  type II pneumocytes in  culture (Saito and
Menzel, 1978).
     Inhaled Cd  also depresses  the number of antibody producing cells and is more potent than
intramuscularly  injected  Cd.   The highest  intramuscular  dose of CdCK examined  by  Graham et
al. (1978) was  11.81  ug Cd/g body weight  (about 266 ug Cd/mouse),  and it produced no immuno-
suppression.   When mice were  exposed to 0.19 mg/m  Cd for 2 hr, a significant suppression was
observed.  In both cases the Cd was administered as CdClp, a highly soluble salt.   The inhala-
tion dose can be calculated on the same basis as that given above for Ni to be at a maximum at
0.74 |jg Cd/mouse.  The inhaled dose was, therefore, at least 350-fold more potent.  Inhalation
also  appeared  to be more  potent  than  ingestion or  interperitoneal  injection (Exon  et al.,
1975;  Keller et  al.,  1975).   Koller et al.  (1975) found that  150 ug  Cd given orally was
required  to produce immunosuppression.
     For  comparative  purposes,  the  lowest  inhalation  exposure  of  CdCl9  found to be immuno-
                          00                                  ^
suppressive was  0.19 mg/m;  0.2 mg/m  was the 1971 Threshold Limit Value (TLV).   The current
TLV  is 0.05 mg/m .  The  human  intake from air  has  been  estimated  to be  7.4  |jg/day and from
water  to be  160 ug/day (Schroeder,  1970).   NiCl,  was found  to  be immunosuppressive  at  an
                                 3                         3
inhalation exposure of 0.25  mg/m  while its  TLV is 1 mg/m .   The human exposure is estimated
to be  2.36 (jg/day from inhalation and 600 ug/day from ingestion (Schroeder, 1970).  Should the
effectiveness of inhaled  aerosols be equivalent in  mice  and  men, then the  inhaled  doses are
biologically almost equivalent to those ingested.
     Inhaled Cd  or  Ni  aerosols  impair the bacterial defenses of the lung through direct cyto-
toxicity  to  AM, depression  of  antibody  production,  and inhibition  of  antibody  dependent
aggregation  reactions.   All  of these mechanisms can help to explain  the increased suscepti-
bility of mice  to airborne pathogens following  inhalation of Ni or Cd aerosols.  The rapidity
of clearance of Ni and Cd from the lung may allow rapid recovery (see Table 12-10).
     Mouse splenic  lymphocytes  have  also been exposed  i_n  vitro to  500 ug of various sizes of
silica (Wirth  et  al., 1980)  and mitogen-induced  transformation  measured (a  reflection of
immune function).  Four silica samples were tested unfractionated, or size-fractionated  into 2
categories  (0.3  and   5.3  urn).   All  the  unfractionated samples  depressed  the blastogenic
response  to  Conconavalin  A  (a  measure  of   T  cell  function)  and  LPS  (a measure  of  B cell
function).   The  T cell  response  was decreased  by  the  0.3 urn size  fraction  of  all samples.
However,  the 5.3 urn particles of 2 samples increased the response, while one sample caused no
change  and another  caused  a small decrease.  When B cell function was  examined,  it was more
depressed by  the 0.3  urn  silca than  the 5.3  urn particles, although 3  of the 4  larger-sized
samples did cause a decrease.
XRD12B/A                                12-52                                         2-5-81

-------
     Kysela et al.  (1973)  administered high  concentrations  (50  mg) of 9 sizes of quartz dust
(0.7 to 35 Mm) to rats by intratracheal instillation.  A variety of biochemical determinations
as well as  a  histological  examination of  the lungs were made 3 mo after dosing.   As particle
size decreased, there was a trend towards  increased wet weight of the lung, hydroxyproline con-
tent,  total   lipids,  esterified  fatty acids  and  phospholipids.   Only cholesterol  showed  a
slight increase.   For hydroxyproline in total  lung, the increase was stepwise, with increments
occurring at  about  0.9,  5, 7, and 10 urn.  Between 0.7 and 14 urn, the increase was significant
(p < 0.05).   Lipid  changes,  based on gram of  tissue, exhibited a trend towards linearity with
particle  size decrease.   The  larger particles  (14-35  urn)  caused  a  stationary granulamatous
response.    With  the intermediate particles  (5-10 Mm),  the  lungs had cellular  nodules  with  a
few collagenous  fibers  and an increased tissue cellularity and endoalveolar foam cells.  With
the smaller particles, the nodules were more  numerous and collagenous.
     Goldstein and  Webster (1966) also investigated the effects  of size graded quartz parti-
cles in rats exposed by intratracheal instillation and examined 4 months later.   The sizes and
concentrations used  (<  1 M"), 13.99  mg;  1-3  MI",  46.1 mg; and 2-5 M"i,  92.7 M9) were such that
the rats were exposed to an equivalent surface area (600 sq. cm.) for each of the size ranges.
The  <  1  Mm  particles caused  more  numerous  nodules.   The two other size  ranges  produced an
equivalent  number  of lungs  with nodules,  but  there  were  many more  lungs  with  confluent
nodules,  compared to the smallest size quartz.  The degree of fibrosis was similar in the 1-3
Mm  and  2-5  iim groups and was  more  severe than that observed in the < 1 \jirn group.   The weight
of  collagen in  lungs  increased as  particle size increased.  However,  it  should  be recalled
that the  concentration of particles was increased as particle size increased.
     Particle size also has an influence on the immunological effects of silica (Wirth et al.,
1980).  Average  particle sizes of the  silica preparations were 0.012, 0.8,  1.5,  and 1.9 urn.
The  silica particles  were  from  different suppliers;  the  crystalline structures  could have
differed  also.  Mice were injected intravenously.  The smaller particles tended to depress the
humoral immune response to a greater extent.
12.4  INTERACTION OF SULFUR DIOXIDE AND OTHER  POLLUTANTS
12.4.1  Sulfur Dioxide and Particulate Matter
     Although man breathes a multitide of  chemicals in various mixtures at various dose-rates,
most animal toxicological  and controlled  human exposures are conducted with single chemicals.
This simplifies  the research and permits  an  improved  estimate  of cause-effect relationships,
but  it prohibits  evaluation  of  the  effects of pollutant  mixtures  which may  be additive,
synergistic,  or  antagonistic  with respect to  the individual pollutants.  However, some  inter-
action  studies  which elucidate  the  complexity of  toxicological  interrelationships have been
conducted.  Some  of this work utilized pollutant combinations that would favor the conversion
of the  primary pollutant to a secondary  pollutant  (i.e.,  S02 altered to H2$04, etc.).  Other
research  was  directed at  evaluating  the  influence of  several  pollutants when  delivered in
combination or in sequence.

XRD12B/A                                12-53                                         2-5-81

-------
12.4.1.1   Acute Exposure  Effects—The  question  of the  possible  effect  of  aerosols  on  the
response  to  S0?  is  a  critical  problem in  air  pollution  toxicology  (Amdur,   1975).   The
phenomenon  has  been  investigated in simple model  systems  of  SOp alone or in combination with
an aerosol  of  a single chemical.  The typical  bioassay  system has been the comparison of the
increase  in  pulmonary  flow resistance  in guinea pigs  produced by a given concentration of SC^
alone with  that produced  in the presence of  the aerosol.   The aerosols used in many of these
studies were  "inert"  in  the sense that  they  did not  produce an alteration in flow resistance
when they were given alone.
     The initial simple prototype aerosol used was sodium chloride (NaCl) at concentrations of
10 mg/m   and 4  mg/m   (Amdur,  1961).  These  experiments with guinea pigs  indicated-that  the
response  to a  given  concentration  of  SO, was  potentiated by 10 mg/m  sodium  chloride.   For
                                     3
example, a concentration of 5.24 mg/m  (2 ppm) SO- alone  produced an increase of 20 percent in
pulmonary flow  resistance;  when the sodium chloride was  present, the increase was 55 percent.
The  potentiation  did  not  occur  until   the   latter  part  of  a  1 hr  exposure.   When  the
concentration of sodium chloride was reduced to 4 mg/m ,  the potentiation was greatly reduced.
Examination of post-exposure data indicated that the response to the combination resembled  the
response to  a  more irritant aerosol.  The length of recovery was related to the concentration
of  SO-,  and  the presence  of  the aerosol delayed recovery to  control  values.   The  chamber
relative  humidities  were  below  70  percent;   but  on  entering  the  high  humidity  of  the
respiratory  tract, the  sodium  chloride  would absorb water  to become  a  droplet  capable  of
dissolving  SO-,  thus  favoring the production of HLSO..   Sodium chloride does not catalyze  the
oxidation of S02 to sulfuric acid.
     Experiments  by  McJilton  et  al.   (1973)  indicate  the  importance  of ambient  relative
humidity and  the solubility of SO,  in the sodium chloride droplet.  They examined the effect
          3                                    3
of 1 mg/m   NaCl on the response  to  2.62 mg/m  (1 ppm)  SO- at low (<40 percent) and high (>80
percent) relative  humidity.   An increase in pulmonary flow  resistance  in  guinea pigs was  the
criterion  of response.   As would have been predicted  from the earlier work, no  increase  was
observed with  this sodium chloride concentration  at low relative  humidity.   At high relative
humidity, the  potentiation  was marked  and was evident during both the early and late parts of
the  1  hr exposure.   The  rapid  onset  indicates  the  formation  of an irritant  aerosol  in  the
exposure  chamber  under   conditions  of  high  humidity.    As  would  have  been  predicted,  no
conversion  to  sulfate  was  found,  but  the  droplets were acid  with an  estimated pH  of  4.
Presumably,  this was  sulfurous acid.  (See the  discussion  of  the effect of relative humidity
on sulfate and nitrate aerosols above and on human exposure experiments in Chapter 13).
     Amdur  and  Underbill  (1968)  studied the effect  of  aerosols  of soluble salts of metals
shown  to convert  SO- to sulfuric  acid using  the Mead-Amdur  method.    Manganous chloride,
ferrous  sulfate,  and sodium  orthovanadate caused a three-fold  increase in  the resistance to
flow over that of 2.62 mg/m  (1 ppm) SO- alone.  The potentiation was evident during the first
10 min as well as during the remainder of the 1 hr exposure.  Chamber relative humidity was 50

XRD12B/A                                12-54                                        2-5-81

-------
percent,  indicating  that  high  humidity was  not necessary  for the  formation  of an  irritant
aerosol  in  the chamber  when the  catalyzing metals were  present.   Analysis of the collected
aerosol  indicated  the  presence of  sulfate,  presumably as sulfuric acid  (Amdur, 1973).  These
analyses indicated that at an S02  concentration  of  0.52 mg/m   (0.2 ppm) about 0.08 mg  sulfuric
acid was formed.  When this  amount of  sulfuric acid was administered  with 0.52 mg/m3 (0.2 ppm)
S02, the  increase  in flow resistance  duplicated the increase  observed with  the iron and vana-
dium aerosols  (Amdur,  1974).   This suggests that  sulfuric acid  formation  is  the most likely
mechanism  of  potentiation  for  the  aerosols  of  these metals.   Amdur  et  al.   (1978a)  have
reported  that  a 1  hr  exposure  to 0.4 mg/m  copper sulfate  also  potentiated  the response to
0.94 mg/m   (0.36  ppm)  SO^-  It  is not certain  whether this  is mediated through the formation
of  sulfuric  acid  or through the  formation of a  sulfite complex.  The increased resistance to
flow  from exposure  to  0.79 to  0.84  mg/m3  (0.3 to 0.32  ppm)  S00  with  ammonium sulfate (0.9
    3                                3                              3
mg/m ),  ammonium bisulfate (0.9  mg/m ),  or sodium sulfate  (0.9  mg/m ) was purely additive.  It
should  be  pointed  out that  these  salts  have  not been  tested  under conditions of high  relative
humidity.
     Amdur  and Underbill  (1968)  also  examined the  effect  of  a variety  of  solid  aerosols
(carbon,  iron  oxide, manganese dioxide, and  fly ash)  which do not catalyze the conversion of
S0? to  HpSO..   None  of these potentiated the  increased resistance to  flow when compared to S0?
(Table  12-11).
12.4.1.2 Chronic  Exposure Effects—Animals  were exposed continuously to various combinations
of  S02,  sulfuric acid (0.5 to  3.4  urn,  HMD),  and  fly ash  (3.5  to 5.9 urn, MMD).  The fly ash had
been collected downstream  from  electrostatic  precipitators  of  coal-burning electric generating
plants  (Alarie et  al., 1975).   Monkeys  were  exposed for  18 mo  and guinea pigs for 12  mo.  For
monkeys,  exposures were  to  S02,  H2$04  + fly  ash, S02  + H2$04,  or  S02 + H2$04  +  fly ash.
Guinea  pigs  received either  0.9  mg/m3  H2$04  (0.49 |jm MMD)  or  0.08 mg/m3 H2$04 (0.54 or 2.23 urn
MMD)  +  0.45 mg/m   fly  ash  (3.5 or  5.31 (jrn MMD).   In  monkeys,  a  battery  of hematological and
pulmonary  function  (tidal  volume,  respiratory  rate,  minute  volume,  dynamic compliance, pul-
monary  flow  resistance, work of  breathing, distribution of ventilation, CO diffusing capacity,
and arterial blood gases)  tests  were applied  at  various times  during  exposure, but no  signifi-
cant  effects  were  attributed  to  the  exposures.  Similar  methods  (except for distribution of
ventilation  and CO  diffusing  capacity)  were used  with guinea  pigs,  and  again no significant
                                                                  3                            3
effects  were observed.   At  the  end of the exposure to 2.59  mg/m   (0.99  ppm) S02 + 0.93 mg/m
H-SO.  (0.5  |jm MMD, a  1.5 to  3.8), the lungs of monkeys  had  morphological  alterations  in the
bronchial mucosa  (focal  goblet cell  hypertrophy and occasional hyperplasia  and focal  squamous
metaplasia).   Monkeys exposed  to  2.65  mg/m3  (1.01 ppm) S02 +  0.88 mg/m  H2S04 (0.54 urn MMD, og
1.5 to  3.8)  + 0.41  mg/m3  fly  ash  (4.1  pm MMD,  a  1.8 to  2.8)  had  similar alterations.  Thus,
fly ash did not enhance the effect.   Monkeys which received  0.99 mg/m  H2$04 (0.64 |jm MMD, og
1.5 to  3.0)  + 0.55  mg/m3  fly  ash  (5.34 pm  MMD, a   1.8 to 2.2)  had  slight  alterations  in the
                                                   y
mucosa  of the bronchi  and  respiratory  bronchioles.    Focal  areas of  erosion  and  epithelial

XRD12B/A                                 12-55                                        2-5-81

-------
        SOX12C/A   11  1-30-81
                                 TABLE 12-11.  EFFECTS OF ACUTE EXPOSURE TO SULFUR DIOXIDE IN COMBINATION WITH PARTICULATE HATTER
 i
en
CTl

5.24
and
Concentration Duration
mg/m3 (2 ppm) S02, 10 mg/ms 1 hr
4 mg/m3 Nad
Species Results
Guinea pig 5.24 mg/m3 (2 ppm) S02 alone produced an increase
of 20% in pulmonary flow resistance; with NaCl at
10 mg/m3 the increase was 55% and the potentiation
did not occur until the latter part of the exposure.
At 4 mg/m3 NaCl, the potentiation was greatly
reduced.
Reference
Amdur, 1961
2.62 mg/m3 (1 ppm) S02, 1 mg/m3     1 hr
 NaCl at low (40 %) and high (SOX)
 relative humidity (RH)

2.62 mg/m3 (1 ppm) S02, an          1 hr
 aerosol of soluble salts
 (manganous chloride, ferrous
 sulfate, and sodium orthovana-
 date) 50% RH

0.94 mg/m3 (0.36 ppm) S02,          1 hr
 0.4 mg/m3 copper sulfate

0.79 to 0.84 mg/m3 (0.3 to          1 hr
 0.32 ppm) S02 and 0.9 mg/m3
 ammonium bisulfate,  or 0.9
 ng/m3 sodium sulfate
                                                                  Guinea pig   No increase in pulmonary flow resistance at low RH.
                                                                                At high RH, the potentiation was marked and evident
                                                                                during both early and late parts of the exposure.

                                                                  Guinea pig   Presence of soluble salt increased pulmonary flow
                                                                                resistance about 3-fold.   The potentiation was
                                                                                evident early in the exposure.
                                                                  Guinea pig   Potentiated pulmonary flow resistance.
Guinea pig   The effect on pulmonary flow resistance was
              additive.
                                                                     McJilton et al.,  1973
                                                                     Amdur and
                                                                      Underhill,  1968
Amdur et al., 1978a


Amdur et al., 1978a

-------
hypertrophy  and  hyperplasia  were  observed.   The  other groups  of monkeys  had  no remarkable
morphological    changes.     All    monkeys    exposed    to    fly    ash    displayed    no
morphological alterations,  although  presence of the fly ash was easily observed.  Guinea pigs
experienced no morphological effects which  could be attributed to  pollutant exposure.
     In  a  previous  study,  Alarie et  al.  (1973bc) found  no  effects on  pulmonary function,
hematology,  or  morphology of monkeys  or guinea pigs exposed to approximately  0.56 mg/m3 fly
ash  in  combination with  3 concentrations  of S02  (0.28,  2.62,  or 13.1 mg/m3;  0.11,  1,  or 5
ppm).  Monkeys  were exposed  continuously  for  78  wk and guinea pigs  continuously for 52 wk.
     Lewis et al. (1969, 1973) investigated the effects of S02 and H2$0. in normal dogs and in
dogs  which  had  been  previously  exposed  for  191  days  to  48.9  mg/m  (26  ppm)  N02>   Dogs
identically treated with N02 had morphological changes in the lung, and one of the animals had
striking bullous emphysema.   Sulfur oxide  exposures were  for  21  hr/day for  a  maximum of 620
days to 13.4 mg/m  (5.1 ppm) S02,  to 0.89 mg/m3 H2$04 (90 percent  < 0.5 urn in diameter), or to
a  combination of the two.   These  concentrations were averaged over time, and when the animals
were examined at 225 days, the concentration  of H2$04 was lower (0.76 mg/m3 H2$04  in the H2$04
group and  0.84  mg/m  H2$04 in the H2$04 + S02 group).  After 225 days  of exposure (Lewis et
al.,  1969),  dogs receiving  H2$04 had  a significantly lower  diffusing  capacity  for  CO than
those  that  did  not  receive HLSO^..   In  the S02-exposed  animals,  pulmonary  compliance was
reduced (p < 0.05), and pulmonary  resistance  was increased (p < 0.05) compared to  animals that
did  not  receive SO,,.   Dogs not pre-exposed  to  NO- which received SO- +  H2S04  had a smaller
residual volume  (p < 0.01) than  all other dogs.
     These dogs  were also examined after 620 days  of exposure (Lewis et al., 1973).  At 3, 7,
19 or 20.5 mo of exposure, sulfur  oxides did  not markedly affect hematological indices (number
of  erythrocytes  and leukocytes, hemoglobin concentration,  hematocrit,  mean  corpuscular hemo-
globulin  value,  mean  corpuscular volume,  and mean  corpuscular  hemoglobin concentration).
There were no morphological changes that could be  clearly identified as resulting from sulfur
oxide exposure.   However,  pulmonary function  was altered.  Generally, the animals pre-exposed
to N0? were  more resistant to the sulfur oxides.   Sulfur dioxide  did not produce  any signifi-
cant  effects except  for  an  increase  in  mean nitrogen  washouts.    Sulfuric  acid  caused  a
significant  (p  < 0.05) decrease  in  diffusing capacity for CO,  residual volume,  and  net lung
volume  (inflated)  with  an  increase  in  total  expiratory  resistance.    There  was   also  a
significant  (p  = 0.1)  decrease  in total  lung  capacity,  inspiratory  capacity,  and functional
residual capacity.   Total  lung  weight and heart weight were  also decreased.  Other measure-
ments  (other lung volumes,  dynamic  and static compliance, and  N2 washout)  were  not signifi-
cantly affected.  These alterations of diffusing capacity  for CO and lung volumes are inter-
preted as  a  loss  of functional  parenchyma,  and,  along with  the  increase in total pulmonary
resistance,  are  in  the  direction expected  for animals  that  develop  obstructive pulmonary
effects.    Although   the  standard  histological techniques  used  did  not  detect morphological
effects, it is conceivable that  the pulmonary function effects preceeded measurable structural
alterations.
XRD12B/A                                12-57                                       2-5-81

-------
     Female beagle  dogs were .exposed  16 hr/day  for  68 mo to raw  or  photochemical ly reacted
auto exhaust,  oxides of sulfur or nitrogen,  or their combinations.   A description of the expo-
sure groups is  given  in Table 12-12.  More  than  90 percent of the  particles  were <0.5 urn in
diameter.  They were  examined after 18 (Vaughn et al., 1969),  36 (Lewis et al., 1973), and 61
mo  (Lewis  et  al.,  1974)  of  exposure  and 32 to  36 mo (Hyde  et al., 1978;  Orthoefer et al.,
1976) after the 68 mo exposure ceased.   A monograph describing  the entire study and results is
available  (Stara  et al.,  1980).   Only those  results  pertaining  to sulfur oxides  will  be de-
scribed here.
     Typical  hematological  examinations  (except  for  differential  counts) were made approxi-
mately every  6  mo (Stara  et al., 1980).   The SO  group had no  major differences from control.
However, in the presence  of  auto  exhaust  (with  or without irradiation), SO   did cause some
significant elevations  in  hematocrit and hemoglobin concentration.   Clinical chemistries were
unchanged  during  or  approximately  1 1/2 yr  after exposure (Stara et al.,  1980).   Although
cardiovascular  function was  also  assessed  after  4 yr  of  exposure and  3 yr  after  exposure
ceased,  no significant changes  which  could  be  attributed  to  SO   were found  (Stara et al.,
1980).
     A variety  of other parameters  were  examined during  or immediately after exposure (Stara
et al., 1980).  SO  caused no significant effect on visual evoked brain potentials.
     After 18 (Vaughn et  al., 1969) or 36 mo (Lewis et al.,  1974)  of exposure, no significant
changes  in pulmonary function  were observed.    A  variety of alterations  were  found  using
analysis of variance  after 61 mo (Lewis  et al., 1974) of exposure,  but only  those significant
results  related to sulfur  oxides  will  be  discussed   in  detail  here.   Residual  volumes were
increased  in  dogs  receiving  R + SO  (see  Table  12-12 for abbreviations)  compared  to  those
receiving  I + SO  ,  SO , and  CA.  Residual  volumes  of the SO  group were  lower than those of
                A    A                                      X
the  CA  group.   When x  analyses were  applied to  the  data of  the number  of  dogs/group having
alterations as  judged by  clinical  criteria, additional  significant differences  were  found.
More dogs  of  the  I + SO  group had higher total expiratory resistance than their controls (CA
and  SO  ).  The  ratio  of residual volume to  total  lung capacity was higher in animals exposed
to  R  +  SO    compared to those receiving clean  air (CA).  This change was interpreted as pul-
monary  hyperinflation.  Although other lung  volumes,  compliance, resistance,  diffusing capa-
city  for  CO,  N2  washout,  peak  expiratory  flow,  and  maximum  breathing capacity  were also
measured,  sulfur oxides had no effects.
     Two years  after  exposure ceased,  pulmonary  function measurements  were  made again (Stara
et  al. ,  1980).  These measurements  were made in a different laboratory than those made during
exposure,  but consistency  among  measurements of  the  control group  and another set of dogs of
similar age at  the  new laboratory  indicated that this difference did not cause a major impact
of  the findings.    Animals in the   R, R +  SO  ,  and   I  + SO  groups  had an  increased PaC09
                                              />              X                                 4-
(p < 0.05) compared to controls.   These groups  and  the SO   group had  a greater dead space
volume compared to  controls.   Respiratory frequency was increased in the SO  group.  Although

XRD12B/A                                12-58                                         2-5-81

-------
               TABLE 12-12.  POLLUTANT CONCENTRATIONS FOR CHRONIC EXPOSURE OF DOGS (Hyde et al., 1978)
             Atmosphere
                                    CO
                   Pollutant Concentration,  mg/m
                                                  HC
             (as CH4)      N0£
                                                                 NO
                       OX
                      (as 0)    S0
        Control Air (CA)C
Nonirradiated auto
exhaust (R)
                                   112.1
              18.0
                                                     0.09
           1.78
Irradiated auto
exhaust (I)
                                   108.6
              15.6
                                                     1.77
           0.23
                                                                           0.39
S02 + H2S04(SOX)C
                                                                                              1.10
                                                                      0.09
en
vo
Nonirradiated auto
exhaust + SO, +
H,SO. (R + S6j
                                   113.1
              17.9
                                                     0.09
           1.86
                                                                                      1.27
                                                                                                 0.09
         Irradiated  auto
         exhaust + SO, + H-SO.
         (I  +  S0x)    ^     i
109.0
                                         15.6
1.68
                                                                0.23
                                                                           0.39
                                                                                     1.10
0.11
         Nitrogen  oxides,  1
         (NO,  high)
                          1.21
                                                                0.31
         Nitrogen  oxides,  2
         (NO  high)
                          0.27
                                                                2.05
          Abbreviations  in  parentheses
         3>90% of  H_SO.  particles were < 0.5 urn in diameter (optical sizing)

-------
DLCO was  unchanged,  the  ratio, of Dl_co to  total  lung capacity was decreased in all pollutant-
exposed dogs.  Vital  capacity  was not changed.  For  the  S0x group compared to control, total
lung capacity  and  residual  volume were significantly increased.   But,  there was no change in
functional  residual   volume;   respiratory,  pulmonary,  and  chest wall  resistance  were  not
affected; and  quasistatic  chest  wall  compliance was decreased.   There was  a greater change in
dynamic  compliance with  increasing breathing  frequency  in dogs exposed  to S0x-  When  the
pulmonary function values  at  the end of exposure were  compared directly to those values 2 yr
after  exposure ceased,  the following  observations  were  made  in the  S0x  group:   residual
volume, total  lung capacity,  vital  capacity, inspiratory  capacity,  and  functional  residual
capacity, DLCO and the  ratio  of DLCO  to  total  lung capacity  increased.    The  magnitudes of
these  changes  were greater than changes in controls,  in  most cases.   From  evaluation  of  all
the  data,  the  authors  state  that  functional  loss  continues   following  termination  of  the
exposure and the  damage  caused by SO  was primarily to the parenchyma.   They also state that
the combination of auto  exhaust and SO  "did not appear to augment specific functional  losses
caused by single species of pollutants."
     Thirty-two to 36  mo (Hyde et al., 1978)  after exposure ceased,  the lungs of the beagles
were examined  using  morphologic  (light,  scanning electron  and  transmission electron  micros-
copy)  and  morphometric  techniques.  Only  the results  for  sulfur oxide combinations will be
described in detail.   In the SO  group, lung weight, total lung  capacity,  and  the displaced
volume  of  the  processed right  lung  were  significantly  increased over the  controls  (CA).   In
the most severely affected SO  dogs, the air spaces enlarged and the number and size of  inter-
alveolar pores  increased.   Only the high NO-  dogs  had  a  greater degree of air space enlarge-
ment.   The  SO   animals  had a loss  of  cilia  in the conducting  airways  without  squamous cell
metaplasia;  nonciliated  bronchiolar  cell  hyperplasia;  and  loss of  interalveolar septa in
alveolar ducts.   When  SO  was combined with  R,  cilia were also lost, but  squamous cell meta-
plasia occurred.   Exposure to R + SO  and I + SO  produced nonciliated bronchiolar cell  hyper-
plasia  and  an  increase  in  interalveolar pores  and  alveolar  air  space  enlargement.   The
enlargement  of the  distal  air  spaces  was centered  on  respiratory bronchioles  and  alveolar
ducts  and was  associated with an apparent loss of interalveolar septa in all animals receiving
S02  and  H-SO..   The  authors consider these changes  to  be analogous to  an  incipient  stage of
human  proximal  acinar (centrilobular) emphysema.   The important observation from these experi-
ments  is  that  mixtures of SO- and HLSO., representing an interacting gas-aerosol system simi-
lar  to that  in urban atmospheres, produced anatomic  alterations at concentrations lower  than
either SO- or H-SO. aerosols alone.
     In a monograph (Stara et al., 1980) describing all  the dog studies, the morphological and
functional changes are compared.  In the  SO   group the changes  in pulmonary function corre-
lated  well with  the  morphological effects.  Since the changes in pulmonary function were  pro-
gressive  over  the post-exposure  period,   it  is  likely that morphological  changes  were  also
progressive.

XRD12B/A                                12-60                                        2-5-81

-------
*
     Biochemical analyses  were performed on these  dogs  at the time of sacrifice, 2.5 to 3 yr
after exposure  ceased.  Hydroxyproline  concentration (used as an  index  of collagen content)
and prolyl hydroxylase activity  (the  rate-limiting  enzyme  in collagen synthesis) were measured
(Orthoefer et al., 1976).  No  significant changes in  hydroxyproline were found.  The SO  and I
+  SOX  groups had  significantly elevated  prolyl  hydroxylase activity compared to the  R,  R +
SOX, and  CA  groups.   While  it is  remarkable that effects  on prolyl hydroxylase remained 2.5 -
3  yr  post-exposure,  it  is  not  possible to interpret further  these  results.   No significant
alterations  were  observed  in  brain, heart,  lung or  liver lipids amongst  the  experimental
groups (Stara et al.,  1980).
     Zarkower (1972)  reported  mixed effects on the  immune  system of mice exposed to 5.24 mg/m
(2 ppm) S02 and 0.56  mg/m  carbon  (1.8 to 2.2 \im, MMD), alone and in combination for 100 hr/wk
for  up  to 192  days.   Animals were immunized with  aerosols  of  bacteria (Escherichia coli) at
various times during  exposure.   After 102 days of exposure, there were no statistically signifi-
cant changes.   Sulfur dioxide exposure  caused an  increase (p < 0.05) in serum antibody titer
at 135 days and a  decrease (p  <  0.01) at 192 days.  Carbon and carbon + S02 produced an equiva-
 lent decrease (p < 0.01) in  antibody  titer at 192 days (but not at 135 days) which appeared to
be a greater decrease than that  found in the SO^-exposed mice.  In the spleen, exposure to S02
caused  an increase  (p <  0.01)  in the   number of  antibody-producing cells at  135  days and a
decrease  (p  <  0.01)  in number at  192 days.   In the  mediastinal  lymph  nodes  (which  drain the
 lung),  S0? caused  no such  changes.  Carbon  + S0?,  but not  carbon  alone,  caused an increase
 (p < 0.01)  in  the  number  of  antibody-producing  cells  in the  mediastinal  lymph  nodes  and a
decrease  (p  >0.05) in the spleen  at  135 days.  After 192  days of exposure to carbon or carbon
+  S0?,  the number of antibody producing spleen cells decreased (p <0.01).  The immunosuppres-
sion  in  these  2 groups was  roughly equivalent and  appeared to be more severe than that in the
S0_  alone group.   In  the  mediastinal lymph  nodes,  only carbon + S0? caused immunoenhancement
 (p  <  0.05).   Thus, for the  pulmonary immune system, only exposure  to  the  combination of S0«
and  carbon  caused  significant  effects.   After  192 days,  the  systemic  immune  system  was
affected  in all 3  exposure groups.  It appeared that  carbon and carbon + SO,, caused equivalent
effects and that both regimens were more effective  than SO.,.
     Fenters et al.   (1979)  showed that  exposure  for 3 hr/day, 5 days/wk for up to 20 wk to a
mixture of 1.4 mg/ny3  H?SO.  plus 1.5  mg/m  carbon  (0.4 (jm,  mean  particle diameter) or to 1.5
mg/m3  carbon only  (0.3  \im,  mean  particle diameter) also altered  the  immune system of mice.
Serum immunoglobulins (Ig) decreased, with the exception of  IgM which was increased after 1 wk
of exposure to  either carbon or  H2SO. +  carbon.  After 1 wk,  some  Ig classes decreased  in both
exposure  groups, but  after 4 or  12 wk of exposure,  alterations were observed only  in the H2S04
+  carbon  group.   Results  for  Ig  were   mixed  at  20  wk.   In the  carbon  group, the number of
specific  antibody-producing  spleen   cells  was increased  at  4 wk,  unchanged at  12  wk, and
decreased at  20 wk.    A similar  trend was observed in the H2$04  + carbon group,  but  only the
immunosuppression  at  20   wk was  significant.   In examining other host  defense systems, no

XRD12B/A                                 12-61                                        2-5-81

-------
alterations of alveolar macrophage viability or cell  numbers were observed.   After 4 and 12 wk
of exposure,  pulmonary  bactericidal  activity was increased in both exposure groups.  By 20 wk
of exposure,  values were  not  significantly different  from controls.   Using  the infectivity
model with  influenza Ap/Taiwan  virus,  a 20-,  but not  a  4-, wk  exposure  to  H2$04  + carbon
increased mortality.
     Morphological  changes were  observed  in these mice  (Renters et  al., 1979) using scanning
electron microscopy  after  12  wk of carbon  exposure.   In the external nares,  there was excess
sloughing of squamous cells.   In the trachea, the number of mucous  cells appeared to increase;
dying cells were  present,  and microvilli  were lost.   No alterations  of the  bronchi were seen.
The  alveoli  had  some  areas  of  congestion  with thickening, loss of  interalveolar septa,  and
enlarged pores.   After  20  wk  of exposure,  damage  was  similar,  but to a  lesser degree.   Mice
exposed  to  the  mixture of HUSO,  and carbon  showed  'equivalent effects, but  the  damage  was
somewhat more severe than that seen in the carbon only group.
     The influence  of  HUSO, and carbon on  the  trachea  of  hamsters was investigated by Schiff
                                                           3
et al.  (1979).   Animals were  exposed for 3  hr  to 1.1 mg/m  HUSO.  (0.12 urn, mean size) and/or
        3
1.5 mg/m  carbon  (0.3 urn, mean size) and were examined either immediately, or 24, 48,  or 72 hr
later.  Carbon  caused  no change in ciliary  beat  frequency.   Sulfuric acid  exposure,  however,
caused  depression in this  frequency at all  time periods.  The combination of HUSO, and carbon
produced  similar effects,  but  recovery  had  occurred  by 48  hr post-exposure.   Using  light
microscopy, the percentage of normal tracheal  epithelium  was determined.  Up  to  48  hr after
exposure, the  combination  of  HUSO, and carbon resulted in more tissue destruction than either
pollutant alone,  although  the  single pollutants did cause some damage.   Morphological  altera-
tions  of  all  pollutant exposure  groups  were  observed  using  light  and  scanning  electron
microscopy (see Table 12-13).
12.4.2  Interaction with Ozone
                                                                                            3
     Cavender et  al.  (1977) exposed rats and guinea pigs to sulfuric acid aerosols (10 mg/m ,
1 urn  MMD),  3.9 mg/m  (2 ppm)  ozone, or a combination of the two for  6 hr/day for 2 or 7 days;
they then measured the ratio of lung to body weight and examined the  lungs histologically.   No
synergism was  observed  between the  ozone  and sulfuric  acid treatments.   The histological
lesions were those ascribed to ozone alone.   This same group (Cavender, 1978) exposed rats and
guinea  pigs to  sulfuric acid  aerosols (10  mg/m  ,  50  percent equivalent aerodynamic diameter,
0.83 urn, o  = 1.66), 1.02 mg/m  (0.52 ppm) ozone, or a combination of the two for 6 hr/day, 5
days/wk for 6 mo.  The histological alterations were those due to ozone alone.
     Last and Cross (1978) found synergistic effects of a continuous  exposure of sulfuric acid
aerosol  (1 mg/m ) and ozone (0.78 to 0.98 mg/m  or 0.4 to 0.5 ppm)  when administered simultan-
eously  to  rats for  3  days.   Glycoprotein synthesis  was stimulated  in  tracheal ring explants
measured ex  vivo.  Ozone alone  caused  a  decreased glycoprotein secretion;  sulfuric  acid was
                                                                      3
relatively  inactive,  requiring concentrations  in excess  of  100 mg/m   to  produce changes in
XRD12B/A                                12-62                                        2-5-81

-------
      SOX12C/A  12 2-5-81
                                        TABLE 12-13.  EFFECTS OF CHRONIC EXPOSURE TO SULFUR OXIDES AND PARTICULATE MATTER
            Concentration
                                             Duration
                                                             Species
                                                                                                   Results
                                                                                                                                          Reference
ro
 i
ci
to
Various combinations of S02,        IB mo,
 H2S04 (0.5 to 3.4 Mm, HMO),        continuous
 and fly ash (3.5 to 5.9 Mm,
 MMD):  S02l H2S04 + fly ash,
 S02 + H2S04, S02 + H2S04 +
 fly ash
     0.9 mg/m3 H2S04 (0.49 MM,           12 mo,
      HMD); 0.08 mg/m3 H2SO«             continuous
      (0.54 or 2.23 Mm. MMD) +
      0.45 mg/m3 fly ash (3.5
      or 5.31 Mm. MMO)

     Approximately 0.56 mg/m3 fly        78 wk,
      ash in combination with S02 at     continuous
      0.28, 2.62, or 13.1 mg/m3 (0.11,
      1, or 5 ppm).
Approximately 0.56 mg/m3 fly ash
 in combination with S02 at
 0.28, 2.62, or 13.1 mg/m3
 (0.11, 1, or 5 ppm)
13.4 mg/m3 (5.1 ppm) S02, or
 0.89 mg/m3 H2S04 (90X <0.5
 urn in diameter), or to a
 combination of the two
52 wk.
continuous
                                         21 hr/day, 620 days
                        Monkey       No significant effects on hematology or pulmonary
                                      function tests during exposure.   At end of exposure
                                      to 0.99 ppm S02 + 0.93 mg/m3 H2S04 (0.5 pm, MMD)
                                      lungs had morphologica'i alterations in the bronchial
                                      mucosa.   Exposure to 1.01 upm S02 +0.88 mg/m3 H-SO.
                                      (0.54 Mm, MMD) + 0.41 mg/m  fly ash (4,1 Mm, MMD} hid
                                      similar alterations, thus fly ash did not enhance
                                      effect.   Exnosure to 0.99 mg/m3 H.SO. (0.64 \w,  MMD)
                                      + 0.55 mg/m3 fly as (5.34 \>m, MMD} hid slight
                                      alterations.

                        Guinea pig   No significant effects on hematology,  pulmonary
                                      function, or morphology.
                                                            Monkey       No effects on pulmonary function,  hematology,
                                                                          or morphology.
Guinea pig   No effects on pulmonary function,  hematology,
              or morphology.
                        Dog          After 225 days,  dogs  receiving H2S04 had a  lower
                                      diffusing capacity for CO than those that  did not
                                      receive  H2S04.   In the S02-exposed group,  pulmonary
                                      compliance was  reduced and pulmonary resistance was
                                      increased compared to dogs that did not receive S02.
                                      Dogs not pre-exposed to N02 who received S02 + H2S04
                                      had  a smaller residual volume than all other dogs.
                                      After 620 days,  pulmonary function was altered from
                                      sulfur oxide exposure but no hematological or
                                      morphological changes occurred.  S02 did not produce
                                      any  effects except for an increase in mean nitrogen
                                      washout.   H2S04  decreased diffusing capacity
                                      for  CO,  residual volume, and net lung volume and
                                      increase in total expiratory resistance.
                                      Total  lung capacity, inspiratory capacity  functional
                                      residual  capacity were decreased.   Total lung weight
                                      and  heart rate were also decreased.
                                                                                                                                      Alarie et al. ,  1975
                                                                                                                                 Alarie et al., 1975
                                                                                             Alarie et al.,  1973b
Alarie et al., 1973b
                                                                     Lewis et al.,  1969,  1973

-------
        SOX12C/A   13  2-5-81
                                                                     TABLE  12-13 (continued).
             Concentration
                                              Duration
                         Species
                                                                                                    Results
                                                                                                                                           Reference
       (see  Table  12-12)
16 hr/day, 68 mo
Dog
cr>
-p.
      5.24 mg/m3 (2 ppm) S02, or 0.56
       mg/m3 carbon (1.8 to 2.2 urn,
       HMD), or in combination
      1.4 mq/m3 H2SO< plus 1.5
       mg/m3 carbon (0.4 urn, mean
       particle diameter), or 1.5
       mg/m3 carbon only (0.3 urn,
       mean particle diameter)

      1.1 mg/m3 H2S04 (0.12 urn, mean
       size), or 1.5 mg/m3 carbon (0.3
       urn, mean size), or in combination
100 hr/wk, 192 days
House
3 hr/day, 5 day/wk,
 20 wk
3 hr
House
                        Hamster
After 18 or 36 mo exposure no changes in pulmonary
 function.   Residual volumes increased in dogs
 receiving R + SO  compared to I + SO ,  SO ,  and CA.
 Residual volumesxof the SO  group were lower than of
 the CA group.  Hore dogs of the I + SO  had higher
 total expiratory resistance than their controls
 (CA and SO ).  The ratio of residual volume to total
 lung capacity was higher in R + SO  than CA.   32 to 36
 mo after exposure ceased, the SO  group had lung
 weight, total lung capacity, and displaced
 volume of the processed right lung increased over
 controls (CA).   SO  dogs had loss of cilia in the
 conducting airways.  SO  + R had loss of cilia
 and squamous metaplasia.  Exposure to R + S0x
 and I + SO  produced nonciliated bronchiolar
 cell hyperjhasia and an increase in interalveolar
 pores and alveolar air space enlargement.

For the pulmonary immune system, only exposure to
 the combination caused significant effects.   After
 192 days, the systemic immune system was affected
 in all 3 exposure groups; carbon and carbon + S02
 were more effective than S02, although S02 did
 cause significant effects.

Altered the immune system.  Morphological changes
 observed; more severe with carbon only exposure.
             Carbon caused no change in ciliary beat frequency.
              Ciliary beat frequency was depressed after
              H2SOH exposure.  The combination produced similar
              effects, but recovery had occurred by 48 hr post-
              exposure.   Up to 48 hr after exposure H2SO« +
              carbon resulted in more tissue destruction than
              either pollutant alone.
Lewis et al.,  1969,
  1973
Zarkower, 1972
Renters et al., 1979
                                                        Schiff et al., 1979

-------
*
glycoprotein secretion.  The  lung DMA, RNA, and protein content  increased in the group exposed
to ozone  and  sulfuric acid aerosols,  while  the ozone-exposed group had only a small increase
and the sulfuric acid group had  none.
     Grose  et  al.   (1980)  investigated the  interaction of H-SO. and  03  on ciliary beat fre-
quency  in  the  trachea of hamsters.  A 2  hr exposure to 0.88 mg/m3 H2$04 (0.23 pm, VMD) signi-
ficantly  depressed ciliary beat frequency.   By 72 hr  after  exposure, recovery had occurred.
Hamsters  exposed  to  0.196 mg/m   (0.1  ppm)  03  for  3 hr  were not  significantly affected.
However,  when  animals were exposed  in sequence,  first to 0_ and then to  H2S04>  ciliary beat
frequency was decreased  significantly, but to  a lesser extent than that caused by H2$04 alone.
Analysis  showed  that  antagonism  (p  < 0.05) occurred in this sequential exposure.
     Gardner et  al. (1977a)  found  that the sequence of exposure to sulfuric acid aerosols and
ozone  altered  the  response of  mice  to  airborne  infections.   Mice were  exposed  alone  or in
 sequence  to 0.196  mg/m  (0.1  ppm)  ozone  for 3 hr and to  0.9 mg/m  sulfuric acid aerosol (VMC
 0.23  urn  ±  2.4  SD,  geometric) for  2   hr.   When given  alone, neither  pollutant  caused  a
 statistically  significant  increase  in  the   mortality  to  a  subsequent  infection  with S.
 pyogenes.   When  the  pollutants  were  given sequentially,  a  significant increase in mortality
 occurred  only when  ozone  was  given  immediately  before  exposure  to  sulfuric acid,  and the
 response  was additive.   The  reverse  procedure had no effect on mortality  due  to S. pyogenes
 infections.  Because  photochemical  oxidants and sulfur oxides often co-exist in polluted air,
 these  studies  are  of very practical  importance.   The question of  the temporal  sequence has
 been  poorly investigated.  Simple  mechanisms to predict  this  additive response sequence are
 not apparent.  Thus,  the results are  opposite  those of the Grose et al. (1980) study described
 above  with the  tracheal model  which  showed  that sequential  exposure  to 0,  and  H_S04 had an
 antagonisitic  effect.   The reasons for this  difference  are  not known.  However, the infecti-
 vity  model is thought  to reflect alveolar level effects  (Gardner  and Graham,  1977). whereas
 the  ciliary beat  frequency model  is  a  measure  of  effects at  the  level  of the trachea.  In
 addition  different animal  species  were  used. These findings  also  indicate the complexity of
 interaction effects and the  need to  exercise care in extrapolating the effects of  pollutants
 from one  parameter to another (see  Table  12-14).
 12.5 CARCINOGENESIS AND  MUTAGENESIS OF SULFUR  COMPOUNDS AND ATMOSPHERIC
     PARTICLES
     Attempts  have been made  for several decades  to correlate various indices of particulate
 air pollution with the development  of  cancer  in man.   In many cases a  positive association has
 been  found between increased community air pollution and cancer of  the  lungs and/or gastro-
 intestinal  tract.   This  knowledge has  led to  suspicions concerning  the chemical nature of that
portion or portions of  airborne particulate  matter  which may be contributing to an excess  of
 human  cancer.   At  least three classes of potential etiologic agents have  been studied in this
 regard:   organic matter (including polycyclic hydrocarbons)  which is adsorbed to  suspended
particles;  sulfur  oxides; and trace metals.

XRD12B/A                                12-65                                        2-5-81

-------
         SOX12C/A  14 2-5-81
                                                   TABLE  12-14.  EFFECTS OF  INTERACTION OF SULFUR OXIDES AND OZONE
               Concentration
                                                Duration
                                                             Species
                                                                                                     Results
                                                                                                                                            Reference
ro
 i
en
10 mg/ma (1 yin, HMD) H2S04
 aerosol, or 3.9 mg/m3 (2 ppm)
 03, or combination of the two

10 mg/m3 (50% equivalent aero-
 dynamic diameter, 0.83 put, o  =
 1.66) H2S04 aerosol, or 1.029
 mg/m3 (0.52 ppm) 03, or com-
 bination of the two

1 mg/m3 H2S04 aerosol and
 0.78 to 0.98 mg/m3 (0.4 to
 0.5 ppm) 03

0.196 mg/m3 (0.1 ppm) 03;
 0.9 mg/m3 H2S04 aerosol (VMC
 0.23 pm ± 2.4 SO, geometric)
 exposed alone or in sequence

0.196 mg/m3 (0.1 ppm) 03;
 0.88 mg/m3 H2SO« aerosol (0.23
 urn, VMD) exposed alone or In
 sequence
                                            6  hr/day,  2  or  7
                                            days
                                            6  hr/day,  S day/wk,
                                            6 mo
                                            3  days,
                                            continuous
                                            3  hr, 03;
                                            2  hr, H2SO«
3 hr, 03;
2 hr. H2SO«
                        Rat and      No synergism in effect on ratio of lung to body
                        Guinea pig    weight.   Histological lesions were those ascribed
                                      to 03 alone.

                        Rat and      Morphological  alterations due to 03 alone.
                        Guinea pig
Rat          Synergistic effects.   Glycoprotein synthesis was
              stimulated in trachea! ring explants; lung DNA,
              RNA, and protein content increased.

Mouse        In response to airborne infections a significant
              increase in mortality only when 03 was given
              immediately before exposure to H2S04, and the
              response was additive.

Hamster      H2S04 depressed ciliary beat frequency.
              By 72 hr after exposure, recovery had occurred.
              03 exposure had no effect.   Sequential 03 then
              H2S04 exposure decreased ciliary beat frequency
              significantly but to a lesser extent than that
              caused by H2S04 alone.
                                                                     Cavender et al.,  1977
                                                                     Cavender et al.,  1978
                                                                                             Last and Cross,  1978
                                                                                             Gardner et al.,  1977a
Grose et al., 1980

-------
*
     Test systems  for the bioassay of potential mutagens and carcinogens are diverse, ranging
from the  measurement  of  chemically-induced  reverse  mutations  in  bacteria  to  the frank pro-
duction of  carcinomas  by administration to  mammals.   However,  it is  commonly believed that
fundamental  similarities  exist  between the molecular  mechanisms  of  both mutagenesis  and
carcinogenesis.   This assumption  is  based on  the theory  that chemical  interaction with DNA
and/or  other critical  cellular macromolecules  initiates  a mutagenic or  carcinogenic trans-
formation.
     Because  of   the   relationship   between  molecular  events  involved  in mutagenesis  and
carcinogenesis  (Miller,  1978), the  demonstration of mutagenic  activity  for  a  substance  is
generally  taken as  strong presumptive  evidence for the  existence of carcinogenic activity.
Therefore,  it  is  believed that an  investigation of  the  mutagenicity of  a substance may be
predictive  of  its  carcinogenic potential,  and  may serve  as  an early  warning of a possible
threat  to human health in cases where positive results are  obtained.
12.5.1  Airborne  Particulate  Matter
12.5.1.1   In Vitro Mutagenesis Assays of Particulate Matter—Organic material associated with
airborne  particles  has  been  investigated to a  limited  extent  for mutagenic and  carcinogenic
 potential.   In these  studies,  particulate  material  is experimentally limited to that which is
 retained  by the filter medium  used  (glass  fiber,  paper...etc.).  Organic compounds associated
with aqueous particles cannot  effectively  be trapped, and  thus there is no  information on the
 biological  effect or nature of these  compounds.   The  particles  that have created most  interest
 are those with a carbonaceous  core.   These particles,  because  of their  large surface area,
 adsorb  many organic compounds  some  of which  are  known to  be mutagenic  and  carcinogenic, such
 as  benzo(a)pyrene.   Because   of the  small   size  (0.2-0.3 ^m   mean diameter) of  many of the
 particles,  they  can be  deposited  in the respiratory regions  of the lung where  the  adsorbed
 organic material  can  desorb   into  the alveolar  fluid  and enter  the associated  tissue.  The
 ability of  soluble  proteins  to leach mutagens  off  particulates has been  demonstrated using
 horse  serum and coal fly ash  (Crisp  et al., 1978).
      A  number  of  studies were  conducted with fractionated  extracts of particulate matter from
 urban   air  in  order  to  obtain information  on the  chemical  nature of the mutagens present
 (Dehnen et  al., 1977;  Teranishi et al.,  1978; Miller and  Alefheim,  1980; Tokiwa et al.,  1980).
 Estimates have been made as  to the  relative  mutagenicity of each extract;  however,  due  to the
 possible  interaction among the many  compounds present in  any fraction of the extracts  the only
 conclusion  that can be  drawn is that both the  polar  and neutral fraction  contain significant
 portions   of  the  total  mutagenic  activity.   The  polar  fraction  contained  direct  acting
 mutagens.    Some   could   be  chemical  derivatives  of  polycyclic   aromatic  hydrocarbon   (PAH)
 compounds.   At present  the  identity  of compounds  which are acting  as  direct mutagens  is
 uncertain.
      In  a   similar  manner  as  in studies with  airborne  particulate  matter,  mutagens were
 extracted from particles  emitted from  a  coal  powered  electric  plant (Crisp et al.,  1978;
 XRD12B/A
12-67                                        2-5-81

-------
Kubitschek et  al.,  1979),  gasoline engines (Wang et al., 1978), and light-duty and heavy-duty
diesel  engines  (Huisingh et al.,  1977).   The  extracts obtained from all  sources  were direct
acting  frame-shift  mutagens.   Only  in  the heavy  duty diesel  engine study  was fractionation
carried  out  on the crude extract. A  review  of diesel  engine particulate  matter  is available
(Santodonato, 1978).
     The Salmonel la assay  has  been used in an  attempt to define air quality by measuring the
mutagenic  potential  of airborne  particulates.   Tokiwa et  al.  (1977) compared ths number of
revertants per ^ig  of  particulate matter collected  in  the industrial  area of Ohmata with that
collected  in the  residential  area of Fukuoka,  Japan.   In a similar manner Pitts et al. (1978)
compared eight urban samples in the California  South Coast Basin with one collected in a rural
area  of the San  Bernadino mountains.  In both  cases  the mutagenic activity was  less in the
residential  and  rural areas  compared to  that  observed in the urban areas.   Also, mutagenic
potential  was  determined in a quantitative manner  for a variety of air  samples  collected in
Chicago  (Commoner  et  al., 1978).   In  order  to  rank samples,  the inverse  of  the  minimum
quantity   of  particulate  matter  needed  to  obtain  a  significant Ames assay   result  was
calculated.  Again,  mutagenic potential was  correlated  with  urban pollution  and prevailing
concentration gradients from sources of pollution.
     Caution must  be  exercised when comparing  in a quantitative manner  results of Ames assays
on complex environmental mixtures.  Indirect mutagenesis is extremely difficult to quantitate,
since microsomal  oxidation  to non-reactive as  well as  reactive compounds occurs.   Mixtures of
direct  and indirect mutagens  may not produce  an  additive result.  For  any  valid comparison
there  has  to be nearly complete  separation of  these  two types of  mutagens  (Commoner et al.,
1978).   Also,  the  effects on mutagenesis of  synergism  and  antagonism  among compounds  in
complex  mixtures  has  not  been  adequately  investigated.   In  the case  of complex  mixtures
obtained  from  tar-sand,  the  mutagenic  activity of the known mutagen,  2-aminoanthracene, was
greatly  inhibited by  interaction  with the mixture (Shahin and  Fournier, 1978).    For these
reasons a  quantitative assessment of air quality is not readily obtainable with the use of the
Ames Salmonel la mutagenicity assay.
     The  data  obtained  with   mammalian  cell   transformation  assays  support the  conclusions
derived from the Ames Salmonella assays.   There appears to be a variety  of biologically active
agents  present  in  the extracts of airborne particulate matter, and these agents are of both a
polar and  nonpolar  nature.  The identity of these compounds is unknown; however,  the activity
present  is  greater  than  that  which could  be accounted for by the PAH present in the samples.
Even  though the   cells  transformed  by  extracts  of  particulate  matter  formed   tumors  when
injected  into  newborn  mice,   it  is presently  unclear how the process of  transformation in
virus-infected cells relates to the process of  chemical carcinogenesis.   Hence, cell transfor-
mation  assays  should  be considered  in the  same  way as  Ames assays;  that  is,   as  only an
indicator of the presence of biologically active compounds.
XRD12B/A                                12-68                                        2-5-81

-------
*
     The dominant  lethal  assay of Epstein  et  al.  (1972) is  the only short term j_n vivo assay
performed on  airborne  participate extracts.   The  water soluble and benzene soluble fractions
produced no  fetal  deaths  or preimplantation losses beyond control  limits.  On the other hand,
the oxygenated fraction showed significant  fetal deaths  and decreased total implants.
12.5.1.2. Tumorigenesis of Participate Extracts—It  was realized as early  as  the 1930's that
increasing amounts  of  particulate matter in the air may correlate with the increasing rate of
human  lung cancer.   Some  of the  earliest i_n vivo  experiments dealt with the repeated exposure
of  mice to  clouds  of soot,  followed by autopsy  examination for tumors at the  end of their
natural  lifespan.   A number of different kinds of soot  have  been chosen for these studies due
to  their significant contribution to airborne particulate matter.  Upon bioassay of soot from
chimneys (Campbell,  1939; Seelig  and  Benignus, 1938), motor exhaust (Campbell, 1939), and air-
borne  particulate  matter collected  in  the vicinity of a  factory and  roadway  (McDonald and
Woodhouse, 1942),  a slight  increase  over  control  in the number of  lung  tumors  was observed.
Only  in the  case where road dust from a freshly  tarred road was  used were there significant
increases, with  57 percent   of the experimental and 8 percent of the control group having lung
tumors  (Campbell,  1934).   However, when five  years  later dust from the  same  road,  which had
not been retarred,  was again tested  only  8 percent of  the experimental group and 1.4 percent
of  the control  group developed lung  tumors (Campbell,  1942).  In a recent study with lifetime
exposure of  rats to automotive exhaust, no tumors were detected in the  lungs  of the treated
animals.  Although  these  studies have all  attempted  to demonstrate the potential of airborne
particulate  matter  to  cause lung tumors,  the results  obtained are ambiguous due  to the low
tumor  incidence  and  the small size of the animal groups.
     Among the   various compounds associated  with airborne  particles, PAH  have  received the
greatest attention  with regard to carcinogenic potential.   PAH were the first compounds ever
shown  to be  associated with carcinogenesis.   To  this  day,  carcinogenic PAH are still distin-
guished by  several  unique features:   (a)  several  compounds  of this class  are  among the most
potent  animal carcinogens  known  to  exist,  producing tumors  by  single  exposures  to microgram
quantities;  (b)  they act both at the site  of application and at organs distant from the site
of  absorption; and  (c) their effects  have been demonstrated in nearly every tissue and species
tested,  regardless  of  the  route of  administration.   The most  widely  studied PAH, benzo(a)-
pyrene,  is ubiquitous  in the environment and produces in animals tumors which closely resemble
human  carcinomas.
     The  production of lung tumors  with airborne particulates  has been extremely difficult.
However, organic extracts  of airborne particulates  readily  cause  tumors when injected subcu-
taneously  into   mice.   As  early as  1942  sarcomas  were produced  in  mice using  the benzene
extracts  of  particulate matter  collected  from an urban area (Leiter  and Shear,  1942; Leiter
and Shimkin,  1942).  In these initial studies  the  tumor  incidence was low, with only 8 percent
of  the  mice  developing tumors by the end   of  the  study; however, none of the control mice had
sarcomas.  In one  later study, the  tumor  incidence  was as high as  61  percent when particles

XRD12B/A                                 12-69                                        2-5-81

-------
were collected in the vicinity, of a petrochemical plant (Rigdon and Neal,  1971).  Even in this
case of  high tumor  production,  no  increase  in  the incidence of tumors  over the spontaneous
rate was observed in any organ of the animal distant to the site of injection.  Only when neo-
natal  mice  were  injected  subcutaneously  with particulate extracts did tumors  appear distant
from the  injection  site (Epstein et al., 1966),  with  a very high incidence  of hepatomas (83
percent)  and multiple  pulmonary adenomas  (67  percent).   Remote  tumor formation  after sub-
cutaneous  injection  of neonatal  mice was confirmed with  both the crude  extract  of particles
collected in New York City and subfractions  of this extract;  the predominant tumors were again
hepatomas (Asahina et al., 1972).
     The carcinogenic  nature  of  extracts  of particulate matter  has  also  been demonstrated by
studies involving skin  painting  on the backs of mice.   With  repeated application (three times
per week  for the life of the animal)  of  the benzene extract of particulates collected in the
Los Angeles area, papillomas were formed which subsequently progressed to  carcinomas (Kotin et
al., 1954).  Papillomas first appeared after 465 days,  and at the time the data were presented
42 percent  of  the mice had developed tumors.  Although papillomas  and carcinomas of the skin
were the  most  commonly observed  tumors, lung tumors have  also  been  noted after skin applica-
tion (Clemo  et  al.,  1955).   Among the different methods of administering  particulate extracts
to the mouse for bioassay, skin painting yields  the highest tumor incidence, with greater than
90 percent of the surviving animals in some  cases developing  tumors.
     In subsequent studies, the phenomenon of two-stage tumorigenesis was  used to characterize
further  the biological  activity  in  airborne particulates.   In  two-stage  tumorigenesis  an
initiator  is  an  agent (usually a carcinogen) which, when  applied in  a single dose to the skin
of a mouse  does  not produce tumors  at  the  applied concentration,  but predisposes the skin so
that later repeated application of a promoter (an agent that  by itself will not produce tumors)
will cause  the  formation of tumors.  A complete carcinogen is one which,  if applied in suffi-
cient  concentration,  can produce  tumors  by  itself.   Extracts  of  airborne  particles  from
Detroit were  fractionated,  and  the fractions examined  for complete  carcinogenicity and tumor
initiating  and  promoting activity  (Stern,  1968;  Wynder  and Hoffman,  1962).   Only the whole
extract and  the  aromatic  fraction proved  to  be a complete  carcinogen,  while  the insoluble,
acidic, aliphatic and  oxygenated  fractions produced no tumors  (there  was insufficient basic
fraction to perform the assay).
     In  order to examine  the aromatic fraction for  initiating  activity, this  fraction was
applied to the backs of mice in a sub-tumorigenic dose followed by repeated application of the
known  promoter  croton  oil.   Tumor initiating activity corresponded in a  general  way to the
benzo(a)pyrene content  of  the  fraction.   The other  fractions of the particulate extract were
not tested for initiating activity.  It should be noted that  an initiator does  not necessarily
have to be  a complete carcinogen, although  most if not all complete carcinogens will  initiate
if applied  at  a  low dose where  their  complete  carcinogenic  action is not apparent.   For this
reason it  is possible that some  of  the fractions could have  initiating  activity even though

XRD12B/A                                12-70                                        2-5-81

-------
they did  not  act as complet> .carcinogens when first tested.   However,  the relevance of two-
stage carcinogenesis to environmentally-caused cancer is not known.
     Several contributing  sources  of airborne particulate matter, gasoline and diesel engines
and the soot  from coal and oil burning furnaces, have been examined individually and shown to
produce tumors.   Extracts of  particulates from  gasoline  engines show  carcinogenic activity
when painted  on  the backs of mice  (Brune, 1977;  Wynder and Hoffman,  1965) and when injected
subcutaneously  (Pott  et  al.,  1977).   Extracts  from diesel  engines have shown tumorigem'c
activity  in  some studies but not  in others;  the  same holds true for extracts of chimney soot
where activity was  shown in some  instances  (Campbell,  1939) while not in  others (Mittler and
Nicholson,  1957).   The  discrepancies  among  these results could  be  due  to qualitative and/or
quantitative  differences  in  the nature of the  organic  compounds adsorbed  to the particles or
difference  in  assay systems.   Differences may have existed in the operating parameters of the
generating  source,  or  variations  in particulate collection procedures.   With diesel engines
the  mode  of  operation (the load  under which the  engine  was  run),  the  type  of  fuel and the
temperature  at which  the  particles  were  collected all  affect  the biological  activity of the
sample.   With  soot  collected from chimneys,  an  important  consideration  is the temperature at
which the particulate  matter is collected.   The organic material on particulates is  generated
in  the gaseous  phase  while condensation on nuclei  occurs  at lower  temperatures.  Unless
particles  are collected  under  similar conditions,  disparities will exist in their chemical
composition and  biological activity.  Taken together, it is nevertheless  apparent that all the
major types  of airborne particulate matter contain  adsorbed compounds which are carcinogenic
to  animals  and may contribute  in some  degree to the incidence of human cancer associated with
exposure  to urban particulate matter.
12.5.2  Potential Mutagenic Effects  of  Sulfite and SO,,
     Bisulfite addition to cytosine can  result in  deamination to form uracil (Shapiro, 1977;
Fishbein,  1976).   The result  would be  a DNA  conversion  of  GC  to AT  sites  and could be
mutagenic.  Transamination of cytosine can occur through  reaction  of an amine with  cytosine-
sulfite  adduct.   Since  the  nucleus  is  rich  in polyamines,  transamination  is  a likely event.
Deamination  of cytosine occurs  most readily  in high (1 M)  concentrations of sulfite; trans-
amination  also  requires  high  sulfite  and  amine  concentrations.   The  decomposition  of the
cytosine-sulfite  adduct is the rate limiting step in both reactions.  At the present time, no
clear  evidence exists  for mutagenicity  caused by  SO^ or  sulfite.   However,  because of the
reactivity  of sulfite  with  cytosine,   the potential  mutagenic  properties  of  sulfite and S0?
have  been examined.   Such experiments have  recently been  reviewed  (Shapiro,  1977;  Fishbein,
1976).  To  date, microbial experiments with  high  concentrations of sulfite in acid solutions
in vitro  have produced mutations.  These  conditions would be similar to those  favoring deamina-
   	                                                              ~3
tion of  cytosine.   Experiments conducted  at  low  concentrations (> 10  m sulfite) and neutral
pH (7-7.4) have  not provided clear-cut  evidence of mutagenesis.   The microbial assays were not
done with strains of  Salmonella known  to be  sensitive to mutagens  (Ames  Assays).   Background

XRD12B/A                                12-71                                        2-5-81

-------
mutation  rates,  mechanisms of.  error-prone  repair,  and corrections  for  cytotoxicity were not
studied.  Negative  experiments  have been reported when insects (Drosophila) (Valencia et al.,
1973)  and  mammals   (mice)  were  exposed.   Cytotoxicity,  rather  than  mutagenicity,  appears
when cultured  animal  and human cells (Thompson and  Pace,  1962;  Nulsen et al., 1974; Kikigawa
and  lizuka,  1972;  Schneider  and  Calkins,  1971;  Timson,  1973) are  exposed  to sulfite.   (See
Table 12-15 for summary.)
12.5.3  Tumorigenes is in Animals Exposed to SO^ or SO,, and Benzo(a)pyrene
     Tumorigenesis  after exposure  to SCL alone or to SCL and an aerosol  of benzo(a)pyrene has
been examined.  Mice  were  exposed over their  lifetimes  in  a 180 liter chamber into which 500
ppm  S02 was  introduced  at  a rate of 20 ml/min for 5 minutes, 5 days/week (Peacock and Spence,
1967).  The  concentration  used  cannot be calculated accurately from the  paper.  Thus, no con-
centration-related  effects  can be  deduced  from  this  study.   Examinations  for  tumors  of the
lung and  other organs were undertaken only  in  mice  that survived longer than 300 days, since
no  primary  lung  tumors  had been  seen  in younger mice.   Only tumors greater than  1 mm were
recorded.   Primary  pulmonary neoplasias increased in the males (n = 35) from 31 percent in the
control group to  54 percent in the S0?-exposed group and in the females (n = 30)  from 17 to 43
percent.  The  incidence  of the next most common tumors in this strain  of mice,  hepatomas and
lymphomatoses,  was  not  affected.    The  authors  classified  only  tumors which  invaded  blood
vessels as carcinoma.  In males, S0? did not affect the incidence of malignant tumors (2/35,  6
percent in  air group; 2/28, 7 percent  in  S0?  group).   However,  in  females,  the  incidence of
primary lung  carcinoma  increased  from 0/30 in  the controls  to 4/30 (18 percent)  in the SO^-
exposed mice.   These  were  early studies and the statistical  analysis reported in the paper is
vague.  Therefore,  Hasselblad  and Stead (1980) analyzed the  data  reported in the Peacock and
Spence  (1967)  study.  A  one-sided Fisher's exact test  was  used.   In the males,  the incidence
of  primary  lung  carcinoma  was  not  significantly  affected  by SO- (p =  0.604).   However, for
females SO-  increased the  incidence of primary lung  carcinoma (p  = 0.056).   The incidence of
lung adenomas  was  marginally  increased in males  (p = 0.065) and  significantly  increased in
females (p = 0.011).  It, thus, appears that female mice of this strain were more susceptible.
The  significance  of  these  increases (Peacock and Spence, 1967),  therefore,  is  questionable.
Peacock and  Spence  concluded that the  increased  incidence  of primary lung  tumors  was  due to
the  initial inflammatory reaction to SO-, followed by tolerance, which accelerated spontaneous
tumor development.  They further state that this study does not "justify the classification of
S0? as a chemical carcinogen as generally understood."
     Lung  tumors  or  other  significant  pathological  effects were  not  observed  in hamsters
exposed for  98 wk to 26.2 mg/m  (10 ppm) SO, for 6 hr/day, 5 days/wk for 534 exposure days or
             3                             3
to  9.17  mg/m   (3.5  ppm) S02 plus  10 mg/m   benzo(a)pyrene  for 1  hr/day,  5  days/wk for 494
exposure days  or  to a combination of the 2 regimens (Laskin et al., 1970).  When rats (Laskin
et  al.,  1970) were  exposed to the  same regimen,  however,  lung  squamous  cell  carcinoma was
found  in  5/21  (23.8 percent) animals receiving the  combined exposure of  26.2 mg/m  (10 ppm)

XRD12B/A                                12-72                                        2-5-81

-------
                                                          TABLE 12-15.  POTENTIAL MUTAGENIC EFFECTS OF S02/BISULFITE
ro
 i
oo
Concentration SO,












1310 mg/m3
(500 ppm)
13.1 - 105 mg/m3
(5 - 40 ppm x 3 min)
14.9 mg/m3









Bisulfite
0.9 M HSO"
pH 5.0 J

3 M HSO'
pH 5-6 J

1 M HSO"
pH 5.2 J
5 x 10~3 M HSOZ
pH 3.6 J
0.04 or 0.08 M








0.0001M
0.01H
0.0001H

0.0040H

0.0025M
Organism
Phage T4-R11 System


Phage T4-R11
System

E. coll K12 &
K15
S. cerevlsiae

D. melanogaster

Hela cells
(Human)
Mouse fibroblasts &
Peritoneal macrophages
Human lymphocytes


Human lymphocytes

Mouse oocytes

Ewe oocytes

Cow oocytes
End Point
GC^AT or
deami nation of
cysocine
deami nation of
cytosine

GC-»AT or
deami nation of cytosine
Point Mutation

Point Mutation

Cytotoxicity



Point Mutation
Chromosomal aberrations
Cytotoxicity
Inhibition of mitosis

Inhibition of meiosis

Inhibition of meiosis

Inhibition of meiosis
Response Comments
+


± Poor dose
response

+

•f

May not be
bioavailable
+



.
-
»
+ Dose related
response
+ Observed
fuzziness of
+ chromosomes may
be due to cyto-
+ toxicity
Reference
Summers and
Drake, 1971

Hayatsu and Miura,
1970,
lida et al. , 1974
Mukai et al. ,
1970
Dorange and
Dupuy, 1972
Valencia et al. ,
1973
Thompson and Pace,
1962
Nulsen et al. , 1974


Kikigawa and
lizuka, 1972
Harman et al . ,
1970
Jagiello et al. ,
1975




-------
*
S02 for 6 hr/day and 9.17 mg/m  (3.5 ppm) S02 plus 10 mg/m  benzo(a)pyrene for 1 hr/day and in
2/21 (9.5 percent) animals exposed to the benzo(a)pyrene plus SO, for 1 hr/day.   Renal metasta-
                                                                        3
sis also occurred.   Control  rats  exposed to air (n = 3) or to 26.2 mg/m  (10 ppm) S02 (n = 3)
had no tumors.
     This study was  subsequently  extended to lifetime (exact time not specified) exposures (5
days/wk) of  rats  (Laskin et al.,  1976).  Exposure  to  air alone (n = 15) or to 26.2 mg/m  (10
ppm) S09 (n  = 15) for 6 hr/day caused no cancers (squamous cell carcinoma).   A 1 hr/day expo-
               3
sure to 10 mg/m  benzo(a)pyrene caused cancer in 1/30 (3.3 percent) rats.  A 6 hr/day exposure
             3                                                  3
to 26.2 mg/m  (10 ppm) S00 plus a  1 hr/day exposure to 10 mg/m  benzo(a)pyrene resulted in a
                                                                                       3
cancer incidence cf 6.7 percent (2/30).   When animals received a combination of 10 mg/m  benzo-
(a) pyrene and 10.48 mg/m  (4 ppm) S00,  4/45 (8.9 percent) of the rats had cancer.   The highest
                                                                                     3
incidence (19.6 percent, 9/46) was found in animals exposed for 6 hr/day to 26.2 mg/m  (10 ppm)
S02 plus a  combination of 10 mg/m   benzo(a)pyrene  and  10.48 mg/m  (4 ppm)  SOp  for 1 hr/day.
     The biological  significance  of these  studies  (Table 12-16) is complex  and  difficult to
interpret,   particularly since  statistical  analyses  were not  reported in  the  publications.
Hasselblad  and Stead (1980) analyzed the tumor  incidence data of the later  study  (Laskin et
al., 1976)  using  a multiple probit approach.   The cancer incidence increases due to S02 alone
and BaP  alone were  not statistically  significant  (p  =  0.116  and p =  0.113,  respectively).
However, the increase  due to the combination of BaP and S0? was significant (p = 0.005).   Few
S02 exposure experiments  have been carried out  for  the  near lifetime of the animal as in the
early  mouse  study (Peacock  and Spence,  1967)  and the  subsequent  rat  study (Laskin  et  al.,
1976).    Most  work  has  centered  around  short-term acute studies  in which  the  experimental
design and other aspects of the study would be inadequate to detect a low incidence of tumors.
The incidence  of  lung  tumors increases as the animals age; but no historical control data are
available for the colony of rats used (Laskin et al.,  1970;  1976), making the increased inci-
dence  by  the  combined  S0p-benzo(a)pyrene treatment difficult  to  interpret.   Tumor formation
may be a multistep process, requiring more than just the initiation for expression.  In order
to assure  the biological  and statistical  validity  of  such  tumorigenicity  studies a careful
control of the diet is needed, along with detailed records of the incidence of tumors through-
out the  life span of the animals.   The  absolute incidence of  tumors, as  well  as the rate of
occurrence  should be determined  for a  large  number of  control  animals.   Given  the lack of
experimental details in the non-peer reviewed publication (Laskin et al., 1976) and the diffi-
culty of performing  statistical  analyses not done  by  the author,  especially with the experi-
mental  design  used, it is not possible to come to a definitive conclusion about the results of
this study.
12.5.4  Effects of Trace Metals Found In Atmospheric Particles
     Among the numerous  trace metals found in  the  atmosphere,  evidence of carcinogenicity in
experimental  animals has  been shown for  at  least  nine  (beryllium, cadmium, cobalt, chromium,
iron,  nickel,  lead,  zinc,  titanium). Limited evidence  also  points to compounds of molybdenum

XRD12B/A                                12-74                                        2-5-81

-------
 SOX12C/A  3 2-5-81
                                    TABLE 12-16.   TUMOROGENESIS IN ANIMALS EXPOSED TO S02  OR S02  AND BEN20(a)PYRENE
       Concentration
                                        Duration
                         Species
                                                                                              Results
                                                                                                                                     Reference
(See Text for details)
5 min/days, 5 day/wk,   Nice
 lifetime
26.2 mg/m3 (10 ppm) S02 for 534
 exposure days, or 1 hr exposure
 <5 day/wk) to 9.17 mg/m3 (3.5
 ppm) S02 + 10 mg/m3 benzo(a)-
 pyrene for 494 exposure days, or
 a combination of the 2 regimens

26.2 mg/m3 (10 ppm) S02 for 534
 exposure days, or 1 hr exposure
 (5 day/wk) to 9.17 mg/nr (3.5 ppm)
 S02 + 10 mg/m3 benzo(a)pyrene
 for 494 exposure days, or a com-
 bination of the 2 r«gimens
6 hr/days, 5 day/wk,
 98 wk
                                                            Hamster
6 hr/day,
 98 wk
                                              5 days/wk,     Rat
26.2 mg/m3 (10 ppm) S02, or 10.5
 mg/m3 (4 ppm) S02 * 10 mg/m3
 benzo(a)pyrene, or a combination
 of the 2 regimes
                                    Lifetime (5 days/wk)    Rat
Primary pulmonary neoplasias increased in the
 males from 31 to 54% and in the females from 17
 to 43%.   Incidence of hepatomas and lymphomatoses
 were not affected.  Carcinoma incidence increased
 in females from 0 to 18%; no change in carcinomas
 in males

No lung tumors or other pathological effects
                                                                                                                                 Peacock and Spence, 1967
Laskin et al., 1970
Lung squamous cell carcinoma:  5/21 (23.8%) animals
 exposed to combined regimen of .26.2 mg/m3
 (10 ppm) S02 for 6 hr/day and 9.17 mg/m3 (3.5 ppm)
 S02 *• 10 mg/m3 benzo(a)pyrene for 1 hr/day;  2/21
 (9.5%) animals exposed to benzo(a)pyrene + S02
 for 1 hr/day; 0/3 in animals  exposed to 26.2 mg/m3
 (10 ppm) S02; and 0/3 in animals exposed to  air

A 1 hr/day exposure to 10 mg/m3 benzo(a)pyrene
 caused cancer in 1/30 (3.3%).   A 6 hr/day expo-
 sure to 26.2 mg/m3 (10 ppm) S02  + a 1 hr/day
 exposure to 10 mg/m3 benzo(a)pyrene resulted in
 squamous cell carcinoma incidence of 6.7% (2/30).
 A combination of 10 mg/m3 benzo(a)pyrene and 10.5
 mg/m3 (4 ppm) caused cancer in 4/45 (8.9%).   Highest
 incidence (19.6%, 9/46) found in exposure for 6 hr/
 day to 26.2 mg/m3 (10 ppm) S02 + 10 mg/m3 benzo(a)-
 pyrene and 10.5 mg/m3 (4 ppm) S02 for 1 hr/day.   The
 air control had an incidence  of  0/15 and the 26.2 mg/m3
 (10 ppm) SO2 exposure caused  an  incidence of 0/15.
Laskin et al., 1970
                                                                                            Laskin et al.,  1976

-------
and manganese as possible tumorigens (Clemo and Miller, 1960).  Moreover, three of these metals
(cadmium,  chromium,   nickel),  in addition  to arsenic, are  implicated as  human  carcinogens.
     Although  trace  metals are  ubiquitous  in the environment, their  levels  are  generally so
low that  it is difficult to predict the magnitude of carcinogenic risk in community settings.
This  problem is compounded by  the  fact that clear dose-response  relationships have not been
well-defined for most carcinogenic metals.  For the present it is  likely that the possible role
of trace  metals in the production of  cancer  due to particulate air pollution will be limited
to qualitative  judgments.
     The  topic of metal  carcinogenesis  has  been extensively reviewed  in recent years  from
various perspectives  (Furst,  1978;  Furst and Haro, 1969;  Sunderman,  1978; 1979).   These sur-
veys  generally conclude that  with  certain compounds  tumors  can  be  induced via  a  mechanism
which is  apparently distinct from the phenomenon of so-called solid-state or foreign-body car-
cinogenesis.   However,  it  is  still  debatable in many cases whether metal-induced  tumors which
are associated  with  a particular route of administration (e.g.,  local sarcoma by  subcutaneous
implantation)  are  indicative  of true chemical carcinogenesis.  While most carcinogenic metals
are active  only in the form of organic and inorganic salts, for nickel and cadmium it appears
that both the pure elemental form as well as several of their salts are carcinogenic.
     One  of the most widely recognized and well-studied carcinogenic metals is nickel  (Inter-
national  Agency for  Research  on  Cancer (IARC),  1973b; 1976b].  Sunderman  (1979,  1978)  indi-
cated that  nickel subsulfide (Ni,S?) is probably the most potent carcinogenic metal studied to
date.    Single  intramuscular injections of 5 umol (1.2 mg) or 10 umol  (2.5 mg) to  Fischer rats
produced  rhabdomyosarcomas  in  77 percent and 93 percent of the treated animals,  respectively.
Numerous  investigators  have confirmed  that Ni.,S? produces local  sarcomas following injection,
and one group has indicated that chronic inhalation of Ni,S2 in rats caused lung cancer (IARC,
1973b;  1976b).   Several  other  forms of nickel have  shown both positive and negative carcino-
genic activity.  The  chronic  inhalation of nickel carbonyl (Ni(CO).) by rats at levels as low
as 0.03 mg/1  has produced  pulmonary carcinomas (IARC, 1976b).  In addition, Lau et al. (1972)
induced carcinomas  and sarcomas  in  various  organs,  including liver  and  kidney,  by multiple
intravenous  injections of Ni(CO). to rats.  Inhalation of elemental nickel powder has produced
equivocal  results  in mice,  rats,  and  guinea  pigs, and  negative  results  in  hamsters (IARC,
1976b).    Single and repeated intramuscular injections of nickel powder induced local  tumors in
rats and  hamsters,  although intravenous injections were  either marginally effective (rat) or
ineffective  (mouse,  rabbit) (IARC,  1976b).   A single  intrapleural  injection  of nickel powder
(0.02 ml  of a  0.06  percent suspension)  did  not produce  neoplasms  in mice;  multiple intra-
pleural   injections  at  high doses in  rats were  effective in the induction of  local  tumors
(IARC, 1976b).
     The  toxicology  and  carcinogenic  potential  of cadmium  have  been  the subject of extensive
reviews in the past several years (IARC, 1976a; U.S. EPA, 1979; Towill et al., 1978).  Cadmium
XRD12B/A                                12-76                                        2-5-81

-------
is similar to  nickel  in that both  the  elemental  form and several salts are carcinogenic, and
that oral administration is ineffective in producing tumors.  The ability of cadmium to induce
tumors by  inhalation exposure  has  not  been adequately  studied.   However,  single or repeated
injections (intramuscular,  subcutaneous)  of cadmium powder, cadmium chloride (CdCK), cadmium
oxide (CdO), cadmium  sulfate  (CdS04), or cadmium sulfide (CdS) to rodents frequently produces
local sarcomas  (Furst and Haro, 1969; IARC, 1976b; Sunderman, 1979).  A unique feature of the
action of  cadmium  is  that single subcutaneous injections of CdCK to rodents (3.7 - 5.5 mg/kg
body  weight)  leads  to  a  high  incidence  of  interstitial  cell  (Leydig  cell) tumors  of the
testis.   Stoner  et  al.  (1976) recently reported that cadmium acetate did not cause a signifi-
cant increase in pulmonary tumor response in the strain A mouse bioassay system.
     Chromium in the  hexavalent (but  not trivalent) state has produced tumors following inhala-
tion, implantation, and  injection (IARC, 1973a; Towill et al., 1978).  The inhalation of mixed
chromate dust failed  to  induce  lung tumors  in mice, rats, and rabbits, although pulmonary ade-
nomas developed  in mice  exposed by  inhalation to calcium chromate (CaCrO.) dust (IARC, 1973a).
Local sarcomas  in  rats, mice, and  rabbits  have resulted from the intramuscular, subcutaneous,
intrapleural,  intraosseous,  and intraperitoneal  injection  of  chromium  powder and hexavalent
chromium compounds  (IARC,  1973a;  Sunderman, 1979).  Several groups of investigators, however,
have failed  to induce tumors by the parenteral administration of chromium compounds.
     Although  arsenic is  recognized  as a  human  carcinogen based  upon  epidemiological data,
there is  little  evidence to indicate carcinogenic activity in experimental animals (Furst and
Haro, 1969;  Sunderman,  1979).   In  particular, the chromic administration of arsenous trioxide
(As-CU)  in drinking water (34 mg/1)  to  rats  failed to  induce  tumors  (Furst  and  Haro, 1969).
However,  others  have reported  that the subcutaneous injection of  a sodium arsenite compound
led  to  an  increase in the incidence  of lymphocytic leukemias and malignant lymphomas in preg-
nant Swiss mice  and their offspring (Sunderman, 1979).
     Although  not  generally recognized  as  a human  carcinogen,  lead compounds have shown con-
siderable  carcinogenic  activity in rodents [IARC,  1972;  U.S.  Environmental  Protection Agency
(U.S. EPA),  1977].   Several studies  confirmed that  renal  carcinomas result from the oral and
parenteral administration  of  lead phosphate, lead  acetate,  or  basic lead acetate to rats and
mice,  but  not  to  hamsters.    In  addition,  tumors of  the testis  (Leydig  cell),  adrenals,
thyroid, pituitary and prostate have  been found among rats fed lead acetate (3-4 mg/day for 18
months) (U.S. EPA, 1977).  In a recent study using the strain A mouse pulmonary tumor bioassay
system,  Stoner  et  al. (1976) reported that lead subacetate caused a statistically significant
increase in  tumor formation.  However, a dose-response relationship could not be demonstrated.
     Beryllium  salts  have  induced  pulmonary cancers  upon  inhalation and  osteosarcomas upon
intravenous  injection in  a variety  of  animal  species  (IARC,  1972).  Aerosols  of beryllium
sulfate  (BeSO.)  induced pulmonary  carcinomas in  all  of a group of  43  rats  (34  mg/m  for 56
weeks),  and  in  2  of 10 Rhesus monkeys  inhaling  the compound at  35  mg/m   for 8  years (IARC,
XRD12B/A                                12-77                                        2-5-81

-------
1972).    In  addition,  3 of 20  monkeys  developed pulmonary  cancers  after the  intrabronchial
and/or  bronchomural  implantation  of  beryllium  oxide  (5  percent  suspension  in  saline).
Numerous  investigators  found  that the  intravenous  injection  of  zinc  beryllium silicate  or
beryllium oxide caused malignant bone tumors (osteosarcoma) in  rabbits (IARC,  1972;  Sunderman,
1979).
     Evidence  to  support  the  carcinogenic  potential  of  zinc  and  iron  is  limited.   Zinc
compounds (ZnCK,  ZnSO., ZnNO,) are carcinogenic only by intratesticular injection  (Furst and
Haro, 1969; Sunderman,  1979).   When evaluated in the strain A mouse  pulmonary tumor bioassay
system,   zinc  acetate was  found to  be  negative (Stoner  et  al.,  1976).   Iron-polysaccharide
complexes (e.g.,  iron-dextran)  have commonly produced local  sarcomas upon  injection in mice,
rats, and rabbits  (Furst  and  Haro, 1969;  IARC,  1973c).   In  contrast to the  sarcomagenic
properties  of  iron-dextran,  ferric oxide  (Fe?0,,  hematite) produced  no  tumors in hamsters
(intratracheal  instillation),  guinea pigs  (inhalation)  or rats (subcutaneous  implantation).
     The  carcinogenicity  of titanium has  not been fully  investigated.   Chronic  studies  with
mice involving  the ingestion of a  titanium  salt in  the drinking water  gave negative  results
(Furst and  Haro.  1969).   However,  Furst and Haro (1969) succeeded  in  producing local sarcomas
and neoplasms in distant organs by the intramuscular injection  of titanocene  to rats and mice.
In  addition,  local fibrosarcomas  developed  in  three out of  50 rats injected  with titanium
dioxide.
     Several  groups of  investigators have  indicated  that  sarcomas  can  be  produced  by  the
subcutaneous, intramuscular, or intraosseous  injection  of cobalt powder, to rabbits and rats
(Sunderman, 1979).  Little  additional  data are available regarding the  carcinogenic potential
of cobalt.  Stoner et al.  (1976) recently found that cobalt acetate had  no effect on tumor in-
cidence in the strain A mouse pulmonary tumor bioassay system.
     Selenium has  recently  received considerable attention as  a potential  carcinogen,  and is
found in ambient air (IARC, 1975).   Oral  administration  of sodium selenite and  sodium selenate
to  mice  and  rats  has  resulted  in  a wide range of neoplasmas including sarcomas,  "lymphoma-
leukemias,"  mammary  carcinomas,   lung  adenocarcinomas,  and  hepatic   tumors  (IARC,  1975).
Because selenium  is  an  essential trace element, its  role in the etiology of environmentally-
induced cancers remains unclear.
     In  an  attempt to  understand  the   fundamental  biological  activity  of  metals and  its
relationship  to carcinogenesis, numerous  j_n vitro experiments have  been  conducted.   Many of
these studies  attempt  to  exploit  the  strong  formal  relationships  between molecular  events
involved  in  mutagenesis and  carcinogenesis.   In particular,  the  interaction  of xenobiotics
with  nucleic   acids   is   believed  to  be  a  critical  event  in  mutagenesis  and/or  cell
transformation.    Cultures  of  mammalian   cells  and bacteria,  as  well   as  cell-free systems,
have been used to explore the potential  mutagenicity/carcinogenicity of various metals.
     Several  biochemical studies  have been completed which  point  to  a  possible direct action
on  nucleic  acids  by metal  cations  as the basis for metal carcinogenesis.   Murray  and Feisel

XRD12B/A                                12-78                                        2-5-81

-------
lie
(1976) prepared mixtures  of synthetic polynucleotides and measured the changes in the melting
curves induced  by the  addition of  carcinogenic  and non-carcinogenic metal  salts  at a 10  M
concentration.   Both   cadmium  chloride  (CdC^)  and  manganese  chloride  (MnCU)  induced
alterations in  spectrophotometric  measurements which were indicative of mispairing of nucleo-
tide bases.
     More  extensive  studies have been conducted  on  the ability of metal  salts  to  affect the
fidelity of DNA synthesis in  a  cell-free  system  (Loeb et al., 1977; Sirover and Loeb, 1976).
These  investigators  found a high correlation between metals which were mutagenic/carcinogenic
and the ability to increase the  error frequency of deoxynucleotide incorporation.   Nine metals
were  scored  as positive  in this  system at concentrations between  20 uM  and 150 uM; silver,
beryllium, copper,  cadmium,  cobalt, chromium, manganese, nickel,  and  lead.   Negative results
were  obtained with  barium,  calcium, aluminum, iron,  potassium,  magnesium,  sodium, rubidium,
strontium,  and zinc.   The  authors concluded  that  the  fidelity of  DNA synthesis  may  have
potential  application as  a screening technique for mutagenic/carcinogenic metals.
     The recent proliferation  of j_n vitro  cell transformation assays  has resulted in further
confirmation  of the  carcinogenic/mutagenic action of several metals.   The most noteworthy cell
transformation  studies thus  far with metals  have been  those employing  primary  cultures  of
Syrian  hamster embryo  cells  (Costa, 1979;  DiPaolo  and  Casto.  1979;  DiPaolo et  al., 1978).
Morphological  transformation  has been obtained with salts of  nickel, lead, cadmium, chromium,
beryllium, and  arsenic.   Salts  of  iron, titanium, tungstate,  zinc,  and aluminum displayed no
transforming  properties.  Unfortunately, there has not yet been an extensive validation of any
single test system for  screening of potential metal carcinogens.  Moreover, techniques are not
yet  available  to  elucidate the molecular mechanism  of  metal-induced transformation,  or  to
explain how the physicochemical  state of the metal affects its carcinogenic potential.
12.6   CONCLUSIONS
12.6.1  Sulfur  Dioxide
     Once  inhaled,  S0?  appears  to  be  converted  to  its  hydrated  forms,  sulfurous  acid,
bisulfite,  and  sulfite.   The  rate  of  absorption  and  removal  of  inhaled  S0?  varies  with
species, but  it is at  least 80 percent of the  inhaled amount.
     The metabolism  of S0? is  predominantly  to  sulfate and is mediated by the enzyme sulfite
oxidase.   Since  sulfite  oxidase  is a  molybdenum  containing enzyme, dietary  factors could
influence  the function of  the  enzyme.   No conclusive evidence  has yet  been reported.   The
reaction of bisulfite with  serum proteins to form S-thiosulfates  is rapid.  The S-thiosulfates
are  remarkably  long-lived  (t  1/2  = 4.1  days  in rabbits),  supplying a  circulating pool  of
bisulfite  which can  reach all  tissues.   Since  some circulating S-thiosulfates decompose to S0»
which  is exhaled, S-thiosulfates can donate their bisulfite content to distal tissues.
     An immediate  effect  of acute  (5 1  hr) SO- inhalation is  either a decrease in  respiratory
rate or an increase in resistance  to  flow within the  lung.   The  decrease in  respiratory rate
depends on afferent conduction  through  the Vth  or IXth cranial  nerve following activation of

XRD12B/A                                 12-79                                         2-5-81

-------
receptors  in the  nose  and  upper  airways.   Nasal  air flow  is  decreased.   The  response is
transient  in nature and  occurs at  44.5  mg/m  (17  ppm)  SO-.  Lower  concentrations were not
tested.
     The  increased resistance to flow  on  inhalation of S0~  is mediated  through receptors in
the bronchial tree and persists during continued exposure.   With this physiological parameter,
lower  concentrations of  S0?  have been  observed to  cause  reproducible  changes in respiration.
The  increased  resistance to   flow  of  air  in the  lung  on SO-  inhalation represents  the
activation of an autonomic reflex arc through the vagus nerves.  The same reflex arc occurs in
man.   The  reflex  is cholinergic since atropine blocks the reflex, presumably at preganglionic
synapses.  The  guinea  pig is the most  sensitive animal  for measuring  airway resistance, with
significant  changes  in   pulmonary   resistance  to   air  flow  occurring on  the   inhalation  of
concentrations  as  low  as 0.42 mg/m  (0.16 ppm) S0? for 1 hr.   Chronic  exposures have produced
alterations  in  pulmonary function  in  cynomolgus  monkeys,  but only  at concentrations greater
than 13.1  mg/m   (5 ppm).   Dogs exposed to 13.4 mg/m  (5.1 ppm) S02 for 21 hr/day for 225 days
had  increased pulmonary  flow  resistance  and decreased compliance.  Lower concentrations were
not  examined.   It  should be remembered that  S0?  appears to  cause  its  immediate bronchocon-
strictive  effect  through action on  airway  smooth  muscles,  as evidenced  by  the  antagonism of
the  SOp-initiated  bronchoconstriction  by   isoproterenol  in  man  and  animals.    Since  smooth
muscles  adapt or  fatigue during long-term stimulation, chronic exposure  to  S0? is not likely
to  evidence bronchoconstriction   equivalent   to   that  occurring  on  short-term  exposure.
Alterations  in  pulmonary function after chronic exposure  to  S0? are  likely  to  occur through
other  mechanisms,  such  as morphological  changes  in  the  airways or hypersecretion of mucus,
which  will  result in narrowing the  airway.  Concentration, rather  than duration of exposure,
seems  to be  the most important parameter in determining responses to S0?, whether the response
is measured  as  a  histopathological   lesion or as a permanent alteration in respiration.  There
is no  theoretical hypothesis available at present to integrate the short-term effects observed
with 1 hr exposures and the effects  of  long-term exposures of several months.
     In  rats, histopathological effects of SO^ alone are confined to the bronchial epithelium,
with most  of the effects occurring  on  the  mucus  secreting goblet cells.  Goblet cell hyper-
trophy  occurs  on  chronic exposure  of  rats,  leading  to  the  suggestion  that S0?  produces  a
chronic  bronchitis  similar in many  respects to that  in man.   Repeated exposure to a critical
concentration of  SO,,  (not less than 131 mg/m  or 50 ppm) may be needed to produce the chronic
bronchitis.   While  SO^-produced chronic bronchitis in rats is similar to that in man and is a
useful   model for  the  study  of  bronchitis,  no  evidence  exists  that chronic  bronchitis is
produced in man from ambient concentrations of S0?.
     The  nasal  mucosa of mice  (particularly  those  with  upper  respiratory pathogens)  was
                                         3
altered  by  72  hr  exposure  to  26.2  mg/m  (10  ppm) S0«.   Continous exposure to 0.37 to 3.35
    3
mg/m   (0.14   to  1.28  ppm)  SOp  for  78 wk  did  not  cause  any significant  lung  morphological
alterations  in  monkeys.   The effects of near ambient  concentrations of S0? on  the morphology
and function of the nasal mucosa are not known.
XRD12B/A                                12-80                                         2-5-81

-------
     Some pulmonary host defense mechanisms are also affected by S0? exposure. After 10 and 23
days of  exposure  (7 hr/day, 5 days/wk)  to  0.26 mg/m3 (0.1 ppm),  clearance  of particles from
the lower respiratory  tract was accelerated  in  rats.   At a higher concentration of S02 (2.62
mg/m ,  1 ppm) there was an  initial  acceleration  (at  10 days), followed by  a  slowing at 25
days.   A 5 day  (1.5 hr/day)  exposure  to  2.62  mg/m3 (1 ppm) reduced  tracheal  mucus  flow in
dogs, but a  longer exposure to this concentration caused no changes in ciliary beat frequency
of  rats.  These  aberrations  in  tracheal  clearance and  mucus   flow  in several  species  are
consistent with  the profound effects of higher concentrations of SO, on mucus glands in rats.
                                                                                       3
     Antiviral defenses were altered by a 7 day continous exposure to 18.3 to 26.2 mg/m  (7 to
10  ppm)  SO-  as  evidenced  by  an  increase  in  viral  pneumonia.    In  this study,  the combined
exposure to  SO,  and virus  produced weight  loss  on exposure to concentrations as  low  as 9.43
    3                                           1
mg/m  (3.6 ppm)  S02-   Mice exposed to 13.1 mg/m  (5 ppm) S02 for 3 hr/day for 1 to 15 days or
for 24 hr/day for 1 to  3  mo did not have  increased susceptibility to bacterial  lung disease.
A variety of  changes in the humoral immune  response of mice exposed for up to 196 days to 5.24
mg/m  (2 ppm) have  been reported.
     Sulfur dioxide and  bisulfite are mutagenic  in  microbial test systems  (f_. coli and yeast
systems).  The  concentration  of  bisulfite  was  high (1m) and the pH  low.   The relevancy to
inhaled  SO™  as  a mutagen is  not  clear.   A  mechanism for the mutagenesis of  SOp could be the
deamination  of  cytosine  at high concentrations.  Free  radical  reactions  breaking glycosidic
bonds in DNA may be responsible  at  low concentrations.   The potency of bisulfite in these j_n
vitro systems is moderate to weak when  compared  to agents such as nitrosamines or polycyclic
aromatic  compounds.   To  date,  experiments testing  for mutagenicity  or carcinogenicity  by
bisulfite  in mammals  have been  equivocal.   On  the  basis  of present  evidence, one  can  not
decide whether or not bisulfite, and hence  S0?, is a mutagen in mammals.
     The influence  of S0» on tumorigenesis  has also been examined.  Unfortunately, the two key
studies  on  tumorigenesis  have  not been replicated.  Rats  exposed (5 days/wk for  98  wk to a
lifetime) to  26.2 mg/m  (10 ppm) SO, for  6 hr/day in combination with 9.2 or 10.5 mg/m  (3.5
                            3
or  4 ppm)  S0? plus 10 mg/m  benzo(a)pyrene had an increased incidence  of  lung  squamous cell
carcinoma.  Hamsters were not affected.  A reanalysis  of the  data shows that the increase in
tumors in  rats  due to S02  and  benzo(a)pyrene is statistically  significant.  As  a result of
these studies,  the  possibility exists that S02 may  be  a co-carcinogen in rats.   The question
of  carcinogenicity  of  SO, alone cannot be  resolved at present.   For the rat studies described
                                                    3
above, a total  of 15 rats were exposed to  26.2 mg/m  (10 ppm) S02 for 6 hr/day, 5 days/wk for
lifetimes, and  none developed  cancer.   However,  this  sample  size is  small  and would have a
very small probability of detecting a  low  cancer incidence.   In a different study, mice were
exposed  over  their  lifetimes to an indeterminable S02 concentration for 5 min/day, 5 days/wk.
This exposure increased  the incidence of carcinoma in female, but not male, mice.  Reanalysis
of  the data  showed the increased incidence of carcinoma  in females was statistically signifi-
cant.   The  incidence of  primary  pulmonary  neoplasias increased  in  both sexes.   The investi-
gators for this mouse study state that although SO™  increased lung tumors, the results  do "not
XRD12B/A                                12-81                                        2-5-81

-------
justify the  classification of. S02  as  a chemical carcinogen as  generally  understood."  Other
chronic SO- experiments  have  been conducted with several  other  animal  species which included
lung morphology as  an  endpoint,  but no  lung  tumors  were reported.   This does  not  negate the
positive  studies,  since they  showed  a  species  susceptibility to tumor development and were
conducted  either  at  very  high  concentrations  or  in  the presence  of benzo(a)pyrene.   The
general conclusion  to  be  drawn  from  these  studies  is  that SO-  has  not been  proven  to be  a
carcinogen or co-carcinogen, but remains suspect.
12.6.2  Particulate Matter
     The  chemical and  physical  diversity of the particulate matter in the  atmosphere presents
a severe  limitation on the scope of the conclusions  presented  here.   Most  of the evidence for
adverse health  effects of  inhaled  particles presented  in this chapter relates  to compounds
arising from sulfur oxides, e.g., sulfuric acid, ammonium sulfate,  metal sulfates, and related
compounds.  A brief treatment is presented for heavy  metals and their  compounds.  A summary of
data  related  to organic material associated  with particles is also presented,  focusing pri-
marily  on polycyclic organic compounds.  Due  to limitations  of space, details dealt  with in
other  criteria  documents  or recent  major reviews on  specific elements and  the broader aspects
of polycyclic organic  compounds  are presented by reference only.  This chapter,  then, should
not be  taken  as a  summary  of  all of  the data available on the  health  effects of atmospheric
particles,  but  rather  as  a  selected summary  related  mostly  to  sulfur  oxides.    The  reader
should  refer to,  and  study,  the more  detailed reports  before  attempting to integrate  the
present  limited material  into  the  generic problem  of  the effects of  atmospheric  particles.
Similarly,  the  subsequent  section  on  the  interactions  between  sulfur dioxide and particles
relates to a limited scope of the atmospheric particles.
     All  inhalation studies of particles available for review in this document were conducted
with particles  which  could be expected  to  be  within  the size  range alveolar  envelope  of de-
position  (>5  urn MMAD,  depending upon  the species exposed).  Although  particle deposition is
related to MMAD, the majority of studies did not report particle sizes as MMAD.  A few j_n vitro
or intratracheal instillation studies have been performed which compared the effects of a wide
range of  particles  including  those  which occur  in the  atmospheric  coarse  mode particle sizes
(>2.5 urn Dae).
     Reports disagree  as  to the potency of acute exposure to sulfate  aerosols.  Some investi-
gators contend  that sulfuric  acid is highly irritating, producing increases in pulmonary flow
resistance  at  low  concentrations.   The increased  resistance  to  air flow  in the  lung was
directly  proportional  to the sulfate aerosol  concentration  inhaled.   The  bronchoconstriction
produced by zinc ammonium sulfate was similar in many properties to that produced by histamine
aerosols.    Unlike  SO^-initiated bronchoconstriction,   intravenous  atropine  had  no  effect.
Inhaled or intravenous  isoproterenol,  however,  blocked  the  zinc ammonium  sulfate  aerosol
bronchoconstriction.  These data suggest that the zinc  ammonium  sulfate  aerosol  receptor and
presumably  other  sulfate  receptors  are not  identical  to the  SO,,  receptor.   The  two  agents

XRD12B/A                                 12-82                                        2-5-81

-------
*
accordingly could  act  at separate sites  in  the lung.   Histamine is implicated in the sulfate
aerosol action more clearly than in the bronchoconstricting action of S0?.
     The  lowest  effective  concentration producing bronchoconstriction so far reported was 0.1
mg/m   H2$04  (1  hr) in the guinea  pig.   Particle size influenced the  results  in  several ways
but  the  smaller sizes were generally  more effective.   Another study has observed  an "all  or
none"  response (increased airway resistance) in guinea pigs exposed for 1 hr to 14.6, 24.3,  or
48.3 mg/m  H2S04.  Exposure to lower concentrations (1.2 or 1.3 mg/m  H-SO.) caused no effects.
Some of  these conflicts may be due  to differences in technique or in age or strain of guinea
pig.   Large interindividual differences in dose-response curves are characteristic for inhaled
histamine.   In  man,  dogs,  cats, and guinea pigs, 100-fold differences in the bronchoconstric-
tive   response  to histamine  have  been  observed.   The  individual  dose-response  curves  are
remarkably  reproducible.   In  dogs   and  guinea  pigs  the  bronchoconstrictive  response  to
histamine  fell   within a  single   log-normal  distribution,  despite the  large  interindividual
differences  in  the  dose  of histamine  required to elicit  a specific  response.   These large
interindividual  differences  could  represent  differences  in  "susceptibility"  of  different
individuals,  suggesting a small fraction  of "susceptible" individuals; or they could represent
a  very flat dose-response curve for a single population.   Currently,  the data favor a single
population  hypothesis  for  histamine.   The dose-response relationship for sulfate and sulfuric
acid aerosols is  not adequate to differentiate  between these  two hypotheses.  It  is clear that
 large  interindividual  differences  in response  to inhaled aerosols are a characteristic of the
biological  response  as  measured  by increased  resistance to flow,  regardless  of the species
used,  and are not  an artifact of the exposure or measurement  system.
     Age  may also play in important part in this response,  since young  guinea pigs are more
susceptible  than older ones.   For histamine  sensitivity, age-dependence has been suggested as
an analog of juvenile asthma, but human  airway sensitivity  does not seem  to  follow the same
developmental pattern.   Further research  is  needed to settle  the question of special  suscepti-
bility of young  animals  and children.
     For  the effects of 1 hr exposure  of guinea pigs to  sulfur oxides from one laboratory, an
apparent  ranking  of   potency  (for   increased flow  resistence)  is  as  follows:   H?SO.   >
ZnS04(NH4)2S04  > Fe2(S04)3 > ZnS04 >  (NH4)2S04 >  NH4HS04, CuS04 > FeS04> Na2S04, MnS04-  The
 latter three  caused  no effects.
     The  toxicology  of H?S04 is complicated  by its partial concentration-dependent  conversion
to (NH4)?SO.  and NH4HS04 by ammonia  in the breath or in the air of animal exposure  chambers.
While  this  chemical  reaction  is  stoichiometric,  the actual concentrations  of  (NH4)2$04 and
NH.HSO.  in  the airways  or chambers  have  not been measured  definitively.   Thus,  comparing
results of  H?SO.  studies using animals  to those using humans  is confounded, particularly since
extensive neutralization would not be  expected in  the atmosphere of human exposure  chambers.
One  theory  for  the irritating action  of  sulfuric acid contends that sulfate salts  can  act to
promote  release of  histamine  or  other mediators of  bronchoconstriction and is supported by

XRD12B/A                                12-83                                         2-5-81

-------
*
biochemical and pharmacological  evidence  in 2 species.   Anionic release of histamine may play
a  role  in the  bronchial  constriction as  evidenced by the blockade with  H-l antihistamines.
The effects of  adrenergic  agonists and antagonists suggest the involvement of tracheal smooth
muscle.   Certainly,  the  clearance  of sulfurous acid, bisulfite, sulfite, and sulfate from the
lung  is  influenced  by  the  cations  present  in the  aerosols  inhaled  simultaneously.   Since
polluted air  is such  a  complex mixture  of these  aerosols,  the question of  the  toxicity of
ambient aerosols can not be approached on  a  simplistic  basis  by estimating toxicity from the
acidity or sulfate content alone.
     Chronic exposure to HUSO, also produces changes in pulmonary function.  Monkeys exposed to
          3
0.48  mg/m   H-SO.  continously for  78  wk  had altered distribution of ventilation early in the
                                                            3
exposure period.   Higher concentrations  (2.43 and 4.79 mg/m   H?SO.) changed the distribution
of  ventilation  and  increased  respiratory  rate,  but  caused  no effects  on  other  pulmonary
function measurements.   A  lower concentration (0.38 mg/m  H,SO.) caused  no  effects.   Morpho-
                                                                        3
logical changes occurred at the lowest concentration tested (0.38  mg/m  HLSO.).   The effects
appeared to be related to size of the particle as well  as to concentration.   Major  findings at
2.43 mg/m  H^SO. included bronchiolar epithelial hyperplasia and thickening of the  respiratory
bronchioles and  alveolar walls.   Guinea  pigs  exposed  continously  for  52  wk to  0.08 or 0.1
    3                                                                                        3
mg/m  H?SO. had  no effects on pulmonary function or morphology.  Dogs which inhaled 0.89 mg/m
HpSO. for  620 days (21 hr/day)  also  had  no morphological  alterations.   However,  CO diffusing
capacity,  residual  volume, and  net lung volume  were  decreased.  Several other changes  were
noted, including an  increase in total expiratory resistance.
     Sulfuric acid also alters  mucociliary clearance which  is responsible  for clearing the
lung of viable  or  inanimate particles.  These particles impact on the  ciliated airways during
inhalation or reach this region as a result of alveolar clearance.   A 1 hr exposure of dogs to
        3                                                               3
0.5 mg/m   H-SO.  increased tracheal mucocilary transport, whereas 1 mg/m  H?SO. depressed this
rate.  A  2 to  3  hr  exposure  to  0.9  to  1 mg/m   H-SO.  also  decreased  tracheal ciliary  beat
                                                         3
frequency  in  hamsters.   Lower  concentrations  (0.1  mg/m   H-SO., 1  hr/day,  5 days/wk) caused
erratic  bronchial   mucociliary  clearance   rates  in  donkeys   after  several  wk of  exposure.
Continued  exposure of the  donkeys which had  not received pre-exposures  caused  a persistent
slowing of bronchial clearance after about 3 mo of exposure.   From these and other studies, it
appears that repeated exposures to low concentrations of H?SO. can slow mucociliary clearance.
This might imply increased lung residence times of materials that would ordinarily be cleared.
     Other host defense  parameters,  e.g., resistance to bacterial  infection, are  not altered
by  low  concentrations of  H?SO., but  are  affected  by  metal  sulfates.  The  apparent relative
potency of various  particles  for increasing susceptibility to infectious (bacterial) respira-
tory  disease  has  been determined  in mice exposed for 3  hr:   CdSO. >  CuSO.  > ZnNO~, ZnSO. >
                                                            O              ^        O      *f
A12(S04)3  >  Zn(NH.)2(SO/.)2.  At concentrations  >  2.5  mg/m   the  following  particles  had no
significant effects  in  this  model  system:   H2$04, (NH.)2SO.,  NH.HSO.,  Na2S04, Fe?(SO.)3,
Fe(NH4)2S04, NaN03, KN03> and NH4N03.

XRD12B/A                                12-84                                         2-5-81

-------
     It is  evident that accurate  estimates  of the toxicity of  complex  aerosols  occurring in
urban air based  solely on their sulfate contents are inappropriate.  The chemical composition
of the  sulfate aerosols  determines their relative toxicities.   For  pulmonary irritance,  the
potency of  a  sulfate  salt aerosol can be correlated with the permeability of the lung to that
specific sulfate  salt.   The  metallic ions are  also  toxic.   Since urban air contains sulfuric
acid, ammonium sulfate, and metallic sulfates  in varying proportions,  it  is  not possible to
extrapolate from the currently inadequate toxicological data on single compounds in animals to
man as he exists in a complex environment.
     No data are available on the toxicity of secondary or complex atmospheric aerosols, since
only  a  very  few published  reports of  animal  studies  have appeared.  The problem  is  highly
complex because  of the variability of aerosols from different urban localities and the compo-
sitional changes  on  collection.   Toxicity can  be  approached,  at present,  only from estimates
of   composition   and   toxicity  of  individual  components.   Using  j_n  vitro  tests,  metal
oxide-coated  fly ash  has  measurable toxicity  which  can be ascribed  to the  insoluble oxides
when alveolar  macrophages  are exposed.  The  effects of  soluble salts  of Ni and Cd  have major
differences.   Nickel and Cd are removed from the lung with relative rapidity but may be stored
or  bound to   intracellular  proteins  to  an  extent  which  is  sufficient for  accumulation on
                                                                         3                   3
repeated  short-term  exposures.   Two-hr  exposures to both  Ni  (0.5 mg/m )  and  Cd (0.1 mg/m )
aerosols  impair  the  anti-bacterial defenses of the  lung,  leading to  an increased sensitivity
to airborne pathogens  in mice.  Ciliary  beat  frequency in  the trachea  can be decreased by Cd
and  Ni  also.  Humoral  immunosuppression in mice  has  been reported after  a  2-hr exposure to
0.19 mg/m3  CdCl2 or 0.25 mg/m3 NiCl2.
12.6.3  Combinations of Gases and  Particles
     Although  man  is  exposed to a  complex mixture of  gases and particles, few animal studies
have  been  conducted  with  mixtures.   The  dissolution  of  SO-  into   liquid  aerosols  or  the
sorption  onto solid aerosols  tends to  increase  the  potency of  SOp.   The  exact  mechanism by
which  potentiation  occurs  is  still  controversial.    Sodium  chloride  and  soluble  salts
(manganous   chloride,   ferrous  sulfate,  or  sodium  orthovanadate)  potentiated  the  effect
(increased  flow resistance)  of  a  1-hr  S02  exposure  of guinea  pigs.   Hypothetically, these
particles favored  the conversion of S02 to H-SO., thus  increasing the response.
     The  effects of  chronic exposure to  a variety of mixtures of S02, H2S04, and fly ash were
examined  in  guinea  pigs  and monkeys.    None   of  these  studies showed effects  on pulmonary
function.   Morphological  changes  were observed in monkeys  after an 18  mo continuous exposure
             o                                  3
to  2.6 mg/m  (0.99 ppm)  S02  plus 0.88  mg/m  H2$04;  but the addition  of  fly ash  did not
potentiate  the response.
                                               3                               3
     When dogs were  exposed to S02  (13.4 mg/m ,  5.1 ppm)  and H2$04 (0.89 mg/m ) alone and in
combination for  21  hr/day  for  620  days,  no  morphological  changes  were  observed.   Sulfur
dioxide did not  cause  any significant changes  in pulmonary function except for an increase in
N? washout, but  H?S04 caused a variety of changes which were interpreted as the development of
obstructive pulmonary disease.
XRD12B/A                                12-85                                        2-5-81

-------
     In another  series  of studies,  dogs were exposed for 16 hr/day for 68 mo to raw or photo-
chemically  reacted  auto  exhaust, oxides  of  sulfur  or nitrogen, or  their  combinations.   The
animals were  examined  periodically  during exposure and at  32  to 36 mo after exposure ceased.
After  18  or  36  mo  of  exposure,  no significant changes in pulmonary  function  were observed.
After  61  mo,  a  few functional alterations were  observed  in  dogs exposed to SO   (1.1 mg/m  ,
                              3
0.42  ppm  S02,  and  0.09  mg/m  H?SO.) alone  and  in combination  with other pollutants.   The
animals had been placed in clean air for 32 to 36 mo after exposure ceased,  at  which time the
S0x group had a variety of pulmonary functional  and  morphological  alterations.  These struc-
tural changes included a  loss of cilia without squamous cell metaplasia,  nonciliated bronchio-
lar  hyperplasia,  and a loss  of  interalveolar septa in alveolar ducts.   The authors hypothe-
sized  that  these  changes  are  analogous  to  an  incipient stage  of human  proximal  acinar
(centrilobular)  emphysema.  Since the pulmonary function changes were progressive  during the
post-exposure period and  they were  correlated with the pathology,  it can be hypothesized that
the morphological alterations were also progressive.
     Combinations of  carbon and H,SO. or SO,  were  investigated also.   In mice exposed  for  3
                                                            3                    3
hr/day, 5 days/wk for  up to  20 wk  to a mixture of 1.4 mg/m  KLSO.  and 1.5  mg/m  carbon or to
carbon  only,  morphological  and  immunological  alterations were  seen.    In  hamsters,  a  3  hr
exposure to 1.1 mg/m  +1.5 mg/m  carbon depressed ciliary beat frequency, as did  H-SO, alone.
Alterations of  both the pulmonary  and  systemic immune  systems were found in mice  at  various
                                                          3                          3
lengths of exposure (100  hr/wk up to 192 days) to  5.2 mg/m  (2  ppm)  S0? and  0.56 mg/m  carbon,
alone  or  in  combination.   Generally, carbon  and  carbon  + S0? caused more  extensive  effects
than S02 alone.
     When the interaction  of 07  and H9SO. was studied,  the  morphological  effects  of a  6  mo
                                                                         3                   3
intermittent  exposure  of rats  and  guinea pigs to the mixture [10 mg/m  H9SO. +  1.02  mg/m
                                                                                   3
(0.52  ppm)  0,]  were attributed to  0, alone.   However,  combined exposure to 1 mg/m  H?SO. and
0.78 to 0.98  (0.4 to 0.5 ppm) 0, resulted in synergistic effects on glycoprotein  synthesis in
the  trachea!  and certain  indices  of lung  biochemistry.   Acute sequential exposure to  first
           3                                   3
0.196  mg/m    (0.1 ppm) 03  and  then  0.9  mg/m   H-SO.  caused   additive  effects on increased
susceptibility  to  infectious pulmonary  disease  and  antagonistic  effects  on  depression  of
trachea ciliary  beat  frequency.   From these studies, the interaction of  03 and  H^SO. is quite
complex and appears to be dependent  on the  sequence  of exposure as well as on the parameter
examined.
XRD12B/A                                12-86                                        2-5-81

-------
lie
12.7  REFERENCES

Adalis, A,  D.E.  Gardner, F. J. Miller,  and  D.  L.  Coffin.   Toxic effects of cadmium on ciliary
     activity using a tracheal  ring model  system.   Environ.  Res.  13:111-120, 1977.

Adalis,  A.,  D.   E.  Gardner,  and  F.  J.  Miller.    Cytotoxic effects  of  nickel  on  ciliated
     epithelium.  Am. Rev.  Resp.  Dis.  118:347-354,  1978.

Adkins, B.,  Jr.,  J.  H.   Richards,  and D. E. Gardner.   Enhancement of experimental  respiratory
     infection following nickel inhalation.   Environ.  Res.  20:33-42,  1979.

Adkins. B.,  Jr.,  G.  H.   Luginbuhl,  and D.  E. Gardner.   Biochemical  changes in pulmonary cells
     following  manganese  oxide  inhalation.   J.  Toxicol.  Environ.  Health 6:445-454,  1980a.

Adkins,  B. , Jr., G.  H.  Luginbuhl,  and D.  E.  Gardner.   Acute exposure of  laboratory  mice  to
     manganese oxide.   J. Am.  Ind.  Hyg.  Assoc.  41:494-500,  1980b.

Adkins,  B. ,  Jr.,  G.  H.  Luginbuhl,  F.  J.  Miller,  and D.  E.  Gardner.   Increased  pulmonary
     susceptibility  to  streptococcal   infection   following   inhalation  of  manganese  oxide.
     Environ  Res. 23:110-120.  1980c.

Alarie, Y., C. E. Ulrich, W. M. Busey,  H.  E.  Swann, Jr.,  and  H.  N.  MacFarland.   Long-term con-
     tinuous  exposure  cf  guinea  pigs  to  sulfur  dioxide.   Arch.  Environ.  Health  21:769-777,
     1970.

Alarie, Y., C. E. Ulrich, W. M. Busey,  A.  A.  Krumm, and H.  N.  MacFarland.   Long-term continuous
     exposure to  sulfur dioxde in cynomolgus monkeys.   Arch.  Environ.  Health 24:115-128, 1972.

Alarie, Y.  Sensory  irritation by airborne chemicals.   CRC  Crit.  Rev.  Toxicol.  2:299-363, 1973.

Alarie, Y., W. M. Busey, A.  A.  Krumm,  and  C.  E.  Ulrich.   Long-term continuous exposure to sul-
     furic  acid  mist in  cynomolgus monkeys  and guinea pigs.  Arch.  Environ.  Health 2_7:16-24,
     1973a.

Alarie,  Y. , R.  J. Kantz II, C. E.  Ulrich,  A. A.  Krumm, and W. M.  Busey.  Long-term continuous
     exposure  to sulfur dioxide  and  fly ash mixtures  in cynomolgus monkeys  and  guinea pigs.
     Arch.  Environ.  Health  27:251-253,  1973b.

Alarie, Y. , C. E. Ulrich, W. M. Busey,  A.  A.  Krumm, and H.  N.  MacFarland.   Long-term Continuous
     Exposure to  Sulfur Dioxide in Cynomolgus Monkeys.   I_n:   Air Pollution and the Politics of
     Control.  MSS  Information Corporation,  New York,  1973c.   pp.  47-60.

Alarie,  Y. ,  I.  Wakisaka,  and  S.  Oka.  Sensory irritation  by  sulfur  dioxide  and chloroben-
     zilidene malononitrile.   Environ.  Physiol.  Biochem.  3:53-64,  1973d.

Alarie, Y.  C., A. A.  Krumm, W.  M.  Busey, C.  E.  Ulrich,  and  R.  J.  Kantz.  Long-term exposure to
     sulfur dioxide,  sulfuric acid mist,  fly ash, and  their  mixtures.   Results of studies in
     monkeys  and  guinea pigs.   Arch.  Environ. Health 30:254-262, 1975.

Allison,  A. C.   Experimental Methods  -  Cell  and Tissue Culture:   Effects of Asbestos Particles
     on  Marrophages,  Mesothelial  Cells  and  Fibroblasts.   In:   Biological  Effects of Asbestos.
     P. J.  Bogorshi,  V.  Timbrel!,  J.  C.  Gilson, and J.  C. Wagner,  eds. , IRAC Scientific Publi-
     cations  No. 8,  International  Agency  for Research  on  Cancer,  Lyon, 1973.   pp.  89-92.

Allison,  A. C.,  and D.  M.  L. Morgan.   Effects  of  Silica,   Asbestos,  and Other Particles on
     Macrophage  and  Neutrophil  Lysosomes.   J.n:   Lysosomes in Biology and Pathology.  Volume 6.
     J.  T.  Dingle,  P.   J.  Jaques,  and  I.  H.   Shaw,  eds.,  North Holland,  New  York,  NY, 1979.
     pp.  149-159.


XRD12C/C                                      12-87                                    2-5-81

-------
Amdur,  M.  0.   Aerosols  formed by  oxidation of sulfur  dioxide.   Review of their  toxicology.
     Arch. Environ. Health 23:459-468, 1971.

Amdur,  M.  0.,  R.  Z. Schulz,  and  P.  Drinker.  Toxicity  of  sulfuric  acid mist to  guinea pigs.
     AMA Arch. Ind. Hyg. Occup. Med. 5:318-329, 1952.

Amdur,  M.  0.   Effect  of a  combination  of  SO,  and H,SO..  on  guinea pigs.   Pub. Health.  Rep.
     69:503-506, 1954.                        *       *  *

Amdur,  M.  0. ,  and J.  Mead.   A method  for studying  the  mechanical  properties of the  lungs  of
     unanesthetized animals.   I_n:   Proceedings  of  the  3rd National Air Pollution  Symposium.
     National Air  Pollution Symposium, Pasadena, CA.  April, 1955.   pp.  150-159.

Amdur,  M.  0.  The  influence of aerosols upon the respiratory response of guinea  pigs to  sulfur
     dioxide.  Am.  Ind. Hyg.  Assoc.  18:149-155, 1957.

Amdur,  M.  0.  The  respiratory response of guinea pigs to sulfuric acid mist.  Arch.  Ind.  Health
     18:407-414, 1958.

Amdur,  M.  0. , and  J.  Mead.   Mechanics  of respiration in unanesthetized guinea  pigs.   Am.  J.
     Physiol. 192:364-368. 1958.

Amdur,  M.  0.   The  physiological  response of guinea pigs to  atmospheric pollutants.  Int.  J.
     Air  Pollut. 1:170-183, 1959.

Amdur,  M.  0.  The  Effect of Aerosols on the  Response to  Irritant Gases.   Iji:  Inhaled  Particles
     and Vapors.   C. N. Davies, ed., Pergamon Press, Oxford, 1961.   pp.  281-294.

Amdur,  M.  0., and  M. Corn.  The irritant potency of  zinc ammonium sulfate of different particle
     sizes.  J. Am. Ind. Hyg.  Assoc. 24:326-333, 1963.

Amdur,  M.  0.   The effect of  high flow-resistance  on the response of guinea pigs to  irritants.
     J. Am. Ind. Hyg.  Assoc.  25:564-568, 1964.

Amdur,  M.  0.  Respiratory absorption data and S09  dose-response curves.   Arch. Environ.  Health
     12:729-732, 1966.                          
-------
Amdur, M. 0., M. Dubriel, and 0. A. Creasia.   Respiratory  response of guinea pigs  to low levels
     of sulfuric acid.  Environ. Res.  15:418-423,  1978b.

Amdur, M. 0., V. Ugro, and D. W. Underbill.   Respiratory  response  of guinea pigs to ozone alone
     and with sulfur dioxide.  J. Am.  Ind.  Hyg.  Assoc.  39:958-961,  1978c.

American  Conference of Governmental   Industrial  Hygenists.   TLVs  Threshold Limit Values  for
     Chemical  Substances  in Workroom Air Adopted by  ACGIH  for 1979.  ACGIH, Cincinnati,  OH,
     1979.

Aranyi,  C. ,  F.  J.  Miller, S. Anders,  R.  Ehrlich,  J.  Renters,  D.  E.  Gardner, and M.  D.  Waters.
     Cytotoxicity  of  alveolar  macrophages  of  trace  metals adsorbed on fly  ash.  Environ.  Res.
     20:14-23,  1979.

Arrigoni,  0.   The  enzymatic oxidation of sulphite in  mitochondria!  preparations of pea inter-
     nodes.  Ital.  J. Biochem. 7:181-186,  1959.

Asada,  K. , and  K.  Kiso.   Initiation of  aerobic  oxidation  of sulfite by  illuminated  spinach
     chloroplasts.  Eur.  J.  Biochem.  33:253-257,  1973.

Asahina,  S. , J.  Andrea, A. Carmel,  E.  Arnold,  Y.  Bishop,  S.  Joshi,  D.  Coffin,  and  S.  S.  Epstein.
     Carcinogenicity of organic  fractions of  particulate pollutants collected in New York City
     and  administered subcutaneously  to infant mice.   Cancer Res.  32:2263-2268, 1972.

Backstrom,  H.   L.  J.   The  chain-reaction theory of  negative catalysis.    J.  Am.  Chem.  Soc.
     49:1460-1471,  1927.

Balchum,  0.  J. , J.  Dybicki, and  G.   R.  Meneely.   The dynamics of  sulfur  dioxide  inhalation,
     absorption, distribution, and  retention.   Arch.  Ind.  Health  21:564-569, 1960.

Barry,  D.  H. ,  and  L. E. Mawdesley-Thomas.   Effect of sulphur dioxide on the enzyme activity of
     the  alveolar  macrophage of  rats.   Thorax 25:612-614,  1970.

Bingham,  E. , E. A.  Pfitzer, W.  Barkley,  and E.  P. Radford.  Alveolar macrophages:   Reduced
      number  in  rats  after prolonged  inhalation of lead  sesquioxide.   Science 162:1297-1299,
     1968.

Bingham,  E. ,  W. Barkley, M. Zerwas,  K. Stemmer,  and  P.  Taylor.   Responses of alveolar macro-
     phages  to metals.    I.  Inhalation of lead and nickel.   Arch.  Environ.  Health 25:406-414,
     1972.

Boushey,  H.  A., M. J.  Holtyman, 0.  R.  Sheller,  and J. A.  Nadel.   Bronchial  hyperreactivity.
     Am.  Reo.  Respir-Dis.  121:389-413, 1980.

Breuninger,  H.   Uber  das  physikalisch - chemische Verhalten  des  Nasenschleims.    Arch.  Ohren
     Nasen Kehlkopfheilkd. 184:133-138, 1964.

Brink,  C., P.  G.  Duncan,  M. Midzenski, and J. S.  Douglas.  Response and sensitivity of female
     guinea  pig respiratory tissues  to agonists during ontogenesis.  J.  Pharmacol. Exp. Ther.
     215:426-433,  1980.

Brune,  H.  F.  K.   Experimental   results with  percutaneous applications of  automobile  exhaust
     condensates in mice.  Air  Pollution and Cancer in Man.  IARC Scientific Publications No.
     16,  1977.   pp. 41-48.

Camner,  P.,  M.  Lundborg, and P.  Hellstrom.    Alveolar macrophages and 5  mm particles coated
     with  different metals.  Arch.  Environ. Health 29:211-213, 1974.
XRD12C/C                                      12'89                                     2-5-81

-------
Campbell, J. A.   Cancer of sk.in and  increase in incidence of primary tumours  of  lung in mice
     exposed  to dust  obtained  from  tarred  roads.   Brit.  J.  Exp.  Pathology,  287-294,  1934.

Campbell, J. A.   Carcinogenic agents present  in  the  atmosphere and  incidence  of  primary lung
     tumours in mice.  Brit. J.  Exp.  Path. 20:122, 1939.

Campbell, J. A.  Lung tumours in mice.  Incidence as affected by inhalation of  certain carcino-
     genic agents and some dusts.  Brit. Med. J., 217-221,  1942.

Cavender, F.  L. ,  W.  H. Steinhagen, C.  E.  Ulrich, W.  M. Busey, B. Y. Cockrell, J.  K.  Haseman,
     M.  D.  Hogan,  and R.  T. Drew.   Effects  in rats and guinea pigs of short-term  exposures  to
     sulfuric acid mist, ozone, and their combination.  J.  Toxicol. Environ. Health 3:521-533,
     1977.

Cavender, F. L.  Effects in rats and  guinea  pigs of six-month exposures to sulfuric acid  mist,
     ozone, and their combination.   J. Toxicol. Environ. Health 4:845-852, 1978.

Charles,  J.  M. , and  D.  B. Menzel.   Ammonium and sulfate  ion  release of histamine from  lung
     fragments.  Arch. Environ.  Health 30:314-316, 1975a.

Charles,  J.  M. , and D. B. Menzel.   Sulfate  removal  from the airways and histamine release  in
     the  isolated perfused rat lung.  Pharmacologist 11:213, 1975b.

Charles,  J.  M.   A  Mechanism  for  Inhaled  Sulfate  Initiated   Bronchoconstriction.    Ph.D.
     Dissertation, Duke University, Durham,  NC, 1976.

Charles,  J.  M. , W.  G. Anderson, and  D. B. Menzel.  Sulfate absorption from the airways of the
     isolated perfused rat lung.  Toxicol. Appl. Pharmacol. 41:91-99, 1977a.

Charles,  J.  M. , D.  E. Gardner,  D.  L. Coffin, and D.  B.  Menzel.   Augmentation of  sulfate ion
     absorption from  the  rat  lung  by heavy  metals.   Toxicol. Appl.  Pharmacol.   42:531-538,
     1977b.

Clemo, G. R.,  E. W. Miller, and F.  C. Pybus.  The carcinogenic action of city smoke.   Brit.  J.
     Cancer 9:137-141, 1955.

Clemo, G.  R. ,  and E. W. Miller.  Tumour promotion by the neutral  fraction of cigarette smoke.
     Brit. J. Cancer  14:651-656, 1960.

Cockrell, B. Y. , and W. M. Busey.  Respiratory tract lesions in guinea pigs exposed to sulfuric
     acid mist.  J. Toxicol. Environ. Health 4:835-844, 1978.

Cohen,  H.  J.,  and  I.  Fridovich.   Hepatic sulfite oxidase.   Purification and properties.   J.
     Biol. Chem. 246:359-366, 1971a.

Cohen, H. J., and I.  Fridovich.   Hepatic sulfite oxidase.   The  nature and function of  the heme
     prosthetic groups.  J. Biol. Chem. 246:367-373, 1971b.

Cohen, H. J., S. Betcher-Lange, D.  L. Kessler, and K. V. Rajagopalan.  Hepatic  sulfite oxidase.
     Congruency  in   mitochondria   of  prosthetic  groups   and  activity.    J.   Biol.   Chem.
     247:7759-7766, 1972.

Cohen, H. J. ,  R.  T.  Drew, J. L.  Johnson, and K. V. Rajagopalan.  Molecular basis of  the bio-
     logical function of  molybdenum.   The relationship  between sulfite  oxidase and the  acute
     toxicity of bisulfite and S02-   Proc. Nat. Acad. Sci.  U.S.A.  70:3655-3659,  1973.
XRD12C/C                                      12-90                                     2-5-81

-------
Cohen,  H.  J.,  I.  Fridovich, and  K.  V.  Rajagopalan.   Hepatic sulfite oxidase.   A functional
     role for molybdenum.  J. Biol. Chem.  246:374-382,  1974.

Committee on Biologic Effects of Atmospheric  Pollutants.   Lead.   National  Academy of Sciences,
     Washington, DC, 1972.

Committee  on Biologic  Effects  of Atmospheric Pollutants.   Vanadium.    National  Academy  of
     Sciences, Washington, DC,  1974.

Committee  on Biologic  Effects  of Atmospheric Pollutants.   Chromium.    National  Academy  of
     Sciences, Washington, DC,  1974.

Committee  on Medical  and  Biologic  Effects  of Environmental  Pollutants.  Nickel.   National
     Academy of  Sciences, Washington,  DC,  1975.

Committee  on Medical  and  Biologic  Effects  of Environmental  Pollutants. Arsenic.   National
     Academy of  Sciences, Washington,  DC,  1977.

Committee on Sulfur  Oxides.  Sulfur Oxides National  Academy of Sciences, Washington,  DC,  1978.

Commoner,  B. ,  P.  Madyastha, A. Bronsdon,  and  A.  J. Vithayathil.   Environmental  mutagens  in
     urban air  particules.   J.  Toxicol.  Environ. Health 4:59-77,  1978.

Corn,  M. ,  N. Kotsko,  D. Stanton,  W.  Bell,  and A.  P.  Thomas.   Response of rats  to  inhaled
     mixture  of S02 and S02 -  NaCl aerosol  in  air.  Arch.  Environ. Health.  24:248-256,  1972.

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.  Ind.  Hyg.  Assoc.  J.  40:680-685, 1979.

Costa,  D.  L. ,  and M. 0.  Amdur.   Effect of oil  mists on the irritancy of  sulfur dioxide.   II.
     Motor Oil.  Am.  Indust. Hyg.  Assoc.  J. 40:809-815, 1979b.

Costa,  M.   Preliminary  report  on  nickel-induced  transformation in  tissue  culture.    In:
     Ultratrace  Metal  Analysis in Biological  Science and  Environment.   T.  H.  Risby,  ed. ,
     Advances in Chemistry Series  172,  American Chemical  Society, Washington,  DC, 1979.

Crisp,  C.  E. ,  G.  L.  Fisher,  and  J.   E.  Lammert.    Mutagenicity of filtrates  from respirable
     coal fly ash.   Science  199:73-75,  1978.

Dehnen,  W. ,  N.   Pitz,  and R. Tomingas.   The  mutagenicity of  airborne  particulate pollutants.
     Cancer  Letters  4:5-12,  1977.

DiPaolo,  J.  A., R.  L.  Nelson,  and B.  C.  Casto.   Ir\ vitro neoplastic  transformation of Syrian
     hamster  cells by lead  acetate and its relevance to environmental  carcinogenesis.   Br.  J.
     Cancer  38:452,  1978.

DiPaolo,  J.  A.  , and B.  C.  Casto.   Quantitative  studies of jm  vitro  morphological  transfor-
     mation  of  Syrian hamster cells by inorganic metal  salts.   Cancer  Rev. 39:1008-1013,  1979.

Dorange, J.-L.,  and  P.  Dupuy.   Mise en evidence d'une action mutagene  du  sulfite de sodium sur
     la  levure.  C.  R.  Hebd. Seances  Acad. Sci.  Ser. D. 274:2798-2800, 1972.

Douglas, J.  S.,  M. W. Dennis, P.  Ridgway,  and A. Bouhuys.   Airway constriction in guinea pigs.
     Interaction of  histamine and  autonomic drugs.   J.  Phamacol.  Exp.  Ther. 184:169-179,  1973.

Douglas,  J.  S., P.  Ridgway, and  C. Brink.   Airway  responses  of the guinea pig ui vivo and in
     vitro.  J.  Pharmacol. Exp. Ther.  202:116-124,  1977.
XRD12C/C                                      12-91                                     2-5-81

-------
Drazen, J. M.  Physiologic bas.is and interpretation of common  indices of  respiratory mechanical
     function.  Environ. Health Perspect. 16:11-16, 1976.

Ehrlich,  R. , J.  C.   Findlay,  and  D.  E.  Gardner.   Susceptibility to  bacterial  pneumonia  in
     animals exposed to sulfates.  Tox. Lett. 1:325-330, 1978.

Ehrlich,  R.   Interaction  between environmental  pollutants  and  respiratory infections.   I_n:
     Proceedings of the Symposium on Experimental Models for Pulmonary  Research.  D.  E.  Gardner,
     E.  P.  C. Hu,  and J.  A.  Graham,  eds.,   EPA-600/9-79-022,  U.S.  Environmental  Protection
     Agency, Research Triangle Park, NC, 1979.  pp. 145-163.

Environmental  Criteria  and  Assessment Office.   Health Assessment  Document  for  Polycyclic
     Organic Matter.  External Review Draft No. 1, U.S. Environmental Protection Agency,  Office
     of Research and Development, Research Triangle Park, NC, May  1978.

Environmental  Criteria  and  Assessment  Office.   Health  Assessment  Document  for  Cadmium.
     Preprint.  EPA-600/8-79-003, U.S.  Environmental Protection Agency, Research Triangle Park,
     NC, January 1979.

Epstein,  S.  S. , S.  Joshi, J.  Andrea,  N.  Mantel,  E.  Sawicki,  T.  Stanley,  and  E.  C.  Tabor.
     Carcinogenicity  of organic particulate  pollutants in urban  air after administration  of
     trace quantities to neonatal mice.  Nature 212:1305-1307, 1966.

Epstein,  S.  S. ,  E.  Arnold, J. Andrea,  W. Bass, and Y. Bishop.  Detection of chemical  mutagens
     by  the  dominant  lethal  assay in  the  mouse. Toxicol. Appl.  Pharmacol. 2:288-325,  1972.

Exon,  J.  H.  , N.  M.  Patton,  and L.  D. Koller.   Hexamitiasis  in cadmium-exposed mice.   Arch.
     Environ. Health 30:463-464, 1975.

Fairchild, G. A.,  J.  Roan, and  J.  McCarroll.   Atmospheric  pollutants  and  the  pathogenesis  of
     viral respiratory  infection.  Arch. Environ. Health 25:174-182, 1972.

Fairchild, G. A.,  P.  Kane, B. Adams, and D. Coffin.  Sulfuric acid and streptococci  clearance
     from respiratory tracts of mice.   Arch. Environ. Health 30:538-545,  1975a.

Fairchild, G.  A.,  S.  Stultz, and  D.   C. Coffin.   Sulfuric acid  effect  on the deposition  of
     radioactive aerosol  in the respiratory tract of guinea pigs.  Am. Indust. Hyg.  Assoc.  J.
     36:584-594, 1975b.

Fenters,  J.  D. , J.  N.  Bradof, C.  Aranyi,  K.  Ketels,  R. Ehrlich,  and  D.  E. Gardner.   Health
     effects  of  long-term  inhalation of  sulfuric  acid  mist - carbon  particle  mixtures.
     Environ. Res.  19:244-257, 1979.

Ferin, J. , and  L.  J.  Leach.   The  effect of S09  on  lung  clearance of TiO,  particles in rats.
     J. Am.  Ind. Hyg. Assoc. 34:260-263, 1973. c                          *

Fishbein,  L.  Atmospheric mutagens.    I.   Sulfur  oxides  and nitrogen  oxides.   Mutat.  Res.
     32:309-330, 1976.

Frank, N.  R. , and  F.  E. Speizer.   S0« effects on the respiratory system in dogs.   Changes  in
     mechanical  behavior  at different  levels of  the  respiratory system during acute exposure
     to the gas.  Arch. Environ. Health 11:624-634, 1965.

Frank, N. R., R. E. Yoder, E. Yokoyama, and F. E. Speizer.35The  diffusion of 35SO?  from tissue
     fluids  into the  lungs following exposure of dogs to   SO^.   Health  Phys.  13:31-38, 1967.
XRD12C/C                                     12-92                                     2-5-81

-------
Frank, N. R. ,  R.  E.  Yoder, J..D. Brain,  and  E.  Yokoyama.   S0? (   S labeled) absorption by the
     nose and mouth under conditions  of varying  concentration and flow.   Arch.  Environ  Health
     18:315-322, 1969.

Fraser, D.  A.,  M.  C.  Battigelli, and H.  M. Cole.   Ciliary activity and  pulmonary retention of
     inhaled dust in rats exposed to  sulfur dioxide.   J.  Air Pollut.  Control Assoc.  18:821-823,
     1968.                                                                           —

Fridovich,  I., and P. Handler.   Xanthine  oxidase.   J.  Biol.  Chem.  233:1578-1580,  1958.

Fridovich,  I., and P. Handler.   Detection of  free  radicals in illuminated dye solutions by the
     initiation of sulfite oxidation.  J.  Biol.  Chem.  235:1835-1838,  1960.

Fromageot,  P., R. Vaillant, and  H.  Perez-Milan.  Oxydation du sulfite en sulfate  par la racine
     d'avoine.  Biochim. Biophys. Acta 44:77-85, 1960.

Furst,  A. ,   and  R.  T.  Haro.   A   survey  of  metal  carcinogenesis.   Progr.  Exp.  Tumor  Res.
     12:102-133, 1969.

Furst,  A.   An Overview of Metal Carcinogenesis.   In:   Advances  in  Experimental Medicine  and
     Biology.  Vol.  91.   Inorganic and Nutritional  Aspects of Cancer.   G.  N.  Schrauzer,  ed. ,
     Plenum Press, New York,  1978.  pp. 1-12.

Gardner,  D.  E.,  and  J.  A.  Graham.    Increased  Pulmonary  Disease  Mediated through  Altered
     Bacterial Defenses.   In:  Pulmonary  Macrophage  and  Epithelial  Cells.   C.  L.  Sanders,  R.  P.
     Schneider,  D.  E.  Dagle,  and H.  A. Ragan, eds.,  ERDA Symposium Series  43,  Energy Research
     and Development Administration,  Washington, DC,  1977.   pp. 1-21.

Gardner,  D.  E. ,  F.  J.  Miller,  J.  W.  Illing, 'and  J.  M.  Kirtz.   Increased  infectivity  with
     exposure to ozone  and sulfuric acid.  Toxicol.  Lett.  1:59-64,  1977a.

Gardner, D.  E. , F. J. Miller, J. W. Illing, and  J.  M.  Kirtz.   Alterations in bacterial  defense
     mechanisms  of  the  lung  induced  by inhalation of cadmium.  Bull.  Europ.  Physiopath.  Resp.
     13:157-174, 1977b.

Gardner,  D.  E.   Impairment  of  pulmonary defenses  following inhalation exposure to cadmium,
     nickel, and manganese.   J.  Aerosol Sci.,  in press,  1981.

Giddens, W.  E. ,  and G.  A. Fairchild.  Effects of  sulfur dioxide on the nasal  mucosa of mice.
     Arch.  Environ. Health 25:166-173, 1972.

Gilbert,  E.  E.   Sulfonation  and Related  Reactions.   Wiley Interscience, New York,  NY,  1965.
     p. 125.

Goldstein,  B. ,  and  I.  Webster.   Intratracheal  injection  into  rats  of   size-graded  silica
     particles.  Brit. J.  Indust. Med. 23:71-74, 1966.

Graham, J. A., D. E. Gardner, F. J. Miller, M. J.  Daniels, and D.  L.  Coffin.  Effect of nickel
     chloride  on  primary antibody  production  in  the   spleen.    Environ.  Health  Perspect.
     12:109-113, 1975.

Graham, J. A., D. E. Gardner, M. D. Waters, and  D.  C.  Coffin.  Effect of trace metals on phago-
     cytosis by alveolar macrophages.  Infect.  Immun.  11:1278-1283, 1975b.

Graham,  J.  A.,  F.  J.  Miller,  M.   J.   Daniels, E.  A.  Payne,  and  D.  E.  Gardner.   Influence of
     cadmium, nickel, and chromium  on primary immunity in mice.   Environ. Res. 16:77-87, 1978.
XRD12C/C                                      12-93                                    2-5-81

-------
Grant,  M.  M. ,  S.   P.  Sorokin.,  and J.  D.  Brain.   Lysosomal  enzyme  activities in  pulmonary
     macrophages from  rabbits  breathing iron oxide.  Am.  Rev. Resp. Dis.  120:1003-1012,  1979.

Green,  G.  M.  The  J.  Burns Amberson Lecture -  In Defense of the  Lung.   Am.  Rev. Resp.  Dis.
     102:691-703, 1970.

Grose,  E.  C. ,  D.  E. Gardner,  and  F.  J.  Miller.    Response of ciliated  epithelium to  ozone and
     sulfuric acid.  Environ.  Res. 22:377-385, 1980.

Grunstein, M.  M. ,   M.  Hazucha, J.  Sorli,  and J.  Milic-Emili.   Effect of SCL  on control  of
     breathing in  anesthetized cats.   J. Appl.  Physio!:   Respirat.  Environ. Exercise Physiol.
     43:844-851, 1977.

Gunnison,  A.  F. ,  and  A. W.  Benton.   Sulfur dioxide:   Sulfite.   Interaction with  mammalian
     serum and plasma.  Arch.  Environ. Health 22:381-388,  1971.

Gunnison,  A.  F. ,  and E.  D.  Palmes.   Persistence  of plasma S-sulfonates  following  exposure of
     rabbits  to  sulfite  and  sulfur  dioxide.   Toxicol.   Appl.  Pharmaco).  24:266-278,  1973.

Habib,  M.  P.,  P.   D.  Pare,  and  L.  A.  Engel.    Variability  of airway  responses  to  inhaled
     histamine in  normal  subjects.  J.  Appl. Physiol.:   Respirat.  Environ. Exercise  Physiol.
     47:51-58, 1979.

Hackney, J.  D.   Effects  of  sulfate aerosols upon  cardiovascular function in squirrel  monkeys.
     Final Report.   APRAC  Project CAPM-20-74, Coordinating Research Council,  Inc.,  New  York,
     Dec.  1, 1978.

Hadley, J. G., D. E. Gardner,  D. L. Coffin, and D. B. Menzel.  Inhibition of antibody mediated
     rosette formation by alveolar macrophages:   A sensitive assay  for  metal toxicity.   RES J.
     Reticuloendothel. Soc.  22:417-425, 1977.

Harkness,  D.  R. ,  and S.   Roth.   Purification  and  properties  of  2,3-diphosphoglyceric  acid
     phosphatase from human erythrocytes.   Biochem. Biophys.  Res. Commun. 34:849-856,  1969.

Harman, D. ,  H.  J.  Curtis,   and J.  Tilley.   Chromosomal  aberrations  in  liver cells  of mice fed
     free  radical reaction  inhibitors.  J. Gerontol. 25:17-19, 1970.

Hasselblad,  V.,  and A.  Stead.   Analysis of the Laskin, et al. and  Peacock and Spence Data for
     Chapter 12 of  the SO /PM  Document.  Personal  Communication  to  L. D.  Grant (Director,  ECAO,
     EPA), Oct. 24,  1980.x

Hatch,  G.  E. ,  D.  E. Gardner,  and  D. B. Menzel.   Stimulation of  oxidant production  in alveolar
     macrophages by  pollutants and latex particles.  Environ. Res.  23:121-136, 1980.

Hayatsu, H. ,  and  A. Miura.  The mutagenic action  of sodium bisulfite.  Biochem.  Biophys.  Res.
     Commun. 39:156-160, 1970.

Hayatsu, H.  Bisulfite modification of nucleic acids and  their constituents.   Prog.  Nucl.  Acid
     Res. Mol. Biol. 16:75-124, 1976.

Hayon,  E. ,  A.  Treinin,  and J. Wilf.   Electronic  spectra,  photochemistry,   and  autoxidation
     mechanism  of   the  sulfite-bisulfite-pyrosulfite  systems.   The S09,  SO,,  SO.,  and  SOr
     radicals.  J.   Am. Chem. Soc.  94:47-57, 1972.                       ^34          b

Hemeon, W.  C.  L.   The estimation  of health hazards  from  air pollution.   AMA Arch.  Ind.  Health
     11:397-402, 1955.
XRD12C/C                                     12-94                                     2-5-81

-------
Heppleston,  A.  G.   The  disposal  of  dust  in the  lungs  of silicotic  rats.   Am.  J.  Path.
     40:493-506, 1962.

Hirsch,  J.  A. ,  E.  W.  Swenson,  and  A.  Wanner.   Trachea!  mucous transport  in beagles  after
     long-term  exposure  to  1 ppm sulfur  dioxide.   Arch.  Environ.  Health 30:249-253,  1975.

Holma,  B. ,  J.  Lindegren, and  J.  M.  Andersen.  pH effects  on ciliomotility and morphology  of
     respiratory mucosa.  Arch. Environ.  Health 32:216-226, 1977.

Horvath,  S.  M. ,  and L.  J.  Folinsbee.   Interactions of Two Air  Pollutants, Sulfur  Dioxide and
     Ozone, on  Lung Functions.  University  of California,  Institute of Environmental  Stress,
     Santa Barbara, CA,  1977.

Howell,  L.  G. ,  and  I.   Fridovich.   Sulfite:  Cytochrome  c  oxidoreductase.   J.  Biol.  Chem.
     243:5941-5947, 1968.

Huisingh,  J. ,  R.  Bradow, R.  Jungers,  L.  Claxton, R.  Zweidinger,  S.  Tejada,  J. Bumgarner,  F.
     Duffield,  and M.  Waters.   Application  of   bioassay  to the  characterization of  diesel
     particle  emissions.   Characterization of  light  and  heavy duty  diesel  particle emissions.
     EPA-600/9-78-027, U.S.  Environmental  Protection  Agency,  Health  Effects Research Laboratory
     and  Environmental Sciences Research  Laboratory,  Research Triangle  Park, NC, 1977.

Hyde,  D. , J.  Orthoefer, D.  Dungworth, W.  Tyler, R.  Carter,  and H.  Lum.   Morphometric and
     morphologic  evaluation of pulmonary lesions in  beagle  dogs  chronically exposed  to high
     ambient levels of air pollutants.  Lab.  Invest.  38:455-469, 1978.

lida,  S. ,  M.  Inoue, K.  Kai,  N.  Kitamura, I.  Kudo, M.  Sono,  T.  Tsuruo, H. Hayatsu,  A.  Miura,
     and  Y.  Wataya.   Some properties  of  the damage of DNA and  phage 2 induced by bisulfite.
     Mutat. Res. 20:433-434,  1974.

International Agency  for Research  on  Cancer.   IARC Monographs on the  Evaluation of  Carcinogenic
     Risk of Chemicals to Man.  Vol.  1, 1972.   pp. 40-50.

International Agency  for Research  on  Cancer.   IARC Monographs on the  Evaluation of  Carcinogenic
     Risk of Chemicals to Man.  Vol.  2, 1973a.  pp.  100-125.

International Agency  for Research  on  Cancer.   IARC Monographs on the  Evaluation of  Carcinogenic
     Risk of Chemicals to Man.  Vol.  2, 1973b.  pp.  126-149.

International Agency  for Research  on  Cancer.   IARC Monographs on the  Evaluation of  Carcinogenic
     Risks of Chemicals  to Man.  Vol.  2,  1973c.   pp.  161-178.

International Agency  for Research  on  Cancer.   IARC Monographs on the  Evaluation of  Carcinogenic
     Risk of Chemicals to Man.  Vol.  9, 1975.   pp. 245-260.

International Agency  for Research  on  Cancer.   IARC Monographs on the Evaluation of  Carcinogenic
     Risk of Chemicals to Man.  Vol.  2, 1976a.  pp.  39-74.

International Agency  for Research  on  Cancer.   IARC Monographs on the Evaluation of  Carcinogenic
     Risk of Chemicals to Man.  Vol.  2, 1976b.  pp.  75-112.

Irreverre,  F. ,  S.  H.  Mudd,  W. D.  Heizer,  and L.  Laster.   Sulfite  oxidase  deficiency:   studies
     of  a patient  with  mental  retardation,  dislocated  ocular lenses,  and abnormal  urinary
     excretion of S-sulfo-L-cysteine,  sulfite, and thiosulfate.   Biochem.  Med.  1:187-217, 1967.

Islam,  M.  S. ,  E.  Vastag, and  W.  T.  Ulmer.   Sulphur-dioxide  induced bronchial  hyperreactivity
     against acetylcholine.   Int.  Arch. Arbeitsmed.  29:221-232,  1972.
XRD12C/C                                      12-95                                    2-5-81

-------
Jagiello, G.  M. ,  J.  S. Lin, and M. B. Ducayen.  S0? and  its metabolite:   effects  of mammalian
     egg chromosomes.  Environ. Res. 9:84-93, 1975.

Kamogawa, A.,  and T.  Fukui.   Inhibition of a-glycan phosphorylase by bisulfite  competition at
     the phosphate binding  site.   Biochim. Biophys. Acta  302:158-166, 1973.

Kaplan,  D. ,  C.  McJilton,  and  D.  Luchtel.   Bisulfite  induced lipid oxidation.   Arch.  Environ.
     Health 30:507-509, 1975.

Katz,  G. V.,  and  S.  Laskin.   Pulmonary Macrophage  Response  to  Irritant  Gases.   _In:   Air
     Pollution  and  the Lung.   E.   F. Aharonson,  A.  Ben-David,  and M. A.  Klingberg,  eds. ,  John
     Wiley and Sons, New York, 1976.  pp. 83-100.

Ketels,  K.  V.,  J. N. Bradof,  J.  D.  Renters,  and R. Ehrlich.   SEM  studies of the respiratory
     tract  of  mice  exposed  to  sulfuric acid  mist-carbon particle mixtures.   In:   Scanning
     Electron Microscopy.   Volume  II, IIT Research  Institute, Chicago,  IL,  1977.   pp.  519-526.

Kikigawa,  K. , and  K.  lizuka.   Inhibition  of platelet aggregation  by bisulfite-sulfite.   J.
     Pharm. Sci.  61:1904-1907, 1972.

Klebanoff,  S.  J.   The sulfite-activated oxidation  of  reduced  pyridine nucleotides  by peroxi-
     dase.  Biochim. Biophys.  Acta 48:93-103, 1961.

Koller,  L.  D. ,  J. H. Exon,  and J. G.  Roan.   Antibody suppression by cadmium.   Arch.  Environ.
     Health 30:598-601, 1975.

Kotin,  P.,  H.  L.  Falk, P.  Mader,  and  M.  Thomas.   Aromatic hydrocarbons.   I.  Presence in the
     Los  Angeles  atmosphere and the carcinogenicity of atmospheric  extracts.   AMA  Arch.  Ind.
     Hyg. Occup.  Med. 9:153, 1954.

Kubitschek,  H.  E. ,  and L.  Venta.  Mutagenicity of  coal fly  ash  from  electric  power  plant
     precipitators.  Env. Mutag. 1:79-82, 1979.

Kysela,  B. ,  D.  Jirakova,  R. Holusa, and  V.  Skoda.   The  influence of  the size  of quartz  dust
     particles on the reaction of  lung tissue.   Ann. Occup. Hyg. 16:103-109,  1973.

Lamb, D. , and L.  Reid.  Mitotic rates, goblet cell  increase, and histochemical changes in  mucus
     in  rat bronchial epithelium  during exposure  to  sulphur  dioxide.   J. Pathol.  Bacteriol.
     96:97-111, 1968.

Larson,  T.  V., D.  S.  Covert,  R.  Frank, and R. J. Charlson.   Ammonia in the  human  airways:
     Neutralization of inspired acid sulfate  aerosols.  Science  197:161-163,  1977.

Laskin,  S., M. Kuschner, and R. T. Drew.  Studies in pulmonary carcinogenesis.   In:   Inhalation
     Carcinogenesis.   AEC   Symposium Series  18.  M.  G.   Hanna,  Jr. ,  P.  Nettesheim, and  J.  R.
     Gilbert, eds., U. S. Atomic Energy Commission, Oak Ridge, TN,  1970.   pp. 321-351.

Laskin,  S. ,  M.  Kuschner,  A. Sellakumar,  and  G.  V.  Katz.   Combined Carcinogen-Irritant Animal
     Inhalation Studies.  In:  Air Pollution  and the Lung.  E. F. Aharonson,  A.  Ben-David, and
     M.  A. Klingberg eds.,  John Wiley and Sons,  New York,  1976.  pp. 190-213.

Last, J. A.,  and  C. E. Cross.  A new model for  health  effects of air pollutants:  Evidence for
     synergistic  effects of mixtures of ozone and sulfuric acid  aerosols  on rat  lungs.  J. Lab.
     Clin. Med. 91:328-339, 1978.

Lau, T.  J. ,  R.  L.  Hackett,  and   F.  W.  Sunderman.  The  carcinogenicity  of  intravenous nickel
     carbonyl in  rats.  Cancer Res. 32:2253-2258, 1972.
XRD12C/C                                     12-96                                     2-5-81

-------
Lebowitz, M.  D. ,  and G. A. Fa.irchild.   The  effects of sulfur dioxide on A? influenza virus on
     pneumonia and  weight reduction in  mice:   An  analysis of stimulus-response relationships.
     Chem. Biol. Interact. 7:317-326,  1973.

Lee, S.  D. ,  and  R. M.  Danner.   Biological  effects  of  S00 exposures on  guinea  pigs.   Arch.
     Environ. Health 12:583-587,  1966.                      i

Leiter, J. ,  and  M.  J.   Shear.  Production  of tumors in mice with tars from city air dusts.   J.
     Nat. Cancer Inst.  3:167,  1942.

Leiter, J., and Shimkin, M. B.   Production of subcutaneous sarcomas  in mice with tars extracted
     from atmospheric  dusts.   J.  Natl.  Cancer Inst.  3:155, 1942.

Leong, K. J. , H. N. MacFarland,  and  E.  A.  Sellers.   Acute sulfur dioxide toxicity.   Effects of
     histamine and  histamine  liberation.   Arch.  Environ.  Health  3:66-73,  1961.

Lewis, T. R. , D.  E. Campbell, and T.  R. Vaught, Jr.   Effects on canine pulmonary function  via
     induced  N0? impairment,  particulate interaction and  subsequent  SO .   Arch.  Environ.  Health
     18:596-6017 1969.                                                 x

Lewis, T. R., W. J. Moorman,  W.  F. Ludmann,  and K.  I.  Campbell.   Toxicity of long-term exposure
     to oxides of sulfur.  Arch.  Environ.  Health 26:16-21, 1973.

Lewis, T. R., W. J. Moorman,  Y.  Yang,  and  J.  F.  Stara.   Long-term exposure to auto exhaust  and
     other  pollutant  mixtures.   Effects on  pulmonary function in the  beagle.   Arch.  Environ.
     Health 29:102-106,  1974.

Lippman,  M. ,  R.  E.  Albert,  D.  B.  Yeats,  K. Wales,  and  G.  Leikauf.  Effect of  sulfuric acid
     mist on  mucociliary bronchial  clearance in  healthy  non-smoking  humans.   J.  Aerosol Sci.
     (in press) 1980.

Loeb,  L.  A.,  M.  A. Sirover,  and S.  S.  Agarwal.    Infidelity of DNA synthesis  as  related to
     mutagenesis and carcinogenesis.   Adv. Exp.  Biol.  Med. 91:103, 1977.

Loring,  S.  H. , J.  M.   Drazen, J. R. Snapper,  and  R.  H.  Ingram.  Vagal  and  aerosol  histamine
     interactions on airway  responses  in dogs.   J.  Appl.  Physiol:   Respirat.  Environ.  Exercise
     Physiol.  45:40-44,  1978.

Lyric, R. M.,  and I. Suzuki.   Enzymes  involved in  the metabolism of  thiosulfate by thiobacillus
     thioparus.   Survey of  enzymes  and properties of sulfite:   Cytochrome  c  oxidoreductase.
     Can. J.  Biochem.  48:334-343, 1970.

MacFarland,  H.  N. ,  C. E. Ulrich,  A.  Martin,  A.  Krumm,  W.  M. Busey,  and Y.  Alarie.   Chronic
     Exposure of Cynamolgus  Monkeys  to Fly Ash.   I_n:   Inhaled Particles III.   Volume 1.  W. H.
     Walton,  ed., Unwin Bros., Ltd., Surrey, England, 1971.   pp.  313-327.

Maigetter,  R.  Z. ,  R.   Ehrlich,   J.   D.  Fenters, and  D.  E.  Gardner.  Potentiating  effects of
     manganese dioxide on  experimental respiratory infections.  Environ. Res. 11:386-391, 1976.

Martin,  S.  W. ,  and R.  A. Willoughby.  Effect of  sulfur dioxide on  the  respiratory tract of
     swine.   J. Am. Vet.  Med.  Assoc.  159:1518-1522, 1971.

Marunouchi,  T. ,  and T.  Mori.   Studies  on the sulfite-dependent ATPase  of a sulfur oxidizing
     bacterium, thiobacillus  thiooxidans.  J. Biochem. 62:401-407, 1967.

Massey, V., F. Muller, R.  Feldberg,  M.  Schuman, P.  A. Sullivan, L. G. Howell, S. G. Mayhew, R.
     G.  Matthews,   and G.  P.  Foust.   The  reactivity of  flavoproteins  with sulfite.   J.  Biol.
     Chem.  244:3999-4005,  1969.


XRD12C/C                                      12-97                                      2-5-81

-------
Matsumura, Y.  The effects of ozone, nitrogen dioxide, and sulfur dioxide on the experimentally
     induced  allergic  respiratory  disorder  in guinea pigs.   I.   The effect on sensitization
     with albumin through the airway.  Am. Rev. Resp. Dis. 102:430-437, 1970a.

Matsumura, Y.  The effects of ozone, nitrogen dioxide, and sulfur dioxide on the experimentally
     induced allergic respiratory disorder in guinea pigs.  III.  The effect on the  occurrence
     of dyspneic attacks.  Am. Rev. Resp. Dis. 102:444-447, 1970b.

McCord, J. M. ,  and I.  Fridovich.   Superoxide dismutase.  J. Biol. Chem. 244:6049-6055,  1969a.

McCord, J. M., and I. Fridovich.  The utility of superoxide dismutase in studying  free radical
     reactions.  J. Biol. Chem. 244:6056-6063, 1969b.

McDonald, S.  Jr. ,  and  D. L. Woodhouse.   On  the nature of mouse  lung adenomata,  with special
     reference  to the  effects  of  atmospheric dust  on the  incidence  of  these  tumours.   J.
     Pathol.  Bacteriol. 54:1-12, 1942.

McJilton, C. ,  R.  Frank,  and R. Charlson.  Role of relative humidity  in the synergistic  effect
     of a sulfur dioxide-aerosol mixture on the lung.  Science 182:503-504, 1973.

Michoud,  M.  C. ,  P.  D.  Pare, R. Boucher,  and J.  C.  Hogg.  Airway  responses  to histamine  and
     methacholine  in Ascaris  suum-allergic  rhesus  monkeys.   J.  Appl.  Physiol.:   Respirat.
     Environ. Exercise Physiol. 45:846-851, 1978.

Miller, E. C.   Some current perspectives on chemical carcinogenesis  in humans and experimental
     animals:  presidential address.  Cancer Res. 38:1479-1496, 1978.

Mittler,  S. , and  S.  Nicholson.   Carcinogenicity of atmospheric  pollutants.   Ind.  Med.   Surg.
     26:135, 1957.

Miller,  M. ,  and  I.  Alefheim.   Mutagenicity and PAH-analysis  of  airborne particulate matter.
     Atmos.  Environ. 14:83-88, 1980.

Mudd,  S.  H., F.  Irreverre, and  L.  Laster.   Sulfite oxidase deficiency in  man:  demonstration
     of the  enzymatic defect.  Science 156:1599-1602, 1967.

Mukai,  F. ,   I.  Hawryluk,  and R.  Shapiro.    The  mutagenic  specificity of sodium  bisulfite.
     Biochem. Biophys.  Res. Commun. 39:983-988, 1970.

Muller,  F. ,  and  V.  Massey.   Flavin-sulfite  complexes  and  their  structures.   J.  Biol.  Chem.
     244:1007-1016, 1969.

Murray, M. J., and C. P. Flessel.   Metal-polynucleotide interactions. A comparison of carcino-
     genic and  non-carcinogenic  metals i_n vitro.  Biochimica  et  Biophysica Acta  425:256-261,
     1976.

Nadel, J.  A.,  H.  Salem, B.  Tamplin,  and Y.  Tokiwa.   Mechanism of broncho-constriction  during
     inhalation  of  sulfur  dioxide;  reflex   involving  vagus  nerves.   Arch.  Environ.  Health
     10:175-178, 1965a.

Nadel, J.  A., H.  Salem,  B.  Tamplin, and Y.  Tokiwa.   Mechanism of bronchoconstriction  during
     inhalation of sulfur dioxide.  J. Appl.  Physiol. 20:164-167,  1965b.

Nadel, J. A., M. Corn, S. Zwi, J. Flesch, and P. Graff.   Location  and Mechanism of Airway Con-
     striction  after  Inhalation  of  Histamine  Aerosol  and  Inorganic  Sulfate  Aerosol.   I_n:
     Inhaled Particles and  Vapours.   Volume II.   C. N.  Davies,  ed., Pergamon Press  Oxford
     1967.   p. 55-67.
XRD12C/C                                      12-98                                      2-5-81

-------
Nakamura, S.   Initiation of sylfite  oxidation  by  spinach ferredoxin-NADP  reductase  and  ferre-
     doxin system:   A model experiment  on  the  superoxide anion  radical  production by  metallo-
     flavoproteins.  Biochem. Biophys.  Res.  Commun.  41:177-183,  1970.

National Academy of  Sciences.  Airborne  Particles.   University Park  Press,  Baltimore,  MD,  1979.

National Academy of  Sciences.  Iron.   University Park Press,  Baltimore,  MD,  1979.

National Academy of  Sciences.  Zinc.   University Park Press,  Baltimore,  MD,  1979.

National Air Pollution Control Administration.  Air  Quality Criteria for Sulfur Oxides.  AP-50,
     U.S. Department of  Health,  Education,  and  Welfare, Washington,  DC,  1970.

NIOSH,  Criteria  for a recommended  standard occupational  exposure to crystalline silica.   Ch.
     Ill, Biologic  Effects  of Exposure.   NIOSH, 1974.  pp. 15 foil.

Nulsen,  A.,  P.  G.  Holt,  and  D.  Keast.  Sulfur dioxide.    Acute  effects  on cell  metabolism  in
     vitro.  IRCS  Libr.  Compend.  2:1464,  1974.

Office  of Research  and  Development.  Air  Quality Criteria  for  Lead.   EPA-600/8-77-017,  U.S.
     Environmental  Protection Agency,  Washington,  DC,  December 1977.

Orthoefer, J.  G. ,  R. S.  Bhatnagar,  A. Rahman,  Y.  Yang,  S. D. Lee,  and  J.  F.  Stara.   Collagen
     and prolyl  hydroxylase  levels in lungs of beagles  exposed to  air pollutants.    Environ.
     Res. 11:299-305, 1976.

Oshino,  N. ,  and B.  Chance.  The properties of  sulfite oxidation in  perfused rat  liver;  inter-
     action  of  sulfite   oxidase  with  the  mitochondrial  respiratory chain.   Arch.  Biochem.
     Biophys.  170:514-528,  1975.

Ottery,  J. ,  and  I.  P.   Gormley.   Some  factors  affecting the hemolytic activity of  silicate
     minerals.  Ann. Occup. Hyg.  21:131-139,  1978.

Peacock,  P.  R. ,  and J.  B.  Spence.   Incidence of  lung tumours in LX mice exposed to  (1)  free
     radicals; (2)  S02.   Br. J.  Cancer 21:606-618,  1967.

Peiser,  G.  D.,  and S.  F.  Yang.  Chlorophyll  destruction by bisulfite-oxygen system.  Plant
     Physiol.  60:277-281,  1977.

Pitts,  T.  N. ,  et al.  Atmospheric  reactions of polycyclic aromatic  hydrocarbons:  facile  for-
     mation of mutagenic nitro-derivatives.   Accepted by  Science,  June 23,  1978,  1978.

Pott,  F. ,  R.  Tomingas,  and J. Misfeld.   Tumours in  mice  after subcutaneous  injection  of auto-
     mobile exhaust condensates.   Air Pollution and  Cancer in Man.   IARC Scientific  Publications
     No. 16, 1977.   pp.  79-88.

Reid,  L.  Evaluation of  model systems for study of airway epithelium, cilia, and  mucus.  Arch.
     Intern. Med.  126:428-434, 1970.

Reiser,  K.  M. ,  and J.   A.  Last.   Silicosis  and   fibrogenesis:   fact and  artifact.   Toxicol.
     13:51-72, 1979.

Rigdon,  R.  H. , and  J. Neal.  Tumors  in mice induced by  air  particulate matter  from  a  petro-
     chemical  industrial  area.   Texas Reports on Biology  and  Medicine 29:109-123,  1971.

Rotilio,  G. ,  L.  Calabrese, A. Finazzi Agro, and  B.  Mondovi.  Indirect evidence for  the  pro-
     duction  of superoxide  anion radicals  by  pig kidney diamine oxidase.   Biochem.  Biophys.
     Acta 198:618-620, 1970.


XRD12C/C                                      12-99                                     2-5-81

-------
Rylander, R.  Alterations of lung defense mechanisms against airborne bacteria.  Arch.  Environ.
     Health 18:551-555, 1969.

Rylander, R. , M. Ohrstrom, P. A. Hellstron, and R. Bergstrom.  S0p and Particles -  Synergistic
     Effects on  Guinea Pig Lungs.   In:  Inhaled Particles III.  volume I.  W. H. Walton,  ed.,
     Unwin Bros., Ltd., Surrey, England, 1970.  pp. 535-541.

Sackner, M. A.,  R.  D. Dougherty, and  G.  A.  Chapman.   Effect of inorganic nitrate  and  sulfate
     salts on cardiopulmonary function.  Am. Rev. Respir. Dis. 113:89, 1976.

Sackner, M. A., D. Ford, R. Fernandez, E. D. Michaelson, R. M. Schreck, and A. Wanner.   Effect
     of  sulfate  aerosols  on cardiopulmonary function of normal humans.  Am.  Rev. Respir.  Dis.
     115:240, 1977a.

Sackner, M.  A., and  M.  Reinhardt.   Effect of microaerosols of  sulfate  particulate matter  on
     tracheal  mucous  velocity  in  conscious  sheep.   Am.  Rev.  Respir.  Dis.  115:241,  1977b.

Sackner, M. A., M. Reinhardt, and D. Ford.  Effect of sulfuric acid mist on pulmonary  function
     in  animals and man.  Am. Rev.  Respir. Dis. 115:240, 1977c.

Sackner, M.  A.,  D.  Ford,  R.  Fernandez,  J.  Cipley,  D.  Peroz, M. Kwoka,  M.  Reinhardt, E.  0.
     Michaelson,  R.   Schreck,  and  A.  Wanner.   Effects of  sulfuric  acid aerosol  on  cardio-
     pulmonary  functions in dogs, sheep and humans.  Am. Rev. Respir.  Dis. 118:497-510,  1978a.

Sackner, M.  A., D.  Perez, M. Brito, and R. M. Schreck.  Effect of moderate duration exposures
     to  sulfate and sulfuric acid  aerosols on  cardiopulmonary function of anesthetized dogs.
     Am. Rev. Respir.  Dis. 117:257, 1978b.

Saito,  K. ,  and  D.  B. Menzel.   Nickel uptake and  efflux from  cultured  type II pneumocytes.
     Pharmacologist 20:275, 1978.

Santodonato, J. ,  D.  K. Basu, and P. H. Howard.  Health effects associated with diesel  exhaust
     emissions:   literature review and  evaluation.   EPA  Report  600/1-78-063,  1978.    165  pp.

Santodonato, J., P. H. Howard, D. K. Basu, S. S. Lande, J. L. Selkirk, and P. Sheehe.    Health
     assessment document for polycyclic organic matter.  Contract 68-02-2800, U.S.  Environmental
     Protection  Agency,  Health Effects Research Laboratory, Research Triangle Park, NC, 1979.

Schiff,  L.  J.,  M. M.  Bryne, J. D. Fenters, J. A. Graham, and D. E. Gardner.   Cytotoxic  effects
     of  sulfuric acid  mist, carbon  particulates, and their mixtures on hamster tracheal  epithe-
     lium.   Environ.  Res. 19:339-354,  1979.

Schlesinger, R. B., M. Lippmann, and R. E. Albert.  Effects of short-term  exposures to  sulfuric
     acid  and  ammonium  sulfate  aerosols  upon bronchial airways  function  in donkeys.    J.  Am.
     Ind. Hyg.   Assoc.  39:275-286, 1978.

Schlesinger, R.  B. ,  M. Halpern, R. E.  Albert,  and M.   Lippmann.  Effect of chronic inhalation
     of  sulfuric  acid mist upon mucociliary clearance  from the lungs of donkeys.   J.  Environ.
     Pathol. Toxicol.  2:1351-1367,  1979.

Schneider,  L. K., and  C. A. Calkins.   Sulfur dioxide-induced  lymphocyte defects  in  human peri-
     pheral blood cultures.  Environ.  Res. 3:473-484, 1971.

Schorlemmer, H. V., P. Davies, W. Hylton, M. DeGugig, and A. C. Allison.   The selective release
     of  lysosomal  acid  hydrolases from  mouse peritoneal  macrophages by  stimuli  of  chronic
     inflammation.  Br. J. Exp. Pathol. 58:315-326, 1977.

Schroeder,  H. A.  A sensible look at air pollution by metals.  Arch.  Environ.  Health  21:798-806,
     1970.                                                                            ~

XRD12C/C                                     12-100                                     2-5-81

-------
Seelig, M. G. ,  and E. L.  Benignus.   Coal smoke  soot  and tumors of the  lung  in mice.   Am.  J.
     Cancer 28:96-111, 1938.

Shahin,  M.  M.,  and  F.  Fournier.   Suppression  of  mutation  induction and  failure to  detect
     mutagenic activity with  athabasca  tar sand fractions.  Mutat.  Res. 58:29-34,  1978.

Shapiro, R. , and J. M. Weisgras.   Bisulfite-catalyzed  transamination  of cytosine and cytidine.
     Biochem.  Biophys. Res. Commun.  40:839-843,  1970.

Shapiro, R. , B. I. Cohen,  and R.  E.  Servis.   Specific  deamination  of  RNA  by  sodium bisulphite.
     Nature, London 227:1047-1048,  1970a.

Shapiro, R. ,  R.  E. Servis, and  M.  Welcher.   Reactions of uracil and  cytosine  derivatives  with
     sodium bisulfate.   A specific  deamination  method.   J.  Am.  Chem. Soc.  92:422-424,  1970b.

Shapiro,  R.   Genetic  effects of  bisulfite  (sulfur dioxide).   Mutat.  Res.  39:149-176,  1977.

Shih,  V.  E. ,  I.  F. Abroms, J.  L. Johnson, M.  Carney, R.  Mandell,  R.  M.  Robb, J.  P.  Cloherty,
     and  K.  V. Rajagopalan.   Sulfite  oxidase  deficiency.   Biochemical  and clinical  investi-
     gations  of  a  hereditary  metabolic disorder  in  sulfur  metabolism.   N.  Eng.  J.  Med.
     297:1022-1028, 1977.

Silbaugh,  S.  A.,   R.  K.  Wolff,  J.  L.  Mauderly, and  C.  A.  Macker.   Effects  of  sulfuric  acid
     aerosols on the  pulmonary  function of guinea pigs.   J. Toxicol.  Environ.  Health,  in press,
     1980.

Singh, J.  Biochemistry  of silicosis.   J.  Scient. Ind. Res. 37:328-333, 1978.

Sirover, M. A., and L. A.  Loeb.   Infidelity of'DNA synthesis  in  vitro: screening for potential
     metal mutagens or carcinogens.   Science  194:1434-1436, 1976.

Snapper, J.  R. ,  J. M. Drazen,  S.  H.  Loring,  W.  Schneider,  and  R.  H.  Ingram, Jr.   Distribution
     of  pulmonary  responsiveness to  aerosol  histamine in dogs.  J. Appl.  Physio!.:   Respirat.
     Environ. Exercise Physiol.  44:738-742, 1978.

Spiegelman,  J.  R. , G.  D. Hanson,  A.  Lazarus,  R. J.  Bennett,  M.  Lippmann,  and R.  D.  Alpert.
     Effect  of acute sulfur dioxide  exposure  on  bronchial  clearance in the donkey.   Arch.
     Environ. Health  17:321-326,  1968.

Stara, J.  F. ,  D.   L.  Dungworth,  J.  G. Orthoefer,  and  W.  S.  Tyler, eds.    Long-term  Effects  of
     Air  Pollutants:    in  Canine Species.   EPA-600/8-80-014,   U.S.  Environmental  Protection
     Agency, Research Triangle  Park,  NC,  1980.   pp.  1-287.

Stern, A.  C.   Air Pollution.   Vol.  II.   Analysis,  Monitoring,  and Surveying.   Academic Press,
     New York, London, 1968.

Stoner, G. D. , M.   B.  Shimkin, M.  C.  Troxell,  T.  L.  Thompson,  and L.  S. Terry.   Test for carcin-
     ogenicity  of  metallic  compounds  by  the  pulmonary  tumore re-sponse  in strain A mice.
     Cancer Res. 36:1744-1747,  1976.

Strandberg, L.  G.   S0? absorption  in the respiratory  tract.   Arch.  Environ.  Health 9:160-166,
     1964.

Summers,  G.   A. ,   and J.  W.   Drake.   Bisulfite mutagenesis  in  bacteriophage T4.   Genetics
     68:603-607, 1971.

Sunderman, F.  W.   Carcinogenic  effects  of metals.  Fed.  Proceedings,  37(l):40-46, 1978.



XRD12C/C                                      12-101                                    2-5-81

-------
*
Sunderman, F. W.  Metal carcinogenesis.  Advances in Modern Toxicol. 2:256-295,  1979.

Tager,  J.  M. ,  and  N.  Rautanen.   Sulphite  oxidation  by  a  plant  mitochondrial  system.   I.
     Preliminary observations.  Biochim. Biophys. Acta 18:111-121, 1955.

Takebe,  I.   Isolation  and  characterization  of  a new enzyme  choline  sulfatase.  J.  Biochem.
     50:245-255, 1961.

Takino,  Y. ,   K.  Sugahara,  and I.  Horino.    Two  lines  of  guinea pigs  sensitive  to  chemical
     mediators and anaphylaxis.  J. Allergy 47:247, 1971.

Tartar,  H. V.,  and H.  H. Garetson.   The thermodynamic  ionization constants of  sulfurous  acid
     at  25°.   J. Am.  Chem.  Soc. 63:808,  1941.

Teranishi, K., K. Hamada, and  H. Wantanabe.   Mutagenicity in Salmonella  typhimurium  mutants  of
     the benzenesoluble organic matter derived from air-borne particulate matter and  its  five
     fractions.  Mutat. Res. 56:273-280, 1978.

Thompson, J.   R., and  D. M.  Pace.   Effects of  SO,  on established cell lines cultivated  in  vitro.
     Can. J.   Biochem. Physiol.  40:207-217, 1962.

Timson,  J.   Action of  sodium  sulphite on the mitosis of human lymphocytes.  Chromosomes  Today
     4:211-214, 1973.

Tokiwa,  H. ,   K. Morita, H.  Takeyoshi,  K.  Takahashi, and Y.  Ohnishi.   Detection of mutagenic
     activity in particulate air pollutants.  Mutat. Res. 48:237-248, 1977.

Tokiwa,  H.,  K. Shigeji, K.  Takahashi, and Y.  Ohnishi.  Mutagenic  and chemical assay  of extracts
     of  airborne particulates.  Mutat. Res. 77:99-108, 1980.

Tomori I., and J. G.  Widdicomble.  Muscular,  bronchomotor and cardiovascular reflexes  elicited
     by  mechanical stimulation of  the respiratous tract.  J. Physiol. 200:25-49, 1969.

Towill,  L.  E. , C.  R. Shrina,  J.  S.  Drury, A. S. Mammons, and J. W. Holleman.   Reviews of the
     environmental  effects  of  pollutants:    III.   Chromium.   EPA-600/1-78-023,  U.S.  Environ-
     mental  Protection  Agency  Health  Effect Research Laboratory,  Cincinnati, OH, 1978.

Tuazon,  P. T. , and S.  L. Johnson.   Free radical and ionic reaction of  bisulfite with reduced
     nicotinamide  adenine  dinucleotide  and   its  analogues.   Biochemistry 16:1183-1188,  1977.

U.S.  Environmental   Protection  Agency.   Air Quality Criteria   for Lead.   EPA-600/8-77-017,
     Office  of  Research and Development, Washington, DC, 1977.

U.S.   Environmental   Protection  Agency.   Health  Assessment  Document  for  Cadmium.   EPA-
     600/8-79-003,  Preprint,  January  1979.   Office  of  Research   and  Development,  Research
     Triangle Park, NC, 1979.

Valencia,  R. , S.  Abrahamson,   P. Wagoner, and L.  Mansfield.  Testing for food  additive-induced
     mutations  in Drosophila melanogaster.  Mutat.  Res.  21:240-241,  1973.

Vaughan, T.  R., Jr.,  L. F.  Jennelle,  and T. R.  Lewis.  Long-term  exposure to  low levels of air
     pollutants:  Effects on pulmonary function  in  the beagle.  Arch.  Environ.  Health  19:45-50,
     1969.

Wang,  Y. Y.  ,  S.  M.   Rappaport,  R. F.  Swayer,  R.  E.  Talcott, and  E.   T. Wei.   Direct-acting
     mutagens in automobile exhaust.  Cancer  Letters (In press)  1978.

Waters,  M.  D.,  D.  E.  Gardner,  and D.  L.  Coffin.   Cytotoxic  effects  of  vanadium on rabbit
     alveolar macrophages jm vitro.   Tox. Appl.  Pharm. 28:253-263.  1974.

XRD12C/C                                     12-102                                     2-5-81

-------
Wattiaux-DeConinck,  S. ,  and  R.  Wattiaux.   Subcellular distribution  of  sulfite cytochrome  c
     reductase in rat liver tissue.   Eur.  J.  Biochem.  19:552-556,  1974.

White,  R. ,  and  C.  Kuhn.  Effects  of phagocytosis  of mineral  dusts on elastase secretion  by
     alveolar  and peritoneal  exudative  macrophages.   Arch.  Environ. Health  35:106-109,  1980.

Widdicombe, J.  G.   Respiratory reflexes  from the trachea  and bronchi  of  the  cat.   J.  Physiol.
     123:55-70,  1954a.

Widdicombe, J.  G.   Receptors in  the  trachea and bronchi  of  the cat.   J.  Physiol.  123:71-104,
     1954b.                                                                         	

Widdicombe, J. G. ,  D. C.  Kent,  and  J.  A.  Nadel.   Mechanism of bronchoconstriction during  inha-
     lation of dust.  J.  Appl.  Physiol.  17:613-616,  1962.

William|+ S. J. ,  K.  M. Holden,  M. Sabransky,  and D.  B.  Menzel.   The distributional  kinetics  of
     Ni   ions  in the rat lung.   Toxicol.  Appl.  Pharmacol.  55:85-93, 1980.

Wilson, D. F.  The  inhibition of  mitochondrial  respiration by bisulfite ions.   Fed.  Proc.  Fed.
     Am. Soc.  Exp.  Biol.  27:830,  1968.

Wirth,  J.  J. ,  W. P. Carney,  and  E. F. Wheelock.  The effect of particle  size  on  the immuno-
     depressive  properties of silica.   J.  Immunol. Methods 32:357-373,  1980.

Wolff,  R. K.,  B.  A.  Muggenburg, and S.  A.  Silbaugh.   Effects  of  sulfuric  acid mist  on  tracheal
     mucous clearance in awake  beagle  dogs.   Am.  Rev.  Respir.  Dis.  119:242, 1979.

Wolff,  R. K. ,  S.  A.  Silbaugh, D.  G. Brownstein,  R.  L.  Carpenter, and J.  L.  Mauderly.   Toxicity
     of 0.4  and 0.8 mm  sulfuric  acid  aerosols  in the guinea  pig.   J.  Toxicol.  Environ. Health
     5:1037-1047, 1979b.

Wynder,  E.  L. , and  D. Hoffman.   A  study  of  air pollution carcinogenesis.  III.  Carcinogenic
     activity  of gasoline engine  exhaust condensate.   Cancer  15:103-108,  1962.

Wynder,  E.  L.,  and D.  Hoffman.  Some  laboratory and epidemilogical aspects of air pollution
     carcinogenesis.  J.  Air  Pollution Control  Assoc.  15:155-159,  1965.

Yang,  S.   F.   Biosynthesis  of ethylene.   Ethylene  formation  from methional by  horseradish
     peroxidase.  Arch.  Biochem.  Biophys.  122:481-487, 1967.

Yang,  S.  F.   Sulfoxide  formation from methionine or its  sulfide analogs  during aerobic  oxi-
     dation of  sulfite.   Biochemistry  9:5008-5014,  1970.

Yip, C. C. , and  L.  D. Hadley.   The  iodination of tyrosine  by  myeloperoxidase  and beef  thyroids.
     The  possible  involvement  of  free  radicals.  Biochim.  Biophys.  Acta 122:406-412,  1966.

Yokoyama, E. ,  R.  E.  Yoder, and  N...R.  Frank.   Distribution  of    S in the blood and  its  excretion
     in urine  of  dogs exposed to    S02-   Arch.  Environ.  Health 22:389-395,  1971.

Zarkower, A.   Alterations in  antibody  response induced by  chronic inhalation  of S02 and carbon.
     Arch. Environ.  Health 25:45-50,  1972.

Ziegler, I.  Action of sulfite  on plant malate dehydrogenase.  Phytochemistry 13:2411-2416,  1974.

Ziskind,  M. ,  R.  N.   Jones, and  H. Weill.   Silicosis.   Am. Rev.  Resp.  Dis. 113:643-665,  1976.

Zucker, M. ,  and A.   Nason.  Hydroxylamine reductase  from  neurospora crassa.   Methods  Enzymol.
     2:415-419,  1955-,
XRD12C/C
                                                12-103                                  2-5-81

-------
                                 13.  CONTROLLED HUMAN STUDIES

13.1  INTRODUCTION
     Evaluation of  health  effects induced by exposure to air pollutants requires that studies
be conducted  under  rigorously controlled conditions.  Controlled  studies  provide  a necessary
bridge between  epidemiology  and animal toxicology data.   In general, such studies should pro-
vide  situations which realistically  simulate  the  exposures experienced by man  in  his normal
environment.  However, the complexity and variability of the ambient environment is such that
most  controlled studies  initially  have  been designed to evaluate the effects of  exposure to
single pollutants,  and then  later have  been  extended  to  the  more complex  mixtures  of pol-
lutants actually present in the environment.
     The high cost  and minimal number of  subjects  who can be studied under controlled condi-
tions make  it imperative  that studies be  conducted  under stringent conditions in order to be
relevant to  larger  populations.   Ideally the design  of  such  controlled  trials should include
normal individuals  of both  sexes and all  age groups,  subjects especially sensitive  to some
particular pollutant,  and  individuals from populations  suspected to be at special  risk.   Con-
sideration  must also be given  to the activity levels of  the  subjects,  ambient  environmental
conditions prevailing prior to the subjects' testing, and exposure variables that realistically
simulate  ambient conditions,  including  such  factors as  temperature,  humidity, duration of
exposure,  and mode of exposure.   Controlled studies also  require  proper  experimental  design
which should include purified air conditions, double blind exposure procedures (this cannot be
complied with when certain pollutants and some levels of these pollutants are being evaluated),
several concentrations of  these pollutants should be employed in order to develop dose response
relationships,  as  well  as  comprehensive  statistical   treatment  of the  data obtained.   In
addition,  adequate  (even   duplicate) pollutant monitoring equipment with  documentation  of
quality control are needed.  Proper attention must also  be given to the presence  of potential-
ly  interfering  pollutants  inadvertently  present  or  developing  under   certain  conditions.
Ideally  not  only should physiological  and  biochemical  evidence be obtained, but  subjective
symptoms and/or changes in performance capability should also be assessed.   Since the respira-
tory  tract  is  the  initial target  of many  air  pollutants,  proper  and  sensitive  respiratory
function measurements are a primary requirement.   Since  diurnal patterns are known to occur in
physiological systems, experiments  should be controlled as to  time of day that they are con-
ducted.  However, various biochemical systems may be affected if pollutants (or their reaction
products or substances absorbed on particulates) pass into the circulatory and other, systems.
     The above criteria need to be applied to any evaluation of clinically controlled studies.
However,  due  to particular restraints placed  on investigators, no  studies meet  all  of these
ideal  requirements.   Nonetheless, certain  basic  information  may be derived  from  a number of
studies.   This  chapter provides  an  overview of controlled air  pollutant  exposure  studies of

XD13A/A                                      13-1                                    2-14-81

-------
certain human  health  effects  of sulfur compounds.   It should be noted that laboratory studies
utilizing man  have been  limited to the  evaluation  of acute effects; thus the  potential for
chronic health effects cannot be predicted from such exposures.
13.2  SULFUR DIOXIDE
     Exposure  of  man to  sulfur dioxide  has  been  shown  to  induce a  number  of  physiological
responses.   Alterations   in  sensory system  responses  such  as  irritation  of eyes  and  nose,
changes  in   odor  perception,  and  dark  adaptation  have  been reported.   Various  changes  in
function  of  the respiratory  system  have also been reported.  The  following  sections address
these  various  functional  changes in greater  detail.   (See Chapter 11 for  more  detailed dis-
cussion of SO- deposition).
13.2.1  Subjective Reports
     The perception of odor and the sensation of irritation in the eyes,  nose, throat, or other
parts of the body are difficult to measure precisely.   Thus subjects may be observed for quali-
tative changes (coughing, rhinorrhea, lacrimation)  or asked to report whether  they detect some-
thing  in  the air  they are breathing.  Several studies have used such subjective  reports as  an
indication of the effects of SO- on human subjects.
     A  number  of early investigators  exposed themselves  to high concentrations  of SOp  (>500
ppm)  and  experienced coughing,   irritation of  the  eyes and nose,  and  difficulty  in breathing
(e.g., Ogata, 1884; Yamada, 1905; Kisskalt, 1904).   In the course  of investigating the effects
of  S0? on industrial workers,  Lehman  (1893)  and his  associates  experienced  nasal  irritation
during exposures of 10 to 15 minutes to 6.5 ppm SO-.   Holmes et  al.  (1915 -- cited by Greenwald,
1954) carried out an extensive study of 60 subjects,  28 of whom  were unaccustomed to breathing
SOp, and  32  of whom were familiar with it.  All of the subjects already familiar with the gas
seemed  to detect it (either  as  S0?  or as "something  foreign") at  3  ppm.   But only  10  of  28
unaccustomed subjects detected something in the air at 3 ppm SO-.   Few subjects found momentary
whiffs  of 5 ppm  disagreeable,  although "Long-continued breathing  of  air  containing slightly
more  than 5  parts per million  would probably cause  discomfort  to  most  people..."  (Holmes  et
al., 1915).   Amdur et al.  (1953) noted that during  exposure to 1 to 2 ppm their subjects could
not  usually  detect the  odor  of S0?;  even at  5  ppm  most  subjects could  not smell  the gas,
although  they  did  complain  of  dryness  in  the throat.   One  subject,  however, objected  so
strongly  to  5  ppm SO- odor that exposure was terminated.   Above 5 ppm the odor was  definitely
detected by all subjects.
     A number of more recent studies have asked subjects to report their subjective  experiences
(e.g., Greenwald,  1954;  Tomono,  1961;  Frank et al.,  1962;  Toyama and Nakamura,  1964; Speizer
and  Frank,   1966a,b;  Melville,   1970;  Weir and Bromberg, 1972,  1973;  Lawther  etal.,  1975;
Horvath and Folinsbee, 1977),  but the results seem  to be quite variable at exposures  less than
5 ppm SOp.  Also, Frank et al. (1962) have shown that subjective reports are in some  situations
an  unreliable  indicator  of  physiological  responses,  since coughing and  a  sense  of throat

XD13A/A                                      13-2                                     2-14-81

-------
irritation tended  to subside  in their  subjects  after  a  few minutes  while  other changes in
respiratory effects were still maximal.
13.2.2  Sensory Effects
     Among the  physiological  functions  that may  reflect  the effects  of  exposure  to  S0? are
certain sensory processes.   These studies have investigated  not  only odor threshold but also
sensitivity  of  the  dark-adapted eye  to light and  interruption  of  the  alpha (a)  rhythm in
electroencephalograms (see  Table 13-1).   Most of these  investigations have been summarized by
Ryazanov (1962).
13-2-2-l  Odor Perception Threshold—In  the  Russian studies odor threshold is typically deter-
mined in  a well-ventilated chamber containing 2 orifices from which emerge 2 small streams of
gas, one  being  very pure air  and the other  other being  a stream of the test gas.   The  subject
sits in front  of  the apparatus,  sniffs  both orifices,  and points out  the  odorous  one.   This
experiment is repeated  with the  same concentration of test gas over a period of several  days.
The experiment is performed with  increasingly reduced concentrations until  the subject, in the
majority of instances, denies  the presence of an odor or gives erroneous answers.    The thres-
hold concentration  for  the most  sensitive subject  in  a  group of volunteers is defined as the
threshold for odor perception.
     Using the 2-orifice apparatus described above, Dubrovskaya (1957) conducted sulfur dioxide
odor perception threshold tests  on 12 subjects.  Sulfur  dioxide concentrations of 0.5 mg/m  to
       3
13 mg/m   (0.17  ppm to 4.6  ppm)  were  used in 530 threshold determinations.  Six test subjects
sensed the odor of sulfur dioxide in  the range 2.6 mg/m  to  3.0  mg/m ;  four subjects sensed
the  odor  in  the range 1.6  mg/m   to  2.0 mg/m ; one sensed the  odor  in the range 2.1 mg/m  to
        3                                                 33
2.5  mg/m  ;  and one  sensed the odor in  the  range  3.1  mg/m  to 3.6 mg/m .  Thus,  the  average
sulfur dioxide  odor threshold concentration was 0.8 ppm to  1 ppm (~2.3 mg/m  to ~2.9  mg/m ),
and  for  the  more  sensitive of  these  persons it was 0.5  ppm to  0.7 ppm  (~1.5 mg/m   to ~2.0
mg/m ).    It  should  be noted,  however, that  most  of the  subjects were of an age at which odor
perception was presumed to be  most sensitive.
     Determination  of sulfur  dioxide  odor  thresholds (1968)  conducted  for the Manufacturing
Chemists'  Association  in  the United States  gave somewhat  lower values  than those cited above
(Arthur D. Little,  Inc.,  1968).  The  concentrations at  which first one-half and  then all of
the panel members  could positively recognize the  odor were  reported to both be 0.47 ppm (1.3
mg/m ).    The  details of  the  test procedure are  thoroughly  discussed  in  the  report,  but one
important aspect  is  reiterated  as  a  reminder  that odor  thresholds  usually  represent values
derived under ideally suited conditions and with trained individuals.  The investigators, who
were highly qualified to judge on the basis  of substantial experience with consumer evaluation
of known  flavor and  odor situations,  derived  threshold  values  under  ideal  conditions  lower
than those which would be recognized by  the  majority of  a population under ordinary atmospheric
conditions.   This does  not mean that normal individuals exposed to sulfur dioxide under ideal

XD13A/A                                      13-3                                    2-14-81

-------
               * XD13A/B-1
                                                         TABLE  13-1.   SENSORY  EFFECTS OF SO,
Concentration
S02 (ppm)
400
6.5
140, 210, 240
210, 240
1, 2, 5
3, 5, plus
0.17 - 4.6
0.34 - 6.9
0.23
0.2 - 1.7
1-10
Exposure
mins.
120
10 - 15
30
30
-
"""
-
15
--
0.33
—
Effects
Dyspnea
Nasal irritation
Marked nasal irritation, sneezing
Eye irritation, lacrimation
All subjects detect odor above 5 ppm
Discomfort to all subjects exposed to 5 plus.
Some noted disagreeable odor at 5 ppm.
Average S02 odor threshold was 0.8 - 1.0 ppm
Positive recognition of SO. was 0.47 ppm
Light sensitivity increased at 0.34 - 0.63 ppm
and above.
Ocular sensitivity to light increased at SO.
levels of 0.23 ppm and above
Attenuation of a-waves at levels above 0.2 ppm
Orpanoleptic effects at levels 2 ppm and above
Reference
Ogata, 1884
Lehman, 1893
Yamada, 1905
Yamada, 1905
Amdur et al., 1953
Holmes, 1915 (see Green-
wald, 1954)
Dubrovskaya, 1957
Arthur D. Little, Inc.,
1968
Dubrovskaya, 1957
Snalamberidze, 1967
Bushtueva, 1962
Greenwald, 1954
U)
 I

-------
*
test  conditions  could not perceive  the 0.47 ppm  level  indicated.   However,  because of back-
ground odor and lack of awareness or concern with  ambient odor conditions, such individuals in
an everyday situation would probably be  less responsive to this low concentration.
13.2.2.2   Sensitivity of the Dark-Adapted Eye—The  sensitivity  of the  eye  to light  while  a
subject  is  in darkness  increases with  time.   Several  investigations  have  been made  of the
effects  of inhalation  of sulfur oxides on this  sensitivity.   Typically, measurements  of  a
subject's normal  sensitivity are taken  in a dark, well-ventilated chamber in complete silence
(sudden  stimuli,  including noise, may affect the  subject's response).  Each subject is tested
once  daily following  preliminary stimulation  at  a high  light  level.    Light  sensitivity is
measured at 5-minute or 10-minute intervals, and a curve of increasing sensitivity to light is
established from measurements taken over a period  of 7 to 10 days.
      Dubrovskaya  (1957)  studied the effect of  inhaling  sulfur  dioxide  in concentrations from
         33
0.96  mg/m   to 19.2 mg/m   for  15 minutes before measuring light sensitivity during dark adap-
tation.  She  reported that light sensitivity was increased by sulfur dioxide concentrations of
          3              3
0.96  mg/m   to 1.8 mg/m  (0.34  ppm  to  0.63  ppm),  that the increase  in  sensitivity  reached  a
                                       O             Q
maximum  at concentrations of  3.6 mg/m   to 4.8 mg/m  (1.3 ppm to 1.7 ppm),  and  that further
increases  in  the  sulfur dioxide  concentration  resulted  in  progressive  lowering of eye sensi-
tivity  to  light  until at  19.2  mg/m   the sensitivity was identical with that of the unexposed
subject.
      In  exposures  during light  adaptation, sulfur dioxide  concentrations  of  0.6  mg/m  to 7.2
    3
mg/m   (0.21 ppm  to 2.5 ppm) caused  slight increases in eye sensitivity.  Maximum sensitivity
                        3
was attained  at 1.5 mg/m   (0.52  ppm); at higher concentrations the increased sensitivity began
to  abate.   Two human subjects were used in these  experiments.  The odor threshold was between
         33                                     33
2.5 mg/m  and 3.0 mg/m   for one subject and between 3.0 mg/m  and 3.6 mg/m  for the other, so
that  changes  in sensitivity to  light during dark adaptations were caused by sulfur dioxide con-
centrations below  the odor threshold.
      Shalamberidze  (1967)  investigated  the effects of S02 and N02, singly and in combination,
on  visual  light  sensitivity as  determined by  measures  of dark adaptation.  According to this
report,  S0? concentrations of 0.6 mg/m   (0.23  ppm) and higher caused "a considerable increase
in  the  ocular sensitivity to  light"  (Shalamberidze, 1967,  p.  11).   So few details on methods
or  results  were  presented, however, that this  report cannot be accepted without reservations.
13.2.2.3   Interruption  of  Alpha  Rhythm—The  electroencephalogram  is  a composite record of the
electrical  activity of  the  brain recorded as  the difference  in  electrical  potential between
two points  on the head.   In  the adult,  the  electroencephalogram  characteristically shows  a
fairly  uniform frequency from 8  cycles  to  12  cycles per second in the posterior head regions
(alpha).  Variations occur with  age, the state  of  wakefulness and attentiveness, or as a result
of  incoming  sensory  stimuli  from  exteroceptive  or  interoceptive  receptors.   The dominant
frequency (a)  is inhibited or attenuated by eye opening and by mental activity.

XD13A/A                                      13-5                                     2-14-81

-------
     Subjects with well defined orrhythms studied in a silent and electrically shielded chamber
show a temporary  attenuation  of the crrhythm each  time  they are given a  light  signal.   When
the light  is  excluded,  the crrhythm returns to normal.   A concentration of test gas is deter-
mined which is so low that by itself it does not cause attenuation of the a-rhythm.   A subject
breathes the gas at this concentration, and then he receives the light signal.   After exposure
to this  sequence  (gas  then light) several times (5 to 30 times in 1 day),  a subject will  show
attenuation before he receives the light signal; that is, he responds to the unperceived odor.
The unperceived  odor thus  becomes  the conditioning  stimulus  and brings  about  the so-called
conditioned electrocortical reflex.
     Bushtueva (1962) reported that 20-second exposures  of six human subjects to sulfur dioxide
                             3          ?
concentrations from  0.9  mg/m   to 3 mg/m   (~0.3  ppm to  ~1.0 ppm) produced  attenuation  of the
                                                              3             3
orwave lasting 2  to  6  seconds; at concentrations  of  3.0 mg/m  to 5.0 mg/m  (-1.0  ppm to 1.7
                                                                                  3
ppm) attenuation  lasted  throughout  the 20-second exposure.   Exposures to 0.6 mg/m  (~0.2  ppm)
did not  cause  attenuation  of the crwave.   The threshold for attenuation of the crwave was the
same as  the  odor  theshold or the threshold of irritation of the respiratory tract.   Bushtueva
further  demonstrated that  electrocortical  conditioned reflexes could be developed with sulfur
dioxide  at 0.6 mg/m  (~0.2 ppm) but not with lesser concentrations of the mixture.
13.2.3   Respiratory and Related Effects
13.2.3.1  Respiratory Function—A number  of studies  have  documented the  various respiratory
and cardiovascular effects  deriving  from exposure to S0? (see  Table 13-2).  (See Chapters 11
and  12  for  further  discussion of  respiratory  effects  of  SO™.)  One  of  the first  clinical
studies  of the effects of inhaling SO- was reported by Amdur et al.  (1953).   They had 14 rest-
ing subjects breathing S0? for 10 minutes through a face mask in concentrations ranging from 1
to 8 ppm.  Pulse rate and respiration rate increased and tidal  volume decreased during exposure
to as  little as 1 ppm S0?.   Several  investigators attempted to replicate Amdur et al.'s (1953)
findings,  including  Mcllroy  et al.  (1954), Lawther (1955),  and Frank et al. (1962).  None was
able to  find consistent respiratory or cardiovascular effects of S0? below 5 ppm.  Nevertheless,
these  and other studies have documented a variety of subjective and physiological  effects  under
various  conditions  of  exposure  to  SO™.    Sim  and Rattle (1957)  performed  extensive  clinical
studies  over a 10-month period on an unspecified number (8 to 12) of "healthy males  aged 18 to
45."   S0?  was  administered either by face  mask  at concentrations ranging from 1.34 to 80 ppm
for 10 minutes or in an inhalation chamber at concentrations of 1.0 to 23.1 ppm for  60 minutes.
Regardless of  exposure  route, the only notable  effects  of  S0? were  stated to be bronchocon-
stric  tion (increased  resistance to air  flow) and  high-pitched chest rales  at 49  ppm and
greater concentrations.   They also reported that when ammonia (no value given) was also present
in the chamber (9.9 ppm S0?) the subjective impressions of bronchoconstriction disappeared.
     Frank et  al.  (1962) examined the effects of acute (10 to 30 minute) exposures  to SO™ via
mouth  in 11  subjects.    Each  subject received  approximately 1,  5,  and 13 ppm of  the gas in
XD13A/A                                      13-6                                    2-14-81

-------
  * X013A/B-2
                                              13-2.   RESPIRATORY EFFECTS OF SO,
Oral or
Concentration Duration of Number of nasal Rest (R) or
SOg (ppm) exposure (rains) subjects exposure exercise (E)* Effects
1.0 3
3.0 3
5.0 3
9-60 5
1-8 10
10
5, 10 10
20 10
£l. 5, 13 10
1.3-80 10
1-45 10
CO
~-J 2.5, 5.0, 10.0 10
4-6 10
8-10 0 R * E
8-9 0 R + E
10 0 R
25 N - 0 R
14 Face mask R
— N R
18 0 - N R
60 R
12 0 R
8-12 Face Mask R
46 Face Mask R
15 0, N R
70 R
Light exercise potentiates
effect of SO. MEF.™
decreased '
Airway resistance increased
Pulse rate, respiratory
increased; tidal volume
rate decreased
Could not duplicate Amdur's
results
No changes in pulse rate,
respiratory rate or tidal
volume (5, 10 ppm) 2 sub-
jects had bronchospasm
No changes in pulse rate,
respiratory rate. Pulmonary
flow resistance increased at
5 and 13 ppm
Bronchoconstriction at the
higher concentrations
Decreased peak flow, decreased
expiratory capacity above
1.6 ppm
SG decreased less with nasal
Breathing
Airway conductance decreased
Reference
Kreisman et al. ,
1976
Nakamura, 1964
Anidur et al . ,
1953
Mcllroy et al.,
1954
Lawther, 1955
Frank et al.,
1962
Sim and Rattle,
1957
Tomono, 1961
Melville, 1970
Nadel et al., 1965
                                                                                 reflex effect
"Intermittent Exercise

-------
   * XD13A/B-3
                                                            13-2.   (continued)
Oral or
Concentration Duration of Number of nasal Rest (R) or
SO, (ppm) exposure (mins) subjects exposure exercise (E) Effects
15 28 10 80 R Pulmonary flow resistance
N increased less with nasal
breathing
5 10 5 0 R MEF50* decreased 1ess wUh
M nlstl inhalation
2,5 - 50 10 5 0 R Increased respiratory and
inspiratory resistance
1.3-80 10 8-12 Face mask R Bronchoconstriction
0.5, 1.0, 5.0 15 9 R MEF50~ decreased at
1 and 5 ppm
1, 3, D 10 7, 7, 7 0 R SR increased significantly
(21) it all cone for asthmatics;
Reference
. ri F b
1966*

Snell and
1969
Abe, 1967


Luchsinger,


Sim and Pattle, 1957
Snell and
1969
Sheppard,

Luchsinger,

et al . , 1980

_   0.1, 0.25, 0.5
     1. 5, 13
                           10
                        10 - 30
7, 6
                                        11
CO
1
CO






16.1

1. 5, 15
1.1 - 3.6
5


25

30
30
30


7

12
10
10


Face mask
0 - N
0
0
0


R

R
R
E
  only at 5 ppm for normals
  and atopic subjects

SR   significantly increased
  fK the asthmatic group at
  0.5 and 0.25 ppm SO, and
  even at 0.1 in the two most
  responsive subjects

Pulmonary flow resistance
  increased at 5 and 13 ppm
  but less during nasal
  breathing; at 1 ppm, one
  subject experienced 7% in-
  crease in flow resistance,
  another a 23% decrease

SO, almost completely
  removal by nasal breathing

Increased in Rl at SO. levels
  above 5 ppm

Deep breathing produced no
  effects

HHFR decreased
                                                                                                                 Sheppard,  et  al.,  1981
                                                                                                                 Frank et  al.,  1962
                                                                                                                 Speizer and Frank,
                                                                                                                  1966b

                                                                                                                 Frank et al.,  1964


                                                                                                                 Burton  et al.,  1969


                                                                                                                 Newhouse et al.,  1978

-------
            * XD13A/B-4
                                                                     13-2.   (continued)
U)
 I
ID
Concentration Duration of Number of
SO,, (ppm) exposure (mins) subjects
1-23 60
1 60
5 60
5-30 10
1 50
3
10, 15, 25. 50 60
•Intermittent
0.37 120
0.37 120
0.40 120
0. 75 120
1.0, 5.0 120
5.0 120
5.0 120
2!>.0 120
8-12
-
9
10
13
17
Exercise
8
4-12
9
4 - 8
15
11
10
15
Oral or
nasal Rest (R) or
exposure exercise (E)
Mask, chamber
N
N
0
CO. stimulus
Chamber (N)
0

Chamber
Chamber
Chamber
Chamber
N
Chamber
Chamber
(oral)
N
R
R
R
(0) R
R
R

E
E
E
E
R
E
E
R
Effects
Bronchoconstriction
No effects observed
No effect or mucus
transport
Deep breathing significantly
increased SR
aw
At higher cone, of SO,
mucociliary activity
decreased
No pulmonary effects
No pulmonary effects
No pulmonary effects
Significant decrease in
MEFR; FVC, FEV, „, MMFR
also decreased '
Increase in nasal air flow
resistance; decrease in
nasal mucus flow
Insignificant changes in
Re and KAQ
MMFR decreased 8.5% increased
tracheobronchial clearance
Reference
Sim and Pattle, 1957
McJilton, 1976
Wolff et al., 1975a
Lawther, 1975
Cralley, 1942
Bates and Hazucha, 1973;
Hazucha and Bates, 1975
Bell et al., 1977
Horvath and Folinsbee, 1977
Bedi et al. , 1979
Bates and Hazucha, 1973;
Andersen et al . , 1974
von Neiding et al., 1979
Newhouse et al . , 1978
Andersen et al . . 1974
                                                                                           resistance;  decreased  nasal
                                                                                           mucus  flow

-------
                        * XD13A/B-5
                                                                                 13-2.   (continued)
Concentration Duration of Number of
S02 (ppm) exposure (mins) subjects
0. 50 180 40
(normal subjects)
0.50 180 40 (asthmatics)
5 180* 10

0.3, 1.0 96 - 120 12 (normal)
and 3.0 Hours 7 (COPO)
1.0, 5.0 Up to 6 hrs/day 15
and 25.0
5 4.5 hours 32
(16 exposed)
Oral or
nasal
exposure
Oral
Oral
0

Chamber
Chamber
(N)
Chamber

Rest (R) or
exercise (E) Effects
R No pulmonary effects
R HMFR decreased 2.7X; recovery
within 30 minutes; 3 subjects
incurred delayed effects and
required medication.
E Increased tracheobronchial
clearance
R No difference in response
between groups. Slight
decrease in pulmonary
compliance but of ques-
tionable significance
R Significant decreases in
expiratory flow and FEV, „
decreased mucus flow
R Number of colds similar in
both groups but severity
less in SO. exposed subjects
Reference
Jaeger et al . , 1979
Jaeger et al., 1979
Wolff et al., 1975b

Weir and Bromberg, 1972
Andersen et al . , 1974
Andersen et al . , 1977

CO
 I

-------
separate exposures  at  least  1 month  apart.   The only significant effects  were  a 39 percent
increase (p <0.01)  in pulmonary flow resistance at 5 ppm and a 72 percent increase (p <0.001)
at 13 ppm.  Only one subject  showed  a significant increase with I ppm S02 concentration, his
control   resistance  was the  highest  encountered.   The recovery of  some  subjects  was complete
within a few  minutes.   As in Sim and Rattle's study (1957), other cardiovascular or pulmonary
measures did not show any significant effects.
     Tomono (1961)  tested 46 men for  the  effects of SO- on their  pulmonary physiology.   The
subjects inhaled  1  to 45 ppm SO,, through a face mask for 10 minutes.   Decreases in expiratory
capacity and  peak flow rate were proportional to the concentration of S0?.   Such effects were
detected at  a concentration  as low  as  1.6  ppm.   Slight increases  in  pulse  and respiration
rates were observed in about 10 percent of the subjects but were not proportional  to S02 expo-
sures.   Nakamura  (1964) exposed 10 subjects  each to a different concentration of S02 (9 to 60
ppm) for 5 minutes.  Airway resistance increased an average of 27 percent.  Since each subject
was  exposed  to  only  one concentration  of  S02 and there was considerable  variability  in re-
sponse  to  the different  concentrations, the  significance  of  those  isolated  findings  may be
questioned.   No   significant  correlation between dosage  and  response  was discovered.   For
example, a subject  had a 17 percent increase after exposure to 9 ppm, another 9 percent after
exposure to 16 ppm, another 75 percent  after exposure  to 4 ppm and  another 22 percent after
exposure to 57 ppm.
     Snell and Luchsinger (1969)  also found  significant  decreases  in pulmonary function con-
sequent to S02 exposure.  Nine  subjects inhaled through a mouth piece SOp at concentrations of
0.5, 1.0, and  5 ppm for 15 minutes each, with 15-minute control  periods interspersed.  Maximum
expiratory flow  (MEF™^ ,.„) was significantly lower  after  exposure to 1 ppm S02 (p <0.02) as
well  as  5  ppm (p <0.01).  Reichel (1972) exposed 32 normal subjects continuously in a chamber
to  7.7  ppm S02  for 6  days.   Intrathoracic  gas volume and  intrabronchial  flow resistance was
not  altered consequent to any  of the 6 days  of exposure. Airway resistance was measured in 16
of  these subjects  by  inhalation  of 3% acetylcholine chloride solution.   The  sensitivity re-
sponse  to  this challenge was  not altered as  a consequence of the exposure of S0?.  Jaeger et
al.  (1979) exposed 40 normal  non-smokers  and 40  asthmatics  (mild  to  moderate  but with no
recent  exacerbations)  subjects for  3 hours  to  0.5 ppm  SOp.   Oral  inhalation was  forced by
having  the subjects wear a nose clip.   These resting subjects  were also studied during expo-
sure  to ambient  air  having an average  S02  content  of  0.005 ppm.   Three  pulmonary function
tests (VC, FEV-, and MMFR) were  performed at intervals during the exposure and a more intensive
series  of  tests  were  made prior to  and after the exposure.  The  only  significant  (p <0.04)
effect  observed  was a 2.7 percent  decrease  in MMFR in  the  asthmatic subjects.   This minimal
change was stated to have little physiological importance.  One normal and two asthmatic  sub-
jects exhibited adverse reactions—the asthmatics requiring standard asthma medication.
     Nadel et  al.  (1965) have  helped elucidate the mechanism of bronchoconstriction resulting
from S0? exposure.   They exposed seven subjects to 4 to 6 ppm S02 for 10 minutes via mouth in
a  closed plethysmograph.   The mean decrease in specific  airway  conductance was  39 percent
XD13A/A                                       13-11                                         2-14-81

-------
(p <0.001).  Injecting  the  subjects  with 1.2 to 1.8 mg atropine sulfate 20 minutes before S02
inhalation  resulted  in only a  3  percent (p >0.20) decrement  in  specific  airway conductance/
thoracic gas volume.   However, atropine did not affect the coughing or sensation of irritation
in the  pharynx  or substernal  area.  From this and other evidence, Nadel et al.  concluded that
the  bronchoconstriction induced by S0?  depends  on changes in smooth muscle  tone  mediated by
parasympathetic motor  pathways.   Thus,  when sensory receptors in  the  tracheobronchial  region
are irritated by a substance such as S0?, a reflexive bronchospasm may be triggered.
     Apart  from fairly consistent bronchoconstriction effects, a  common element in  these and
other reports of  the effects of  S02  has  been  the notable variability among subjects in their
responses  to such exposures.   In Frank et  al.'s  study  (1962), for example, 9  of  11 subjects
showed  no  effects at 1  ppm, but 1 subject showed a significant (p <0.01) decrease in  pulmonary
flow resistance,  whereas  the  remaining subject showed a  significant  (p <0.01)  increase.   Sim
and  Rattle (1957) reported that they themselves appeared to be exceptionally sensitive  to S02
encountered  in  the  course  of their research.   They experienced  persistent  and uncomfortable
spells  of  coughing  and wheezing upon contact with the gas.  Other investigators (e.g.,  Burton
et al.,  1969;  Frank, 1964; Nadel  et  al,  1965;  Lawther,  1955; Lawther et al.,  1975;  Jaeger et
al., 1979) have  reported  "hyper-reactors"  among their subjects.   Indeed,  some investigators
have suggested  that  about 10 percent of  the total  population is made up of especially  sensi-
tive persons (Amdur,  1973,  1974;  Horvath and  Folinsbee,  1977).   However,  in at  least  one
instance (Andersen et al., 1974), a subject's response was exaggerated even under control  con-
ditions, which  raises  the possibility of psychological factors  contributing  to this observed
sensitivity.
13.2.3.2   Water Solubility—One  of the first points to note is that because of  its high solu-
bility  in  water,  S0? is readily  absorbed when  it comes  in contact with the moist surfaces of
the  nose  and upper respiratory passages (Frank et al., 1973).  This has a  number of  important
implications for the analysis of the effects of SO- on respiratory functions.   These  consider-
ations will be illustrated in the following sections (see Chapter 11).
13.2.3.3   Nasal Versus Oral Exposure—A  number of  studies have demonstrated significant re-
sponse  differences between the nose and mouth as routes of exposure to S0?.  Speizer  and Frank
(1966a), for example,  compared the effects of SOp  (10-minute exposures at 15  and 28 ppm) in
eight subjects  breathing  the  gas either by  nose  or by mouth.  The subjects coughed  less and
reported  less  irritation of the  throat  and chest when breathing  through  their noses.   Also,
pulmonary  flow  resistance  increased  less  during nasal   exposure  than  during  oral  exposure.
     A  second  study  by  the  same investigators  (Speizer  and  Frank,  1966b)   refined  their
analysis of these effects,  using seven subjects  and  a  specially designed face  mask.  Air was
sampled  at various  points,  including:   (1) within  the  face mask  before  being inspired, (2)
within  the  subject's nose, and (3) within the subject's oropharynx.  Exposures  lasted 25 to 30
minutes.  The average concentration of SO- within the mask was 16.1 ppm; within the oropharynx
the concentration was  too low for the investigators'  equipment to measure.  Thus, essentially
all of  the SO- (90 to 99 percent) in the inspired air was removed by the nose.   Similar
XD13A/A                                      13-12                                        2-14-81

-------
results were  obtained  by Andersen et al.  (1974)  in a study that  will  be described  in detail
later.
     Melville (1970) also  compared oral and  nasal  routes  of administration.  He used 15 sub-
jects and  exposed  them (for 10 minutes) sequentially to 2.5, 5, and 10 ppm  S02.  More SO^ was
cleared per  minute with  nose breathing  than with mouth breathing.  There  was  a clear dose-
dependent  response  reflected  in measures of  the subjects' specific airway conductance (SG  ):
                                                                                          oW
as  the  S0? concentration  increased,  SG    decreased  (p <0.05).   This  was  true regardless of
          ^                             aW
administration route (for 2.5 ppm S02), but the average decrease under oral  administration was
greater (in 80  percent of subjects), than  the decrease under nasal administration (p <0.05).
During a  1-hour  exposure to 5  ppm  SO,  no significant difference was observed in SG   regard-
                                      £.                                              aw
less of whether the 49 subjects breathed through mouth or nose.
     Snell and Luchsinger (1969) also examined the differences between nasal and oral exposure
using S02  at  5 ppm.  Five subjects' average maximum expiratory flow (MEF™*, vc) was 10 percent
lower  following  oral  exposure  than following nasal exposure.   This  difference,  however,  was
not  statistically  significant.   See  Chapter 11  for  further  discussion of  S02 deposition.
13.2.3.4   Subject Activity Level—One  of  the practical  implications of the  above findings is
that  vigorous activity, such as  heavy  exercise or work, may significantly  affect  the actual
dose  received by a person during exposure to  SO,,.  At some level of ventilation, inhalation of
air  shifts from  nasal  to mouth breathing.  Studies under way (Horvath, Ph.D. theses, personal
communication)  suggest  that  subjects  who  are  nasal  breathers  at  rest move  to  oral-nasal
breathers  when  ventilatory  exchange  is   approximately  30  L/min.   However,   it  should  be
remembered that  many individuals are always  mouth breathers.  Saiben et al. (1978) studied 63
subjects  while  they exercised at increasing  work  loads.   Incomplete  information was obtained
on  13 subjects.   Ten subjects  breathed through  the  mouth at all  work  loads while  five never
opened  their  mouths.   In  the remaining 35 subjects, the  highest  ventilation volume attained
with  nasal breathing was 40.2 liters per minute.  Determination of the shift to oral breathing
was obtained  by a subjective observation by an observer.  In a second study  using 10 subjects,
ventilation was  more precisely (but still  not a completely adequate technique) determined by
movements  of the  rib  cage.   The mean  value of  ventilation at  the  point  of  shift  to  oral
breathing  was 44.2  liters/min.   It should  be noted that there remains  the possibility that
some  air  continues  to enter the  lungs  through the nose, but the  volume  definitely is reduced
(Horvath,  personal communication).
      Kreisman et  al.  (1976),  for example,  reported that exercise  may potentiate the effect of
S02  on  respiratory  function.   In their study,  subjects  inhaled a mixture of SO,, in air for  3
minutes while exercising on a  bicycle  ergometer  at a pace sufficient to double their resting
minute ventilation  rate.   Eight subjects recieved 1 ppm SOp and nine subjects received 3 ppm.
Those  receiving 3  ppm  showed  a  significant (p <0.05)  decrease  in maximal  expiratory flow
(MEF.p.0,  ,DN)  compared to a control  (untreated air) exposure.   However,  it  is not clear that
     -    \ r )
this change differed significantly from the change in MEF,,^,  ,„.. occurring  in  resting  subjects.
XD13A/A                                      13-13                                         2-14-81

-------
Bates and Hazucha (1973) reported significant decreases in FVC (10 percent), FEV1 Q (10%), MMFR
(10%), and MEFR (23%) in 4 subjects (who exercised intermittently during the exposure) exposed
in a  chamber  containing 0.75 ppm S02-  At  0.37  ppm S02, Hazucha and Bates (1975) observed no
significant pulmonary  function  changes.   Horvath and Folinsbee  (1977)  and Bedi  et al.  (1979)
exposed  nine   intermittently  exercised subjects  in  a  chamber  to  0.4 ppm  S02  and  found  no
pulmonary function changes.
     Lawther  et  al.  (1975) have  demonstrated  that  simply instructing 12  subjects  to  take  25
deep breaths  by  mouth  resulted in a significant (p <0.001) increase in specific  airway resis-
tance (SRaw) during exposure to S02 at 1 ppm.  While sitting quietly in an inhalation chamber,
the same subjects had previously shown no such increase after breathing concentrations of 1  to
3  ppm  S02 for an  hour.   As  part of a  series  of experiments in this study, 17  subjects  also
received 3 ppm S02 by a mouthpiece and were instructed to take 2, 4, 8,  16, and 32 deep breaths
at 5-minute  intervals.   Increases in SR    due to  S09 were significantly  greater after  16  (p
                                        3W           c.
<0.01) or 32 (p <0.001) deep breaths.
     Burton et al.  (1969), however,  found no consistent effects in  10 subjects exposed to S02
at 1.1 to 3.6 ppm for 30 minutes, regardless of whether the subjects breathed normally or at a
forced  hyperventilation rate of  up  to 2.5  L/sec.   One (other) difference  between  these two
studies  was  the duration  of exposure.   Burton  et  al.   (1969)  exposed their  subjects  for  30
minutes, whereas, Lawther  et al. (1975) maintained exposures for an  hour.   This raises another
important  consideration in reviewing  the  effects  of S02 on  human  subjects, namely,  temporal
parameters.
     Sheppard  et al.  (1981),  using 13 non-smoking mild asthmatic volunteers (10  men,  3 women,
20 to  30 years of age), demonstrated that moderate exercise increases the bronchomotor effect
of S0? at concentrations of 0.5, 0.25, and 0.1 ppm.   In seven subjects with mild  asthma,  inha-
lation of  0.50 and 0.25 ppm of  S02  during the performance of moderate exercise  significantly
increased SRaw, whereas neither inhalation of 0.50 ppm of S02 at rest nor inhalation of humidi-
fied,  filtered air  during exercise  had  any effect on  SRaw.   Inhalation of  0.50  ppm  during
exercise  significantly increased SRaw  in  all  seven subjects (p <  0.05),  and  three developed
wheezing and shortness  of  breath.  During the corresponding period of exercise  alone and during
inhalation  of 0.50  ppm at rest, SRaw  did  not increase in any  subject.   After  inhalation  of
0.50  ppm of  S02  during exercise, SRaw  was  significantly greater than after exersise alone  or
inhalation  of 0.50  ppm of S02  at  rest  (p  <  0.05).   Inhalation of  0.25  ppm  during exercise
significantly  increased SRaw  in three of the seven subjects, and the increase  in SRaw for the
group  was significant  (p <  0.05).   No  subject developed  wheezing  or shortness  of  breath.
During the  corresponding  period of exercise alone,  SRaw did not increase in any subject.  In
the two  most  responsive subjects, inhalation of 0.10  ppm of S02 as well as 0.25 and 0.50 ppm
significantly  increased SRaw, and there appeared to be a dose-response relationship.
     In the second set  of  studies, in all six subjects, inhalation of 1 ppm of S02 dramatically
increased SRaw, both when  it was delivered during exercise and during eucapnic hyperventilation.
XD13A/A                                      13-14                                        2-14-81

-------
*
In  every  case, the  increase in  SRaw was  accompanied  by dyspnea  and audible wheezing.   The
magnitude of  the  increase in SRaw was the  same when the  subjects inhaled SOp while  they  exer-
cised or while they performed eucapnic hyperventilation at the same minute ventilation.
     The  bronchoconstriction produced by  inhalation of  0.50 ppm  of  S02 during exercise  was
gradual in onset.  Immediately after  exercise, SRaw did not differ  significantly from baseline
values.   It  then  increased over  the  first  3.5 tnin,  reached  a plateau, and gradually returned
to  baseline values by 30 min after exposure.   A similar time  course was seen in those subjects
who developed  bronchoconstriction after exposure to 0.25  and  0.10 ppm  of SO,,.
13.2.3.5   Temporal Parameters—Early  studies  (e.g.,   Lehman,  1893)  suggested  that  workers
chronically  exposed  to  relatively  high  concentrations  of  S02  were  less  conscious  of  its
presence  in the atmosphere than persons not as familiar with  the gas.  However, Holmes et al.'s
data  (1915)  indicated that subjects  already  accustomed  to  S02 could  detect its odor at  lower
concentrations  than  could persons unaccustomed to it.   Nevertheless,  it would seem plausible
that  "self-selection" would tend to reduce the number of  relatively  sensitive persons among
the population  of workers chronically in contact with supra-threshold  levels of SO,,.
     As previously noted, a  study by  Frank  et  al. (1962)  has  indicated that subjective reports
are not  a reliable indicator of  physiological  responses  in any event.  After 5 to 10 minutes
of  exposure  to either 5 or  13 ppm S0? their  subjects' pulmonary resistance measures were just
reaching  their peaks, while  subjective reports of an odor of  S0? had already subsided.
      In  a later study by Frank  et  al.  (1964) the increase in pulmonary resistance  induced by
S0? peaked  at about  10 minutes  and  then  gradually decreased over  the next  15 minutes.   This
finding   corresponds  closely  to  Sim and  Rattle's  (1957)  report that,  if  lung   resistance
increased at  all  in  individual  subjects,  the increase occurred within  the  first 10 minutes.
      Similar  short-term responses (within  5  to 10 minutes after the  start  of exposure) have
been  recorded by  other investigators.   Melville (1970)  found in  49  subjects  that percentage
decreases in  specific airway conductance (SG   ) were greatest during the first 5 minutes of up
                                            aW
to  60 minutes of exposure to  S02 by mouth/nasal  breathing.  At 5  ppm,  for example, he noted
that  SG    decreased  significantly  (p  <0.05)  within  5  minutes  of   exposure  and  stabilized
        clW
slightly  above the values recorded under control conditions of no SO,,.
      Similar  results  were obtained by Lawther  et al. (1975),  who noted that SR   increased  most
                                                                              QW
during  the  first 5 minutes  of exposure.  Recovery to baseline levels  generally required  about
5  minutes,  although 3 "S02  sensitive"  subjects  out  of a total of  14  took 10 to 65  minutes to
recover from  higher exposure levels  (up to  30  ppm SO,,).   In this last  regard, similar findings
were  reported by  Gb'kenmeijer  et al.  (1973)   for  bronchitic  patients exposed  to 10 ppm SO,,.
Respiratory  effects  were maximal at the  end of  a  3-minute inhalation  period,  and recovery
following removal  to  clean environment required 45 to 60  minutes.
     Abe  (1967)  compared  the  temporal  course  of  S02   exposur.es.   His  five mouth-breathing
subjects  were  given 2.5 or 5.0 ppm SO,,.  He reported immediate significant (p <0.05) increases
in  expiratory  resistance (42 percent) and inspiratory resistance (25 percent).
XD13A/A                                       13-15                                        2-14-81

-------
*
     Longer term effects (over a period of hours) have been reported by Andersen et al. (1974),
who investigated nasal mucus flow rates as well as airway resistance and subjective responses.
Nasal mucociliary  flow was measured by placing  a  radioactivity labeled resin particle on the
superior  surface  of  the  inferior  turbinate and tracking its  position  with a si it-collimator
detector.  A total of  15 subjects were exposed via an inhalation chamber to increasing concen-
trations  (1,  5,  and 25 ppm) of S02 for approximately 6 hours per day over 3 consecutive days.
Baseline measurements  were made under conditions of filtered air on a day prior to experimental
exposures.  This  study found a number of effects reaching their maximum after 1 to 6 hours of
exposure.  Nasal  cross-sectional  airway area generally decreased  throughout  the 6-hour daily
trials,  but the  decreases were only significant (p <0.05) at 1 ppm and 5 ppm, since there was
an overall drop  in this measure (approaching a "floor level") by the time 25 ppm was adminis-
tered  on the  third  day of  the  study.   Nasal airflow resistance  increased significantly (P
<0.05) with the 6-hour exposure to each concentration (1, 5, 25 ppm SO-).  Significant (p <0.05
or less) decreases in  forced expiratory flow (FEFpryra,) and forced expiratory volume (FEV. „)
also occurred  both within daily exposures and across  days  (i.e.,  increasing concentrations),
although  the  within-day  decrease  in FEV-, Q was  only significant  on  day 3  (at  25  ppm)  (see
Andersen et al., 1974, Figure 7).
13.2.3.6  Mucociliary  Transport--Cralley (1942) investigated mucociliary clearance when sophis-
ticated  radioactive  measurement  techniques  were not available.  A  drop of red dye was placed
in the active  ciliary  region of the inferior meatus of a volunteer subject.  The rate of mucus
clearance was  reflected  in the time between the  dye's  introduction and its appearance in the
expelled mucus.  Exposure  to S0» at 10 to 15 ppm for 60 minutes produced only a small decrease
in  the rate  of  mucus removal.  A  30- to 60-minute exposure  to  25 ppm SOp  resulted  in  a 50
percent  reduction  in mucociliary transport and a  65  to  70 percent reduction at 50 to 55 ppm.
Mucositis  in  the  anterior region of the  nose  was observed in 14  of  15 subjects after 4 to 5
hours  of exposure on  successive days to  1,  5,  and 25 ppm S0? (Andersen et al., 1974).  There
appeared to be no  carry-over effect from the previous days exposure.  Mucous flow rates on the
first day of exposure  (to  1 ppm) tended to be lower but were not significantly lower than those
observed  on  the  control  day (0 ppm).  Mucus flow rates were significantly lower on the second
day  (5  ppm)  and were  further  decreased  on  the third day (25  ppm)  of  exposure.   The subjects
noted  discomfort  only on  the second  and third day exposures.  At these  concentrations  some
subjects  also  had sporadic mucostasis, although  there were  pronounced individual differences
in these measures  even at  baseline.  Andersen et al. (1974) calculated the cross-sectional area
of  the nasal  airways.  A  significant  decrease  (0.02 


-------
exposed to  5  ppm SCL for 1  hour  while sitting quietly in an inhalation chamber and breathing
through their mouths.   Mucociliary clearance was assessed by having the subjects first inhale
a radioactively  tagged  aerosol  and then monitoring its subsequent tracheobronchial deposition
and retention during S0? exposure.  No significant effects were found in mucociliary clearance,
except for a small transient change (p <0.05) after 1 hour of exposure.
     In their second study, Wolff et al. (1975b) used similar methods to compare subjects while
resting or  exercising.   Exercise  was performed on a  bicycle ergometer  for 0.5 hour at a pace
to  yield  heart  rates  70 to 75 percent  of estimated maximum values.   Exposure  in  this study
lasted for  2.5  to 3 hours.  The combination of exercise and exposure (via mouth) to 5 ppm SO^
resulted  in  a significantly (p <0.05) greater rate of tracheobronchial  mucociliary clearance.
This result  contrasts  with Andersen et al.'s  findings  (1974)  that nasal clearance rates were
reduced by exposure to 5 ppm S0?.   However, the difference between the two studies can probably
be  explained on  the  basis of  dose.   Dose to  the  lung will  be much  lower  than  to  the nose
because of  the  absorption of S02 onto upper airway mucosal surfaces.  Therefore, lung effects
could  be  typical of lower  concentrations  and  increases  might be anticipated as  seen  for low
levels of HpSO,.   Of course, the  two  studies  focused on different regions of the respiratory
tract  (tracheobronchial versus nasal), but this in itself provides no cogent account for these
contrasting  effects.   Both  of these investigators replicated their  findings  in later studies
[Andersen et al., (1977) and Newhouse et al., (1978)].  Extension of these studies was made by
Newhouse  et al.  (1978) whose 10  subjects  breathed either  S0? (5 ppm) or HUSO, mist (1 mg/m )
delivered as  an aerosol of 0.58  urn  MMAD.   An  aerosol containing a  0.025  percent  solution of
  mTc-albumen  was  inhaled  prior  to pollutant  exposure.   The  bolus technique  (exposure to
short-term  peak concentrations)  employed achieved deposition of the aerosol,  primarily in the
large  airways.    One-half  hour  later  the  subjects  were  exposed  to  the pollutants.   They
immediately  exercised  for the next 0.5 hour.   A  total  of  20 minutes of  exercise  at  approxi-
mately 70 to 75 percent of  predicted  maximum  heart  rate was performed,  followed  by  an addi-
tional 1.5  hours  of rest exposure.  The subjects breathed through the mouth to eliminate nasal
ventilation  and absorption of pollutants.   Pulmonary function tests conducted at the end of 2
hours' exposure to  SO™ indicated no changes in FVC  or FEV, Q but maximum mid-expiratory flow
rate (MMFR) decreased 8.5 percent, possibly due to a reflex bronchoconstriction.  No pulmonary
changes   were  found  consequent  to  the  H»SO.  mist  exposures.   Tracheobronchial  clearance
increased in both S0? (6 of 10 subjects) and H?SO» (5 of 10 subjects) exposures.  The investi-
gators  did  not present  their  data  in  a manner which  would provide  information as  to the
relationship between clearance rates and MMFR.   It should be noted that even these data are in
contrast  to the  replicated  observations by Andersen et al. (1977), who  showed a slowing of
nasal clearance on exposure to 5 ppm S0?.
     Mucociliary  transport is a significant aspect of the respiratory system's defense against
airborne  agents.  A disturbance in this function might have important implications for a number
of  health effects,  such as susceptibility to  cold-virus  infections.   Andersen et al. (1974),
XD13A/A                                      13-17                                         2-14-81

-------
for example,  noticed  that 4 of 17  subjects  caught  colds within a week of their participation
in a  study where mucostasis generally  occurred  during S0? exposure.  Andersen  et al.  (1977)
followed up this observation by inoculating volunteers with a strain of rhinovirus (RV3).   The
basic design of the study and reactions of the subjects are shown in a table (Andersen et al.,
1977, p. 121).   Although there was no difference in the number of colds that developed in the
two groups  of subjects (all nose breathers), cold  symptoms  were judged (under a double-blind
procedure)  to  be  less severe (p <0.05) in the group exposed to SO^.   It was unknown, however,
whether this result reflected a direct effect of S02 on the host, the rhinovirus, or both.   In
addition,  the  average incubation  period was somewhat  shorter  for  the group exposed to S02 (p
<0.06).   Virus shedding (a measure of infection determined from nasal washings) also seemed to
be somewhat decreased  in the S02 exposed group, but not significantly.
13.2.3.7  Health Status—Some studies have considered the preexisting health status of subjects
as a  variable in assessing the physiological effects of SO™.   Weir and Bromberg, for example,
conducted  separate  studies  on  12 healthy subjects  (Weir  and  Bromberg,  1972) and on 7 smokers
who  showed early signs  of chronic obstructive  pulmonary disease (Weir and  Bromberg,  1973).
The subjects  were  exposed to 0, 0.3,  1,  and 3 ppm SOp in an inhalation chamber for 96 or 120
hours (smokers or  nonsmokers,  respectively),  with  several  days separating  each  trial.   The
individual  variablity among the  smokers  in their  daily lung functions was so  great  that no
effects  could  be  attributed to SO,, exposure.  Also, subjective complaints  also appeared to be
randomly distributed  throughout the course of the study and could not be related to S02 expo-
sure  levels.
      Gunnison  and  Palmes  (1974) compared heavy smokers  (7) and  non-smokers (13) with respect
to blood plasma levels of S-sulfonate  after exposure  to 0.3,  1.0, 3.0,  4.2, and 6.0 ppm  SO,,.
Both  groups showed  highly significant correlations  (p <0.001) between SO,,  concentrations  and
S-sulfonate  levels.   But there was  no significant differentiation between the  two  groups of
subjects in this regard.
      Several  other  studies of  SO,,  (e.g.,  Snell  and Luchsinger,  1969; Andersen  et al.,  1974;
Gokenmeijer  et al.,  1973;  Burton  et  al.,  1968,  1969)  have  included asthmatic  patients  or
smokers, but  have  not  provided even  qualitative  ratings of their health  status.   This alone
would  make  it difficult  to compare  the  results  of  different studies  using "healthy"  or
"impaired"  subjects.  Morever, the great individual variability among both normal and impaired
persons  in these  studies  makes  it  difficult to  reach  any  conclusions  about the relative
importance  of  an  individual's  health status in determining his physiological response to SO,,.
13.3.  PARTICULATE MATTER
      One of the significant factors influencing physiological  responses to S0? is the presence
of particulate matter  in  the  atmosphere  (Amdur,  1969)  (see  Table  13-3).  Particulate matter
interacts  with SO,, in  at  least  two  distinct ways:  as a carrier  of SO,, and  as  a factor in
chemical reactions  resulting  in the conversion of SO,, to other forms.  In their carrier role,
particles  may  adsorb  S02 and,  depending on their size, solubility, and other characteristics,
XD13A/A                                      13-18                                        2-14-81

-------
                                                               13-3.  PULMONARV EFFECTS OF AEROSOLS
CO

i—»
ID
Duration of
Concentration exposure (mins)
SO, (1.6-5 ppm) 5
NaCl 0.22 pm HMD
SO, (9-60 ppm) 5
N3C1 (CMD = 0.95 MID)

SO, (0.5, 1.0 and 5.0 ppm) IS
Saline particles 7.0 M«I

High cone, aerosol
(1 Mm/or each)
Low cone, aerosol
(0.1 mg/m3 each)
NaHSO. 16*
NH.HSO,
(NB )JO
H2s642 *





S02 (1 ppm) 30
NaCl 1 mg/m3
MMD 0.9 M og = 2.0 Mm

SO- (1.1 - 3.6 ppm) , 30
NSC1 2.0-2.7 Mg/m
MMD = 0.25 Mm
SO, (1-2, 4-7, 14-17 ppm) 30
NSC1 10-30 mg/mj
MMD 0.15 Mm
S02 (1 ppm) 60
NaCl 1 mg/m3
MMD 0.9 M og = 2.0 Mm
SO, (Ippm) - 120
NRC1 1 mg/mj
MMD 0.9 M og = 2.0 Mm
Mixture of: SO, 120
(0.37 ppm); 0, £
(0.37 ppm) ana ,
H-SO, (100 Mg/nr)
MMD 0.5 Mm, og = 3.0
Ammonium tulfate 150
100 Mg/m


Ammonium bisulfate 150
85 M9/m aerosol size
distribution
0.4 Mm (MMAD)
Number of
subjects
13

10


9





16 normals
17 asthmatics






8
(asthmatics)

10

12

9
(asthmatics)

(normals)

19 (normal)




5 (normal)
4 (ozone
sensitive)
6 (asthmatics)
16



Source
Mask

Mask


Oral





Oral







Mask
(exercise for
10 minutes)

Oral

Oral

Oral


Mask

Chamber
(exercise)



Chamber
(exercise)


Chamber
(exercise)


Effects Reference
Synergistic increases in Toyama, 1962
airway resistance with aerosol
Airway resistance greater after Nakamura, 1964
exposure to aerosol than to
exposure to S02 alone
MEF,™ significantly greater Snell and Luchsinger,
diseases in aerosol (NaCl) 1969
condition




SG induced by carbachol was Utcll et al., 1981
Significantly potentiated
in asthmatics breathing H,SO,
and NH.HSO. at 1 mg/m each. 3
Low sulfate exposure (0.1 mg/m )
produced no changes in SG ;
however, the two most respon-
sive asthmatics to high HjSO.
dose via inhalation exhibited
a potential effect to the
lower acid exposure
'max 50%- 'max 75%- Koenigetal.. 1981
FEV, 0 and RT decrease
significantly in aerosol
condition
No effect on pulmonary functions Burton et al., 1969

Changes in pulmonary function Frank et al., 1964
similar to changes due to SO,
alone not influenced by aerosol
Significant decreases in V eg* Koenig et al., 1980
and V . ,„
max 75%
No pulmonary effects demon- Morgan et al . , 1977
strated

Small but statistically signif- Kleinman et al., 1981
icant decrements in FEV,
and slight increases in the
incidence of clinical symptoms

No changes in pulmonary Bell and Hackney, 1977
functions


No changes in pulmonary Kleinman and Hackney, :
functions Avol et al., 1979


                   •Rest

-------
transport it deep  into  the respiratory system (see Chapter 11, Section 11.2 for more detailed
discussion of deposition.)
     This point is illustrated by the results of studies by Nakamura (1964) and Toyama (1962),
who reported that sodium chloride (NaCl) aerosol potentiated the response of human subjects to
S02.   In  Nakamura's  (1964) study, 10 subjects  were  first exposed to NaCl aerosol (CMD = 0.95
urn;  Horvath's  estimate MMAD  =5.6  |jm) alone for  5  minutes,  allowed to  recover  for 10 to 15
minutes,  exposed  to S0?  alone at  9  to 60  ppm for  5  minutes, allowed  20  to  30  minutes to
recover,  and  then  exposed  to  SOp and  the NaCl  aerosol  together for  5 minutes.   Airway
resistance  was  greater after  the combination exposure  than after exposure to  862  alone (see
Table  1  and Figure 4a, Nakamura, 1964).   As  noted,  the combination condition always followed
exposure  to SOp alone, thus  raising the  possibility that the  effects  of the  latter exposure
were  confounded.   However, on average, the subjects' airway  resistance  measures returned to
only  4 percent above their pre-exposure  control  levels,  thus making it  more  likely that the
reported  effects were independent of preceding conditions.
     Toyama  (1962)  also reported that  5 minutes' exposure S02  in combination with submicronic
(0.22  (jm  MMD;  Horvath's estimate MMAD  = 0.36 urn) particles of NaCl aerosol produced synergis-
tic  increases  in  airway resistance in  13  subjects, even at levels as low as 1.6 to 5 ppm SOp.
There  was also  a  linear relationship between S0? concentration and percentage increase in air-
way  resistance.
     On  the other hand, Burton et al.   (1969) were unable to demonstrate comparable effects in
10  subjects exposed to SO,  (1.1 to  3.6  ppm)  in combination  with  NaCl  aerosol  (2.0  to 2.7
     3
mg/m  ;  0.25 pro MMD; Horvath's estimate MMAD =  0.4 urn).   There was, however,  a great deal of
variability  within  and between subjects in this  study,  including  one  or two possible "hyper-
reactors" who  did show effects below 3 ppm.  Frank et al. (1964) studied 12 subjects who were
exposed  to  three  conditions of S0? and NaCl aerosols.  There were six subjects in each group,
but  the  same subjects were not  evaluated  under each of the three conditions.   The purpose of
this  study  was to determine whether acute changes  in respiratory dynamics R,  (pulmonary flow
resistance)  noted to  occur  during  S02 exposure were intensified  by  the presence  of sodium
chloride  particles.   The  NaCl aerosols had a  mean geometric  diameter of  0.15 urn (Horvath's
estimate  MMAD =0.3  urn) and a  concentration of 10 to 30 mg/m ; S0? concentrations were 1 to 2,
4  to  7,  and 14  to  17 ppm.   The subjects'  response to the S0? exposures  were as previously
noted  in  that Rl was not  affected  by  the lower levels of  S02 and progressively increased at
the  higher  levels.   The  only  statistically  significant  difference   (p  <0.05) between the
effects  of  the gas alone  and  the gas-aerosol mixture was a slightly greater average increase
in pulmonary flow resistance at 4 to 7  ppm SOp than under the  combination condition.  Addition
of  the NaCl  aerosol  resulted in similar  changes  as observed  to  SO,, alone.   This  effect was
interesting  in  that earlier work was cited  suggesting  that HpSO. may have been  formed in the
droplets.   (See discussion of  similar animal studies in Chapter 12).

XD13A/A                                      13-20                                        2-14-81

-------
     Snell  and Luchsinger  (1969)  also compared  the  effects S02  alone and  in mixture  with
aerosols of  either  NaCl  or distilled water.   Nine subjects inhaled S02  at  0.5, I, and  5 ppm
alone  and  in  combination with aerosols for 15-minute  periods  separated by 15-minute  control
periods.   For  the  SO^ - saline  aerosol exposure,  decreases in maximum expiratory flow  rate
(MEF50% vc)  were  significant (p <0.01) only at  5 ppm S02; whereas, the  SOp - distilled  water
aerosol exposure  produced  significant decreases  (p <0.01)  at all exposure levels (0.5, 1,  and
5 ppm  S02).   (See Figures 3  and  4, Snell  and Luchsinger,  1969.)   The authors  noted that the
size of the  aerosol particles differed  considerably, saline particles  averaging  around  7  urn in
diameter  and water aerosols  averaging  less  than 0.3 (jm in  diameter  (see Figure 5, Snell  and
Luchsinger,  1969).   (See  also Ulmer,  1974.)   Koenig et  al.  (1980)  exposed  nine  adolescent
resting subjects  (extrinsic asthmatics) for 60 minutes to either filtered air, 1 ppm SO,  and  1
    3                                                 3
mg/m   of  sodium  chloride  droplet  aerosol  or  1  mg/m   of  NaCl  droplet aerosol  (HMD  0.9  pm,
unable  to  estimate  MMAD, and a   of 2.0 |jm).   Exposure to  SO,,  alone  was not performed.   Oral
breathing  was  forced  on all  subjects.  Total  respiratory  resistance  (RT), maximal flow  at 50
and 75 percent of expired vital  capacity  (partial flow volume), FEV,  Q, and functional  resi-
dual capacity  were  measured before, during (30  minutes), and after exposures.   No  significant
changes were found  during exposures to  filtered  air or NaCl aerosol.   Significant decreases (p
<0.025) were  observed  in  V    t-n
jects  (normal,  atopic and mild  asthmatic)  for  10  minutes to 0, 1, 3  and 5 ppm  SO,,.  The  sub-
jects  breathed  these gases  orally while  their  specific  airway  resistance (SR   ) was measured
                                                                              aW
in a body  plethysmograph.   Despite large  inter-and  intra-subject variability  in  these subjects
breathing  clean  air,  it  was  found  that  asthmatic subjects  SR    increased  significantly
                                                                   3W
(0.05-0.025)  at  all  concentrations of  S02.   Normal  and  atopic  subjects  had significant
increases  in SR   only  while  breathing  5 ppm S09.   Some asthmatic subjects exhibited  marked
                aW                               c.
dyspnea  requiring bronchodi lator  therapy.   The increased SR   seen  in either normal or  mild
                                                             clW
asthmatic  subjects were  prevented by treatment  with atropine confirming  the  involvement of
parasympathetic pathways  in  this response.   Reichel  (1972) exposed two groups of subjects  with
obstructive  bronchial  disease  to  varying concentrations  of  SO, in his chamber.   Patients  with
                                                                          3
minor  obstructive disease were exposed continuously for  4 days to 10  mg/m  S09  (n =  8),  for  4
                 3                                                 3
days to 4.7 mg/m  (n =  4)  and 5  subjects  for  6  days to 0.75 mg/m   (n = 5).    Patients  with
serious obstructive  bronchial  disease were  also exposed--4  to  4.7 mg/m  for 4 days and  4 to
2.6 mg/m   for 6 days.   Airway resistance was not influenced by such  exposure.   The  details of
XD13A/A                                      13-21                                         2-14-81

-------
the measuring  procedures were not adequately  presented  in his report.  Koem'g et  al.  (1981)
exposed 8 adolescent extrinsic asthmatics to the same conditions as in her above study but had
them also  undergo  a 10-minute period of moderate exercise during the exposures.   Vmax ^ and
Vmax 75«£  decreased  44 and 50 percent  respectively  from  the baseline mean after the exercise.
Significant  changes in  FEV,  _  and R,  were  observed, suggesting  that exercise and  SO^-NaCl
exposure  resulted in  effects  on both  large as  well  as small airways.   The functional  changes
seen  after exercise  with exposure to filtered air  or  NaCl droplet  aerosol  alone were  not
statistically  significant.   Although  V    rnv  was depressed in resting subjects (extrinsic
                                       IT) 3 X
asthmatics) 8  percent  (t = 2.83 p  <  0.025)  and 6 percent (t =  0.38,  p = N.S),  respectively,
in the  1980  and 1981 studies by Koenig  et al., it should be mentioned that the  latter change
was  not significant after  30 minutes of exposure.  In  the  1980 study, all subjects  (N  =  9)
decreased  in  V     5Q^;  however,  in the 1981  study  some of the eight  subjects  increased and
some decreased.
     As  chemical   interactants,  particles  such  as aerosols of  certain soluble  salts  (e.g.,
ferrous  iron,  manganese, vanadium)  may  act as  catalysts to convert  S0~ to HUSO..   HpO  from
atmospheric  humidity or from  physiological  sources figures  prominently in these  reactions.
The  following  sections  deal  with common compounds of sulfur oxides and point up  the influence
of a number of variables that affect human physiological  response to these compounds.
13.4  SULFUR DIOXIDE AND OZONE
     Sulfur  dioxide and  ozone  (0,)  may  combine  to  form  sulfuric acid  on the warm,  moist
surfaces  of  the respiratory tract.   Studies have  not  yet demonstrated, however, that  a  true
synergistic bond exists between SO^ and 03 (see Chapters  6,  7, and 11).
     Bates  and Hazucha  (1973)  and Hazucha and  Bates  (1975)   exposed  eight volunteer  male
subjects  to  a mixture  of  0.37 ppm 0, and  0.37 ppm S02  for 2 hours.   Temperature,  humidity,
concentrations  and particle  sizes  of ambient  aerosols  (if any)  were  not  measured.   Sulfur
dioxide  alone  had no  detectable   effect  on  lung function, while  exposure  to ozone  alone
resulted  in  decrements  in  pulmonary  function.   The  combination of  gases resulted  in  more
severe  (10 to  20% decrement) respiratory  symptoms  and  pulmonary  function changes  than did
ozone alone.   Using the maximal  expiratory flow rate at  50 percent vital capacity as the most
sensitive  indicator,  it was  evident that after 2 hours exposure  to 0.37  ppm  S02  no change
occurred.  However,  during  exposure to 0.37 ppm 0, a 13  percent reduction was observed, while
exposure  to  the  mixture of 0.37 ppm 0, and 0.37 ppm SO^  resulted in a reduction  of 37 percent
in this  measure  of pulmonary function.  The effects resulting  from 0, and S0« in combination
were apparent in 0.5 hours, in contrast to a 2-hour time  lag for exposure to 0~ alone.
     Bell  et al.  (1977) attempted  to replicate  these  studies  alone with four normal and four
ozone-sensitive subjects.  They showed that 0,  + SOp mixture had greater detrimental effect on
all  pulmonary  function measured than did 0,  alone.   However,  only some  of these parameters
showed  statistical  significants  decrement  when compared to  0,.  Four  of  Hazucha  and Bates'
subjects were  also studied  by Bell et al.  (1977).  Two  of these subjects had unusually  large
XD13A/A                                      13-22                                        2-14-8

-------
decrements in  FVC  (40 percent) and FEV-j^  (44  percent) in the first  study  (Bates and Hazucha,
1973), while  the other two  had  small  but statistically significant  decrements.   None  of the
subjects  responded  in a  similar manner  in  the Bell  study.   Restrospective  sampling  of the
ambient air conditions utilizing particle samplers and chemical  analysis in the chamber showed
that  acid sulfate  particles could  have  been  10-  to 100-fold  higher  in Hazucha  and  Bates'
chamber  and  thus might  have been  responsible  for the  synergistic  effects  observed.   In the
Montreal  chamber,  concentrated streams of S09  and  0., exited from tubes separated by 8 inches
                                         3            i
(20 cm)  under a fan which forced  167  ft /min (4.7 m /min) of air  conditioned laboratory air
with SO^  and 0, through the  chamber and out an exhaust line on the opposite wall.  The concen-
trated  streams of  SO,,  and  0., could  have reacted  rapidly with  each other and  with  ambient
                      £»       -j
impurities  like olefins,  to form  a  large number  of H?SO.  nuclei  which grew  by homogenous
condensation,  coagulation, and absorption of NHL during their 2-minute average residence time
                                                •J
in the chamber.
     Horvath's  group  (Horvath  and Folinsbee,  1977; Bedi et  al.,  1979)  exposed nine young men
(18 to 27 years old)  to 0.4  ppm 0, and 0.4 ppm S0? singly and in combination for 2 hours in an
inhalation chamber  at 25°C  and 45 percent RH.  The subjects exercised intermittently for one-
half of the exposure  period.   A  large number of pulmonary function tests were conducted before,
during,  and  after  the exposure.   Subjects exposed to filtered air or to 0.4 ppm SO- showed no
significant changes in pulmonary function.  When exposed to either 0, or 03 plus SCL, the sub-
jects  showed  significant  decreases in  maximum expiratory  flow,  forced vital  capacity,  and
inspiratory  capacity.   There were no significant differences between the  effects of 0, alone
and  the  combination  of  03  +  SO,,; thus,  no synergistic effects  were discernible  in their
subjects.   Although  particulate  matter was  not  present  in  the inlet  air,  it  is  not known
whether particles developed  in the chamber at a later point.
     The  question  of  potential synergistic interaction between SO* and 03 remains unresolved.
Chamber  studies were conducted by  Kagawa  and Tsuru (1979) exposing  six subjects for  2 hours
with  intermittent  exercise  (50 watts i.e. ventillation of 25 1/min)  for periods of 15 minutes
exercise  separated  by periods  of 15 minutes rest.  The exposures were performed weekly in the
following sequence:   filtered  air,  0.15 ppm 03;  filtered  air,  0.15  ppm SO^; filtered air and
finally  0.15 ppm 03  - 0.15  ppm  SO,,.   Pulmonary function measurements  were  obtained prior to
exposure  after 1  hour  in the chamber and after  leaving  the chamber.   Although a number of
pulmonary function  tests  were  performed, they  utilized  change  in specific airway conductance
(SG  )  as the most sensitive  test  of  change  in function.   They  found  a significant decrease
   QW
in five of the  six  subjects  (5/6) exposed to 03 alone.   In three of the six young male  subjects,
they found a  significant enhanced decrease in SG   after exposure to  the combination pollutants
                                                3W
compared  to  the decrease  in SG    in  these  subjects in 0,  exposure.   Two  other subjects had
similar decreases in  either  03 or Oj-SO,, exposure.  They further suggest that the effect of the
two gases on SG   is  more than simply additive and results from a combined pollutant exposure.
               3W
Subjective  symptoms  of  cough and  bronchial  irritation were  reported to  occur in subjects
exposed to 03 or 0,-SO,,.
XD13A/A                                      13-23                                        2-14-81

-------
     Von Nieding et  al.  (1979) exposed 11 subjects  to  03>  N02 and S02  singly and in various
combinations.   The  subjects were  exposed  for 2  hours  with 1 hour devoted  to exercise which
doubled  their ventilation.  The  work periods were  of 15  minute duration  interspersed with
15-minute  periods  at rest.   In the  actual  exposure experiments,  no  significant alterations
were observed for P. , P.  , pH  , and thoracic gas volume (Vtg).   Airway resistance total
                   H02  HC02
(R+) and P.  were altered  in certain studies.  P.  was decreased (7-8 torr) by exposure to
          "n                                    "n
           U2                                    02
5.0 ppm  N02  but  was not further  decreased following exposures  to 5.0 ppm N02 and 5.0 ppm S02
or 5.0  ppm N02,  5.0 ppm S02 and  0.1 ppm 03  or 5.0 ppm N02 and 0.1 ppm 03-  Airway resistance
increased  significantly  [0.5  to 1.5 cm H?0/(L/s)] in the  combination  experiments to the same
extent as  in  the exposures to N02 alone.  In the 1-hour post exposure period of the NO,,, S02,
and 03 experiment,  Rt continued to increase.   Subjects were also exposed to 0.06 N02>  0.12 S02,
and 0.025 03 (all in ppm).   No changes in any of the measured parameters were observed.   These
same subjects were  challenged  with a 1, 2,  and  3 percent  solution of acetylcholine following
control  (filtered air) exposure and to the 5.0 N02> 5.0 S02, and 0.1 03 (ppm) as well  as after
the  0.06  N02,  0.12  S02,  and  0.025 0,,  (ppm) exposures.    The  expected  increase in  airway
resistance was  observed in  the control study.   Specific  airway  resistance  (R   x  Vtg)  was
                                                                                3W
significantly greater  than in  the control  study following the combined  pollutant exposures.
(See Table 13-4 for  a  summary of the pulmonary  effects  of S0?  and  other  air  pollutants.)
     Three groups of eight subjects, each of  different ages (>30,  >49 and between 30-40 years)
were exposed  for 2  hours  in a  chamber  on  three  successive days (Islam and Ulmer, 1979a).   On
the first  day,  subjects breathed air and exercised  intermittently (levels not given);  on the
second day they were exposed at rest to 5.0 ppm S02,  5.0 ppm  N02 and 0.1 ppm 03;  on the third
day the  environment  was again 5.0 ppm  S0?,  5.0  ppm  N0? and 0.1 ppm 0., but the subjects exer-
cised  intermittently  during  the exposure.   Statistical  evaluation of  the  data on the 11 lung
functions and the two blood parameters (P.   and P. )  was not adequately performed.  These
                                         A02       C02
measurements were made  before,  immediately and 3 hours post exposure.   Individual variability
was quite  marked.   The  investigators concluded that  in their  healthy  subjects no synergistic
effects  occurred.   However, since  they did   not  systematically expose these  subjects  to the
individual components of  their mixed pollutant environment, the conclusion can only be justi-
fied in  that  they  apparently saw  no  consistent  changes.   There were some apparent changes in
certain  indiviuals   related to  exercise  (unknown  level)   and   age  but  the  data were  not
adequately analyzed nor could they be from the information  presented.
     Islam and  Ulmer (1979b) studied  15 young healthy  males during chamber  exposures  to 0.9
    •33                   O
mg/m   S02, 0.3  mg/m  N02  and 0.15 mg/m 03.   Ten subjects were  exposed  to  1 day of filtered
air and  4  successive days to the above gas mixture.   Another group of 5 subjects were exposed
for 4  days to the  pollutant mixture followed by  1  day to filtered air.  Each exposure was 8
hours  in duration.   Following  each exposure   the  subjects were  challenged by an acetylcholine
                                                              p     p
aerosol.  Nine pulmonary function tests and four blood tests ( An  ,  AGO,, Hb and  lactate
                                                                U2      *
XD13A/A                                       13-24                                        2-14-81

-------
                                                             13-4.   PULMONARY EFFECTS OF S02 AND OTHER AIR POLLUTANTS
CO
 I
ro
en
Duration of
Concentration exposure (mins)
S02 (0.15 ppm) 120
and
03 (0.15 ppm)

S02 (0.37 ppm) 120
and
03 (0.37 ppm)

S02 (0.37 ppm) 120
and
03 (0.37 ppm)

S02 (0.40 ppm) 120
and
03 (0.40 ppm

S02 (5 ppm) 120
and
N02 (5 ppm)
S02 (5 ppm) 120
N02 (5 ppm)
and
03 (0. 1 ppm)
S02 (0.12 ppm) 120
N02 (0.06 ppm)
and
0, (0.025 ppm)
Mixture of: S02 (5 ppm) 120
N02 (5 ppm)
03 (0.1 ppm)
Mixture of: S02 8 hr/da for
(0.33 ppm) 4 successive
N02 (0. 16 ppm) days
03 (0.075 ppm)
Number of
subjects Source
6 E*



8 Chamber
(exercise)


4 (normal) Chamber
4 (ozone (exercise)
sensitive)
4 (from Bates)
9 Chamber
(exercise)


11 Chamber
(exercise)

11 Chamber
(exercise)


11 Chamber
(exercise)


8 Chamber
(exercise)

15 Chamber
(rest)


Effects
Significant enhanced
decrease in SGaw after
exposure to S02 - 03 in
comparison to 0, alone
Decrease pulmonary functions
(in synergistic effect of
S02 on Oj) FRC, FEV^ n,
HMFR, HEFR5Q%
Unable to confirm
synergistic effects
pulmonary decrement due
to 0, alone
Unable to confirm
synergistic effects
changes due to ozone
alone
No changes in PA , P^,-
pHa or TGr -R^j- 2
increased
No changes in PAQ , PACQ2,
pHa or TGr -Raw
increased

No changes in pulmonary
functions


Data not adequately analyzed
and could not be from the
data presented.
Statistical analysis of the
data not adequate


Reference
Kagawa et al . , 1979



Hazucha and
Bates, 1975
Bates and
Hazucha, 1973
Bell et al., 1977



Horvath and Folinsbee
1977;
Bedi et al. , 1979

von Nieding et al., 1979


von Nieding et al. , 1979



von Nieding et al. , 1979



Islam and Ulmer,
1979a

Islam and Ulmer,
1979b


                     *Exercise.

-------
*
dehydrogenase)  were  performed  before  and  after the  exposure.    The  study  suffers  from  a
deficiency in  statistical  analysis of the data. No impairments of lung functions, blood gases
or  blood chemistry  were  found.   However,  some of  the  subjects were  said to  have unusual
reponses.
13.5  SULFURIC ACID AND SULFATES
13.5.1  Sensory Effects
     A  number of  studies  have been  directed  toward determining  threshold  concentrations of
H2$04  for various  sensory  response  (see  Table 13-5).   In  a study  with 10  test  subjects,
Bushtueva (1957)  found  that the minimum concentration of sulfuric acid aerosol  (particle size
                                                         33                   3
not given) which  was sensed by odor ranged from 0.6 mg/m  to 0.85 mg/m  (average 0.75 mg/m ).
                                                                                             3
In  tests  with  five  subjects  (Bushtueva,  1961),  a combination of sulfur dioxide at 1 mg/m
(0.35 ppm)  and sulfuric  acid  mist at 0.4  mg/m  was  below the odor threshold.    Amdur  et  al.
(1952)  reported on  15  subjects (males  and females)  exposed  for  5 to 15 minutes to various
concentrations of sulfuric acid mist the subjects breathed via a face mask.   It  was found that
      3                                       3
1 mg/m  was usually not detected, while 3 mg/m  was detected by all subjects.
     Bushtueva (1957) studied  the effect of sulfuric acid mist on  the light sensitivity of  two
test  subjects.   Sensitivity was measured  every 5 minutes during  the first half-hour of each
test,  then  at  10-minute  intervals  thereafter.   A  control  curve was  established   for each
subject by seven repeated tests, and then sulfuric acid aerosol was administered for  4 minutes
and  for 9 minutes  at the  15th and 60th  minutes,  respectively.   With sulfuric  acid mist of
undetermined  particle size  at a concentration  of  0.6 mg/m  ,  a  just detectable  increase in
light sensitivity occurred with the first exposure but not with the second.   Concentrations in
                        3                3
the  range  of  0.7  mg/m   to  0.96  mg/m   brought  about  a  well-defined increase   in  light
sensitivity.   With  2.4  mg/m ,  increased sensitivity to light was  elicited by the exposures at
both  the 15th  and  60th  minutes of  the  test;  normal  sensitivity was restored  in  40  to 50
minutes.
     Bushtueva  (1961)   studied  the  effect  of  sulfur  dioxide,  sulfuric  acid  mist  and
combinations  of the two on sensitivity of the eye to light in three subjects.   The combination
                               3                                               3
of sulfur dioxide at  0.65 mg/m (0.23 ppm) with sulfuric acid mist at 0.3 mg/m  resulted in no
change  in sensitivity of the  eye  to  light.   An increase of approximately 25 percent in light
sensitivity resulted  from  exposure to either sulfur dioxide at 3  mg/m  (~1.0 ppm) or sulfuric
                      3                                              3
acid mist at  0.7  mg/m .   The  combination of sulfur dioxide at 3 mg/m  with sulfuric  acid mist
             o
at  0.7  mg/m   resulted  in  an increase  of approximately  60 percent  in light  sensitivity.
Exposures lasted for  4 1/2 minutes.
                                                                                       •3
     Bushtueva  (1962) demonstrated that  combinations  of  sulfur  dioxide at  0.50 mg/m  (0.17
                                           3                               3
ppm) with sulfuric acid mist  at 0.15  mg/m  or sulfur dioxide at  0.25  mg/m   (0.087  ppm) with
sulfuric  acid mist  at  0.30 mg/m  could produce  electrocortical  conditioned  reflexes.   There
are some uncertainties regarding this study.

XD13A/A                                      13-26                                        2-14-81

-------
                                XD13A/B-8

                                                                      13-5.   SENSORY  EFFECTS OF  SULFURIC ACID AND  SULFATES



                                  Concentration       Subjects                               Effects                                  References


                                    0.75 mg/m3           5                         Threshold detected  by odor                    Bushtueva, 1957,  1961
                                                                                     -  increase  in  light sensitivity
                                                                                     -  increase  in  optical chronaxie

                                    1-3 mg/m3             15 (exposed 5-15 min)      3  mg/m3 detected by all subjects              Amdur et al., 1952
CO

ro

-------
     Bushtueva  (1961)  studied  the effects  of  different  concentrations  of  sulfur  dioxide,
sulfuric acid  mist,  and combinations of the  two on the optical chronaxie  of  three subjects.
Optical  chronaxie  was  determined  in each  test subject at 3-minute  intervals  as  follows:   at
the start  and  on the 3rd, 6th,  9th, 12th  and 15th minutes.  Between  the  6th  and 9th minutes
the subjects  inhaled sulfur  dioxide,  sulfuric acid mist,  or  their combination for 2 minutes.
In  each  subject, the threshold  concentrations  of sulfur dioxide and  sulfuric  acid mist were
first  determined  independently,  and then threshold concentrations for combinations of the two
were determined.  Sulfuric acid mist (0.75 ug/m ) increased optical chronaxie.
13.5.2   Respiratory  and Related Effects
     Amdur et  al.  (1952)  found respiratory changes in  all  subjects  exposed for 15 minutes to
                                             •3          O
H2$04  aerosol  at concentrations of 0.35 mg/m  to 5 mg/m .   Vapors from an  electrically heated
flask  containing  concentrated  sulfuric  acid were carried by  compressed  air into  the main air
stream  and then  into  a lucite mixing chamber,  delivering  a  mist  of MMD 1  um.   The  subjects
breathed through a pneumotachograph, permitting measurement of inspiratory  and  expiratory flow
rate.   In  15  subjects,  exposed to 0.35,  0.4, or  0.5  mg/m , the respiration  rate increased
about  35 percent above control values,  while the maximum inspiratory  and expiratory flow rates
decreased  about 20  percent.   Tidal volume  decreased  about 28 percent in subjects  exposed to
0.4 mg/m .   These changes occurred within the first 3 minutes of exposure  and  were maintained
throughout the 15-minute  exposure  period.   Lung  function returned rapidly  to  baseline levels
after  the  exposure  ended.   The tidal  volume rose above control  values during the  first minute
after  termination  of the  exposure and then returned to preexposure levels.   Breathing through
the  same apparatus  without  the acid mist  was done  as  a control,  and  no  such  changes were
observed.  Some subjects showed a marked reaction to 5 mg/m ,  a level of acid mist perceptible
to  all.   Individual responses  were much more  varied  at this level, the main  effect  being  a
decrease in  minute  volume.   The investigators suggest that bronchoconstriction may have been
the response to sulfuric acid.
     The  effect of  breathing  sulfuric acid  mist at different  relative humidities  (RH)  was
studied  by Sim and Rattle (1957).  Healthy males  (variable number of  subjects), 18 to 46 years
of  age,  breathed 3  to  39 mg/m  concentrations of  HUSO, at  62  percent RH  either  via  mask or
                                                                                             3
exposure   chamber.   Subjects   were  also  exposed  in  the  chamber  to  11.5  to  38  mg/m
concentrations  at  91 percent RH.  At the lower RH, particles were 1  um in  size.  The addition
of water vapor to raise RH increased the mean particle size to 1.5 |jm and intensified irritant
                                                                              o
effects  of exposure.   For example,  the  irritancy  of wet  mist  at  20.8 mg/m   was much more
severe  ("almost intolerable  at  the onset")  than that of  the  dry mist at  39.4  mg/m  ("well
tolerated  by  all").   Air flow resistance  ranged from  43  to  150   percent above  normal  in
response to  the wet mist, compared to increases  ranging from 35.5 to 100 percent above normal
in  response  to the  dry mist.  Two subjects exposed to sulfuric acid  mist developed bronchitic
symptoms but  may have  been previously exposed  to other  substances.   Adding ammonia (quantity

XD13A/A                                      13-28                                        2-14-81

-------
*
not  given)  to  the  acid mist  annulled  its  irritant  properties.   There  was  no  consistent
evidence that the  acid mist caused changes  in  respiratory functions or blood pressure, pulse
rate, or other cardiovascular functions.
     Toyama  and  Nakamura (1964)  investigated the  synergistic  effects of  S02 in combination
with  hydrogen peroxide  (HJL)  aerosol  mixtures,  the  latter of which  oxidizes S02  to form
H2S04-   S02  concentrations  ranged from 1  to  60 ppm; the  KL02 concentrations  were  0.29 mg/m
for  particles of  4.6 urn CMD (Horvath estimated MMAD = 13) and 0.33 mg/m3 for particles of 1.8
urn CMD  (Horvath  estimated MMAD = 5).  Airway resistance increased significantly in the combi-
nation  (HLCL +  S02) exposure,  particularly  for the group of 15  subjects  inhaling  the larger
particles  (p <0.01).  Toyama  and Nakamura  (1964)  exposed subjects to  a  mixture  of  S02 and
H2SO^ aerosols.   They  used  an  inadequate method to measure airway resistance.   They described
the  aerosols as  having  a 4.5  urn diameter.   They  found  a strong constricting  effect on the
upper airways.
     Sackner et al.  (1978) studied normal resting young adults and seven asthmatic middle-aged
subjects  who breathed,  by  mouth,  either sodium  chloride or sulfuric  acid aerosols  for  10
minutes  at  concentrations of  10,  100,  and 1000 M9/m  (0.1-0.2 MMAD).  Measurements  on these
individuals  continued  for up to 3 hours after exposure.    The asthmatic patients represented a
wide range of clinical status  and treatment.  Neither normal nor asthmatic individuals showed
significant  alterations  of  lung volumes, distribution  of ventilation,  earoximetry,  dynamic
mechanics  of breathing,  oscillation  mechanics  of  the chest-lung system,  pulmonary capillary
blood flow,  diffusing  capacity, arterial oxygen saturation, oxygen uptake, or pulmonary tissue
volume.  No  delayed  effects were observed during a  follow-up period of a few weeks.
     Kleinman and  Hackney (1978) and Avol et al. (1979) reported on the pulmonary responses of
six  normal and  six  asthmatic subjects  exposed  in  an ambient environment of 88°F dry bulb and
40 percent relative humidity,   and 94 ug/m  H2SO..  The asthmatics had pulmonary function test
results  which ranged  widely  from normal  to  abnormal.   A sham exposure  was followed  by  2
consecutive  days  of acid  exposure.   Sufficient  excess  acid aerosol  to  neutralize  the NH,
                       3
present  (about  56 ug/m  ammonia  neutralization  product)  was  added to the  air  to  provide for
the  desired acid  concentration (75  ug/m  ).   The aerosol  MMAD was approximately  0.48  to 0.81
urn.   The  effective  exposure  time was  2  hours, with  the first  15  minutes of each half-hour
devoted  to exercise which increased ventilation to twice  the resting level.  Only one subject
was  exposed  at  a time to minimize the effects of ammonia  neutralization.   The normal subjects
showed  no  exposure-related  changes.   The  lung  functions  of  the  asthmatics showed no signifi-
cant changes.   Two  asthmatics, the extent  of  their disease  state  not  given,  exhibited in-
creases  in respiratory resistance on both exposure days.   Nonetheless,  it was concluded that
there were  no convincing adverse short-term health effects of sulfuric  acid.   However, they
also noted the small size of their subject pool and recommended additional  studies.
XD13A/A                                      13-29                                        2-14-81

-------
     Utell  et al.  (1981) exposed  16  normal  subjects  and 17  asymptomatic  asthmatics  (all
subjects  non-smokers)  to acidic  aerosols  (MMAO =  0.5-1.0  |jm,  o  1.5-2.2)  for  periods  of 16
minutes.  Several aerosol exposures  were given each day in a double-blind random pattern.  At
the  beginning of  each  study,  an approximate dose-response curve  to inhaled  carbachol  was
obtained.  All aerosols [NaHS04, (NH4)2S04; NH4HS04, H2S04,  Nad] were given orally.   The data
presented in the manuscript  is incomplete,  but what is available suggests that specific airway
conductance (SGaw)  induced by carbachol  was significantly potentiated (p <0.01) in asthmatics
                                          3                                    3
breathing H2$04  and NH4HS04  (each  1 mg/m  ).   Low sulfate  exposure  (0.1 mg/m  )  produced no
changes in SGaw,  however; the two asthmatics most responsive to  the high H-S04 dose via inhala-
tion exhibited a  potential effect to the lower sulfuric acid exposure.   No effects were noted
in the  normal  subjects.   A  more extensive  presentation of the data obtained by these investi-
gators will be required  before final decision of the effects of sulfates on asthmatics can be
determined.
     Lippmann et al. (1980)  had 10 non-smokers inhale  via  nasal  mask 0.5 urn (a  = 1.9) H,SO.
                                                 3                              "
at 0 and  approximately,  100,  300, and 1,000 ug/m  for 1 hour.   The exposures were random over
the 4 days  of testing.   Pulmonary functions (assessed  by body  plethysmograph, partial forced
expiratory maneuver, and  nitrogen washout) were measured before,  and at 0.5, 2,  and  4 hours
post exposure.      i"c-tagged  monodispersed  Fe^O,  aerosol  (7.5 urn MMAD,  0  =1.1) was  inhaled
10 minutes  before  exposure   for  the determinations  of  lung  retention  of  these particles.
Tracheal mucus transport rates (TMTR) and bronchial  mucociliary  clearance were determined.  No
significant changes  in  respiratory mechanics or TMTR were observed following H2S04 exposure at
any  level.    However,  bronchial  mucociliary  clearance  halftime (TBjJ  was  on  the  average
markedly altered  at  all concentrations of H,SO., inhaled.  Bronchial  clearance was increased (p
                                     3                                               3
<0.02) following  exposure to  100 ug/m  H2$04, while  following exposure to 1,000 ug/nr , it was
significantly (p <0.03) reduced.  Mucociliary  transport in  the  airways  distal  to the trachea
was affected  more by H2$04  exposure  than was  transport in  the  trachea.  Out  of ten subjects
four did  not  respond.   "The  alterations in bronchial  clearance  half-time were all transient,
which was  consistent  with the results seen  earlier in  similar  inhalation  tests  on  donkeys
(Schlesinger et al., 1978).   However, when  donkeys were repeatedly exposed to sulfuric acid at
comparable concentrations, four  of six  animals developed persistently slowed clearance, which
remained  abnormal   for at  least  several  months  (Schlesinger  et  al.,  1978,  1979).   Taken
together, these results  suggest that at the concentrations  employed  persistent changes could
occur in  mucociliary  clearance  in  previously healthy  individuals and  exacerbate preexisting
respiratory disease.
     Kleinman and Hackney (1978) and Avol  et  al.  (1979)  presented in greater detail the pre-
liminary  findings reported by Bell  and Hackney (1977).  They evaluated the effects of various
sulfate  compounds  on  normal  subjects,  ozone-sensitive  subjects,  and asthmatic  subjects
(requiring medical  treatment).   The  exposures were approximately 2.5 hours  in duration, with

XD13A/A                                      13-30                                        2-14-81

-------
the subjects  exercising the first 15 minutes of each half hour at a pace sufficient to double
their ventilation rates.  Measurements of pulmonary functions, which included FVC, FEV,, MEFR,
^50%'  ^75%' ^^>  ^'  delta nitrogen  (AN,,),  closing  volume,  and total  respiratory  re-
sistance  (Rt) were made  before and  2  hours after the work-rest  regimen  began.   The ambient
conditions were 88°F dry bulb and either 40 or 85 percent relative humidity.  Most of the expo-
sure  studies  were made  on five to  seven  subjects.   Four to  five  sensitive  subjects and six
asthmatics completed  the  subject pool.   Subjects were  first exposed to a control (no pollut-
ant)  environment  and  then to 2  or  3 consecutive days of the  pollutants.   The asthmatics were
not studied in the high humidity conditions, but were exposed  to a higher concentration (up to
372  ug/m ) of  (NH^SO^.   Nominal  exposure  concentrations were  100  ug/m   for  ammonium bi-
sulfate  (NH4HS04)  and  85  ug/m  for  ammonium  sulfate  [(NH4)2S04~|.  The  sulfate  aerosol  size
distribution  was  nominally 0.4  urn MMAD (a  2.5  to  3).   There was  some ammonia  (NH.,)  in the
exposure  chamber.   Pulmonary  functions  were unaffected by  exposure  to the two types of aero-
sol.
     An  interesting  side  observation  was  made  on  the  asthmatics.   On  their  first  day of
exposure  to NH4HS04  aerosol,  they exhibited worse lung functions in the pre-exposure measure-
ments  than they had on a  control  day.   Their functions  improved  consequent  to the pollutant
exposure.  Subsequent  analysis  of local ambient conditions  showed that these subjects arrived
for their aerosol testing  after a  3-day  period of  increased SO-  and ozone levels during a
"mild  air pollution  episode."   (See Table  13-6 for  a summary of  the pulmonary  effects  of
sulfuric acid.)
     Kleinman et  al.   (1981)  conducted  studies  in  which 19 volunteers with  normal  pulmonary
function  and  no history  of asthma were exposed on  two separate days to clean air  and to an
atmosphere mixture  containing 03  (0.37 ppm),  S02  (0.37 ppm), and  H2$04  aerosol (100  ug/m ,
MMAD 0.5  urn;  ag = 3.0).  During this 2-hour period, the subjects alternatly exercised for 15
minutes,  at   a  level   calibrated to  double  minute  ventillation,  and  rested for  15 minutes.
Statistical analysis   of  the group  average  data suggested that  the mixture may  have  been
slightly more irritating  to the subjects than 03 alone.  A  large percentage (13 of 19)  of the
subjects exhibited small  decrements  in pulmonary function.   The groups averaged FEV, g on the
exposure day  was  significantly  depressed,  3.7 percent of the  control value.  One might expect
0,  alone  to  depress  FEV,  Q by  approximately  2.8 percent  under similar  exposure conditions.
     Kerr  et  al.  (1981) investigated the respiratory effects  associated  with exposure to low
levels of sulfuric acid (H2$04) aerosol.  Twenty eight normal  subjects were exposed for 4 hours
to  100  ug/m3  H2S04 aerosol of  particle size  0.1 to 0.3 urn (HMD  =  0.14  pm; ag  =  2.9)  in an
environmentally controlled  exposure chamber.  At one and three hours into the study on  each
day,  bicycle  ergometer exercise was performed at  a workload at  100  watts at 60  RPM  for 15
minutes.   Of  the 28  subjects,   14  were nonsmokers  and 14  were cigarette smokers.  None  of
the subjects  complained of symptoms attributable to the  exposure.   Measurements  of pulmonary

XD13A/A                                      13-31                                        2-14-81

-------
                          XD13A/B-9
                                                                   13-6.   PULMONARY  EFFECTS  OF  SULFURIC  ACID
OJ
 I
oo
ro
Duration of
Concentration exposure (mins)
0.35 - 5.0 mg/m3 H,SO, 15
MMD 1 Mm


3-39 mg/m3 H,SO. 10 - 60
MMD 1-1.5 MA


SO. (1-60 ppm) plus Variable
H,0, to form H-SO.
alr&sol ' *
CMO 1.8 and 4.6 Mm
H.SO. mist , 120
(lOOO Mg/m
MMD 0.5 Mm (og = 2.59)
H,SO. aerosol , 10
10, 100, 1000 Mg/m
MMD 0.1 Mm
H,SO. (75 Mg/m3) 120
MMAD 0.48 - 0.81 Mm
H,SO. (0, 100, ,300, 60
Sr 1,000 Mg/m
MMAD 0.5 Mm
(og = 1.9)




H SO. - 240*
100 M9/»
MMD 0.14 Mm
og = 2.9
Number of
subjects
15



Variable



24



10

6 normal
6 asthmatics

6 normal
6 asthmatics
10







2fi normals



Source
Mask (rest)



Mask (rest)
Chamber (rest)


(Rest)



Chamber
(exercise)

Oral


Chamber
(exercise)
Nasal







Chamber
(exercise)


Effects
Respiratory rates increased,
max. insp. and expiratory
flow rates and tidal
decreased volumes
Longer particles due to "wet
mist" resulted in increased
flow resistance cough, rales
bronchoconstri cti on
Airway resistance
increased especially
with larger particles

No pulmonary function
changes but increased
tracheobronchial clearance
No pulmonary function
changes, no alterations
in gas transport
No pulmonary effects
in either group
No pulmonary function
effects
Broncial mucociliary
clearance t following
100 Mg/m ,but * following
1000 M9/m mucociliary
clearance distal to trachea
more affected
No pulmonary function effects



Reference
Amdur et al. , 1952



Sim and Rattle, 1957



Toyama and Nakamura,
1964


Newhouse et al. , 1978

Sachner et al . , 1978


Kleinman and Hackney,
1978; Avol et al., 1979
Lippmann et al. , 1980







Kerr et al., 1981




-------
*
function were  obtained  2 hours into the exposure, immediately following exposure and 2 and 24
hours  post-exposure.    These  measurements  were  compared  with  control   values obtained  at
comparable hours  on  the previous day when the subject breathed only filtered clean air in the
chamber.   No  significant differences  in pulmonary  function  were observed  either  during the
exposure,  immediately after  exposure or 2 and 24 hours post-exposure.
13.6  SUMMARY
     Human experimental  studies of the health effects of exposure to pollutants  in the ambient
environment  require  strict  controls so  that  their findings can be  generalized  to  the entire
population.   Although  no  studies meet all  the requirements  for  strict  control,  some basic
information can be garnered  from  many published studies.
     SOp has  been found to  have  effects on several physiologic functions.   Through subjective
reports, the  reliability of which has been  questioned,  a level  of 5 ppm  has been established
for  detecting S0?, with considerable  variation below  that  level.   Several  sensory processes
are  affected  by  generally  agreed-upon  levels  of concentration of  S0?.   The  odor threshold
averages 0.8  to 1 ppm,  with  0.47 ppm  set in one study performed under ideal conditions.   The
sensitivity  of the eye  to  light  increases  at 0.34 to 0.63 ppm, is maximal at 1.3 to 1.7 ppm,
and  decreases to  normal  by 19.2 mg/m   during dark adaptation.  During  light adaptation, the
figures  increase  and  decrease  similarly  but  at  slightly  higher  levels  of  exposure.  The
                                                           3
alpha-wave has  been found to  be attenuated by 0.9 to 3 mg/m  SOp during 20 seconds of exposure.
     Studies  of the  effects of S0? on the respiratory system of the body  have arrived at con-
flicting  conclusions.    Although  one  study  found  respiratory effects  after exposure to  as
little  as  1  ppm SO,,, others  could find no effect below 5 ppm.  At the latter level, pulmonary
flow  resistance increased 39 percent in one study.  Respiratory effects have been found to be
proportional  to the concentration of  S0? to which study subjects are  exposed.   Although the
bronchoconstrictive  effects  of  exposure  to  SOp  have been  found  to  be  fairly consistent,
subjects vary considerably  in response to exposures,  and there  are some  especially sensitive
subjects,  which may represent  as much  as 10 percent of  the  population.   Recent studies  have
shown  that SR   significantly  increased  in asthmatics at 0.5 and 0.25 ppm S09 and even at 0.1
              ctW                                                             c.
ppm in  some asthmatic subjects.
     Because  SO,,  is  readily water soluble, and nasal passages are high in humidity, the route
of  exposure  will  affect the response  of individuals.   Subjects report  less  throat and chest
irritation when breathing  through the  nose,  and pulmonary flow  resistance  increases less in
subjects who  are  nose  breathing.  Regardless of  the  route of exposure, 5 ppm S02 had  limited
effects  on specific  airway conductance  (airway  bronchoconstriction),  although higher levels
had  a dose-dependent  effect;  that is,  higher concentrations  decreased  SG   more than lesser
                                                                           9W
concentrations.  The average  decrease was greater after oral exposure than after nasal admini-
stration.
     The level  of activity of  the subjects tested affects the results because the actual dose
delivered  to  lungs and  airways  is greater when subjects breathe through their mouth,  as during
exercise.  Just having  subjects breathe deeply through  the mouth significantly affected
XD13A/A                                       13-33                                        2-14-81

-------
specific airway  resistance  during exposure to 1  ppm  S02 in one study, although another study
found no such effect.  Respiratory effects of exposure either by nose or by mouth are greatest
after 5 to 10 minutes of exposure. Recovery takes about 5 minutes in normal subjects, but much
longer (10 to 60 minutes) in sensitive subjects and those who are asthmatic.  Studies of nasal
mucus flow  rates and airway resistance following about 6 hours of exposure to 1 and 5 ppm S0?
per day for 3 days found some effects maximal after 1 to 6 hours.
     An early  study  found mucus clearance reduced increasingly as length and concentration of
exposure to S0?  increased.  Long exposures to 5 ppm S0? increased mucociliary clearance in one
study; a decrease had been found in nasal clearance rates in another study.  Available studies
have not found a significant interaction of smoking with S02.
     The  interaction of  S02  and  particulate  matter is an important factor  in  respiratory
effects studies.   Airway  resistance increased more after combined  exposure to S02 and sodium
chloride than after  exposure to S0? or sodium chloride alone in several studies although others
have  failed to  reach  the same conclusion.   This may have  been due to  formation  of sulfuric
acid mist  during the study.   MEFrQc/ was found to be significantly reduced after exposure to a
combination of  saline  aerosol  to 5 ppm S0?.  After exposure to combined hydrogen peroxide and
0.5  to  5  ppm sulfur dioxide,  airway  resistance  was  found to be significantly increased.   The
combination  of SOp  and ozone  may  have  synergistic effects  on  lung function.  At  low concen-
trations  (0.37  ppm)  S02 had no effect on lung function, ozone impaired lung function, and the
combination  impaired lung function even more.  A similar study did not find the same results.
Other studies  have found reductions in pulmonary function after exposure to low levels of S02
or  ozone  alone  and  in combination, with  no synergistic effect  observed with the combined
exposure.  Japanese  studies involving exposure to 0., alone and a combination of S02 (0.15 ppm)
and 03 (0.15 ppm) have observed a significant enhanced decrease in specific airway conductance
(SGaw) after  exposure  to the combination pollutants compared to the decrease in SGaw in these
subjects  in  07 exposure.   They suggest  that  the  effect is  synergestic and not just additive.
              
-------
*
demonstrated after exposure to sulfuric acid and sulfate salts at concentrations less than 0.1
    3                                              1
mg/m .   However, at higher concentrations (1.0 mg/m ) reduction in specific airway conductance
and  FEV-^ have  been  observed after  H2$04 and  NH.HSO,  exposures.   Mucociliary  clearance was
affected  by exposure to  sulfuric acid,  being  significantly increased  after  exposure  to 100
    3                                                             3
|jm/m   and  significantly  decreased  after exposure  to  1000  ug/m .    Another  study  found no
pulmonary  effect of  exposure  to sulfuric  acid,  ammonium bisulfate,  and  ammonium sulfate by
normal and  asthmatic  subjects.
 XD13A/A                                       13-35                                         2-14-81

-------
*
ADDENDUM
     Recent Abstract
     Schlenker, E. ,  and  M.  Jaeger.   Airway response of young  and elderly subjects to 0.5 ppm
S02 and 0.5 ppm Oj.  Physiologist 23:77, 1980a.
     Ten  elderly  (73 ±7.7 years  of  age) and ten young  (25.5  ± 4 years of  age)  were first
studied (presumably at rest) in a clean air environment and on the succeeding day were exposed
to the combined pollutants for 1 hr.  A follow-up period of 3 hr was made on each day.   No pul-
monary function changes  were observed on  either day  in  the old subjects.   However, the young
subjects  had  a decrease  in MMFR (5.23 to 4.65 L/sec) during the pollutant exposure.  Recovery
to control  levels was  not complete in  these  young  subjects in the following 3 hours in clean
air.
XD13A/A                                      13-36                                        2-14-81

-------
*
13.7  REFERENCES


Abe, M.  Effects of mixed nitrogen dioxide-sulfur  dioxide  on  human  pulmonary functions.   Bull.
     Tokyo Med. Dent. Univ. 14:415-433,  1967.

Amdur, M.  Animal studies.  In:   Proceedings  of  the  Conference  on Health  Effects  of Air Pollut-
     ants, National Academy of Sciences, Washington,  DC, October 3-5,  1973.   Serial  No.  93-15,
     U.S. Senate, Committee on Public Works,  Washington, DC,  1973.   Washington, DC,  1973.   pp.
     175-205.

Amdur, M. 0.  The long  road from  Donora.   1974 Cummings Memorial Lecture.   Am.  Ind.  Hyg.  Assoc.
     J. 35:589-597, 1974.

Amdur, M. 0.  Toxicological appraisal of particulate  matter,  oxides  of sulfur and sulfuric acid.
     J. Air  Pollut. Control Assoc. 19:638-646, 1969.

Amdur, M.  0.,  W.  W. Melvin,  Jr., and P.  Drinker.   Effects of  inhalation of sulfur dioxide by
     man.   Lancet 2:758-759,  1953.

Amdur, M.  0. ,  L.  Silverman,  and  P.  Drinker.   Inhalation  of  sulfuric  acid mist  by  human  sub-
     jects.  Arch.  Ind.  Hyg.  Occup.  Med. 6:305-313,  1952.

Andersen,  I. ,  P.  L. Jensen,  S. E. Reed, J. W. Craig,  D. f. Proctor, and  G.  K.  Adams.   Induced
     rhinovirus  infection under controlled exposure  to sulfur  dioxide.   Arch.  Environ.  Health
     32:120-126, 1977.

Andersen,  I.,  G.  R. Lundqvist, P. L. Jensen, and  D.  F. Proctor.  Human response  to controlled
      levels  of sulfur dioxide.  Arch. Environ. Health 28:31-39, 1974.

Arthur  D.  Little  Incorporated.   Research on Chemical Odors.   Part I.  Determination  of  Odor
     Thresholds  for  53 Commercial  Chemicals.   The Manufacturing   Chemists'   Association,
     Washington, DC, January  1968.

Avol,  E.  L. , M. P.  Jones, R.  M. Bailey,  N. M-N.  Chang, M.  T.  Kleinman, W.  S.  Linn,  K.  A.  Bell,
     and J.  D. Hackney.   Controlled  exposures of human volunteers to sulfate aerosols.   Health
     effects and aerosol  characterization.  Am.  Rev.  Respir.  Dis. 120:319-327,  1979.

Bates, D.  V.,  and M. Hazucha.  The  short-term effects of  ozone on  the lung.   J_n:   Proceedings
     of  the Conference on Health  Effects of Air Pollutants,  National  Academy  of  Sciences,
     Washington,  DC, October 35, 1973.   Serial No.  93-15,  U.S.  Senate  Committee on  Public
     Works,  Washington,  DC, 1973.  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,  K.  A., and J. D.  Hackney.   Effects of Sulfate Aerosols  upon Human  Pulmonary Function.
     Coordinating Research Council,  Inc.   APRAC  Project CA PM-27-75, 1977.

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.
     Am. Ind. Hyg.  Assoc. J.  38:696-706, 1977.

Burton,  G.  G. , M.  Corn, J.  B.  L.  Gee, D. Vassallo,  and  A.  Thomas.   Absence  of "synergistic
     response"  to  inhaled  low  concentration gas-aerosol mixtures  in  healthy  adult  males.
     Presented at 9th Annual  Air  Pollution Medical Research Conference, Denver, Colorado, July
     1968.


XD13A/A                                       13-37                                        2-14-81

-------
Burton, G. G. ,  M.  Corn, J.  B.  L.  Gee, C. Vasallo, and A.  P. Thomas.   Response  of  healthy men
     to inhaled low concentrations of  gas-aerosol mixtures.  Arch.  Environ.  Health  18:681-692,
     1969.                                                                          "~

Bushtueva, K. A.   New studies of the  effect of  sulfur dioxide and  of  sulfuric acid aerosol  on
     reflex  activity  of man.  Jji:  Limits of  Allowable  Concentrations of Atmospheric  Pollut-
     ants.   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  S0?  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.   lr\:   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  S09  on  respiratory  mechanics in healthy  male adults.    J.  Appl.  Physiol.
     17:252-258, 196?.

Frank,  R. ,  C.  E.   McJilton, and  R.   J.  Charlson.   Sulfur  oxides  and particles;  effects  on
     pulmonary  physiology  in man  and  animals.  I_n:   Proceedings  of  Conference  on  Health
     Effects  of Air  Pollution.   National Academy  of  Sciences,  Washington,  DC, October  3-5,
     1973.   Serial  No.  93-15,  U.S.  Senate,  Committee on  Public  Works,  Washington,  DC, 1973.
     pp.  207-225.

Gokenmeijer,  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, 1973.

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-Sulfonates in  human plasma  following  inhalation  of
     sulfur  dioxide.   Am.  Ind. Hyg. Assoc. J. 35:288-291, 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.
     Bureau  of  Mines  Bulletin  98,  U.S.  Department of  the Interior,  Washington,  DC,  1915.

XD13A/A                                      13-38                                         2-14-81

-------
*
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, March 1977.

Islam, M. S. , and W. T. Ulmer.  The effects  of  long-time  exposure  (8  h  per day  on  4 successive
     days) to a gas mixture of SO, + N02 + and  03  in the  threefold MIC  range (maximum emission
     concentration) on  lung function ana reactivity of  the bronchial  system  of  healthy persons.
     Wissenschaft und  Unwelt 4:186-190, 1979 (b).

Islam,  M.  S. ,  and W.   T.  Ulmer.   The influence of  acute  exposure  against a  combination of 5.0
     ppm SO,,,  5.0 ppm N0?, and 0.1 ppm 0, on the  lung  function  in the  MAK (lower  toxic limit)
     area (Ihort-time  test).  Wissenschaft und  Unwelt 3:131-137, 1979(a).

Jaeger, M. J., D. Tribble,  and H. J. Wittig.  Effect of 0.5  ppm  sulfur  dioxide  on  the respira-
     tory function  of  normal and asthmatic subjects.  Lung 156:119-127,  1979.

Kagawa, J.,  and K.  Tsuru.   Respiratory effect of 2-hour exposure with intermittent exercise to
     ozone  and  sulfur dioxide  alone and  in combination in  normal  subjects.   Jap. J.  Hyg.
     34:690-696,  1979.

Kerr,  H.  D. ,  T.  J. Kulle, B.  P.  Parrel 1,  L.  R.  Sauder, J. L.  Young,  D.  L Swift,  and  R.  M.
     Borushok.   Effects  of sulfuric  acid  aerosol on  pulmonary  function  in human  subjects.
     Environmental  Research, 1981 (in press).

Kisskalt,  K.  Uber den Einfluss der  inhalation schwelfiger  Saure  auf die  Entevickelung der
     Lungentuberculose:   Ein  Bietrag zum Studien  der Gewerbekrankheiten.  Z. Hyg.  48:269-279,
     1904.

Kleinman, M. T.,  and J. D.  Hackney.  Effects of sulfate aerosols upon human  pulmonary function.
     APRAE  Project  CAPM-27-75, Coordinating  Research Council,  Inc., New York, NY,  1978.

Kleinman,  M. T.,  R. M. Bailey,  Y.  C.  Chang, K. W.  Clark,  M.  P.  Jones, W.  S.  Linn,  and J.  D.
     Hackney.   Exposures  of  human  volunteers  to  a controlled  atmospheric  mixture  os  ozone,
     sulfur  dioxide and sulfuric acid.  Am.  Indus.  Hyg. Assoc. J.  42:61-69,  1981.

Koenig,  J.  Q. , W.  E.   Pierson,  and  R.  Frank.   Acute effects of  inhaled SO,,  plus  NaCl droplet
     aerosol on  pulmonary function in asthmatic adolescents.  Environ.  Res.  22:145-153, 1980.

Koenig,  J.   Q.  ,  W.  E.   Pierson,  M.  Horike,  and R. Frank.   Effects   of  S0?  plus  NaCl  aerosol
     combined  with  moderate exercise on pulmonary  function in  asthmatic adolescents.   Environ.
     Res.,  1981  (in press).

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.

Lawther,  P.  J.   Effects  of inhalation  of  sulfur  dioxide   on respiration  and 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.

Lehmann,  K.  B.   Experimentelle  Studien Uber den  Einfluss  technisch und hygienisch  wichtiger
     Gase  und  Dampfe  auf  den  Organismus.   VI.   Schwefliger Saure.   Arch. Hyg.  18:180-191,
     1893.
XD13A/A                                       13-39                                        2-14-81

-------
Lippman, M. ,  R.  E.  Albert, D.  B.  Yeats,  K.  Wales,  and  G.  Leikauf.   "Effect of  sulfuric acid
     mist on  mucociliary bronchial clearance  in  healthy  non-smoking  humans."   J.  Aerosol Sci.
     In Press, 1980.

Lunn, no data, cited on  p. 13-47.

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 S02-   West Indian  Med. J.  19:231-235, 1970.

Morgan,  M.  S. , J. Koenig, D.  S.  Covert,  and  R.  Frank.   Acute  effects  of  inhaled S02  combined
     with   hygroscopic   aerosol   in  healthy   man.    Amer.   Rev.   Respir.  Dis.   115:	-231.
     (Abstract).

Nadel,  J. ,   H.  Salem,  B. Tamplin,  and Y.  Tokiwa.   Mechanism  of  bronchoconstriction  during
     inhalation of sulfur dioxide.  J. Appl. Physiol. 20:164-167, 1965.

Nakamura,  K.   Response  of pulmonary airway resistance by interaction of aerosols and  gases  in
     different physical  and chemical nature.   Nippon Eiseigaku  Zasshi 19:38-50, 1964.

Newhouse, M.  T. ,  M.  Dolovich, G.  Obminski,  and R.   K. Wolff.   Effect of TLV levels of SC>2 and
     FLSO.  on bronchial  clearance in exercising man.   Arch.  Environ.  Health 33:24-32,  1978.

Ogata,  M.   Uber die Giftigkeit der schweffigen Sa'ure.  Arch. Hyg. 2:223-245, 1884.

Reichel, G.   The effect  of sulfur dioxide on  the airway  resistance  of  man.  Annual  Meeting  of
     the German Society  for Industrial Medicine,  1972.

Ryazanov, V.  A.   Sensory physiology as basis for  air quality standards.  Arch.  Environ.  Health
     5:479-494, 1962.

Sackner, M. A.,  D.  Ford, R.  Fernandez,  J. Cipley, D.   Perez,  M. Kwocka,  M.  Reinhart,   E.  D.
     Michaelson,   R.   Schreck,   and   A.   Wanner.    Effects  of  sulfuric  acid   aerosol   on
     cardiopulmonary  function of dogs, sheep  and humans.  Am.  Rev.  Respir. Dis.   118:497-510,
     1978.

Saibene,  F. ,  P.   Magnoni,  C.  L.  Lafortuna,  and  R.   Mostardi.   Oronasal  breathing  during
     exercise.  Pfluegers Arch.  378:65-69, 1978.

Schlesinger,   R.  B. ,  M.  Lippmann, and  R.  E. Albert.   Effects  of short-term  exposures  to
     sulfuric  acid and ammonium  sulfate aerosols  upon bronchial  airway  function in the donkey.
     Am. Ind.  Hyg. Assoc. J.  39:275-286, 1978.

Schlesinger,  R.  B. ,  M.   Halpern, R. E.  Albert, and  M. Lippmann.   Effect of chronic inhalation
     of  sulfuric  acid mist upon mucociliary clearance from  the lungs  of donkeys.   J.  Environ.
     Pathol.  Toxicol. 2:1351-1367,  1979.

Shalamberidze, 0. P.  Reflex  effects of mixtures  of  sulfur and  nitrogen dioxides.   Hyg.  Sanit.
     32:10-15, 1967.

Sheppard, D. ,  W.  S.  Wong, C.  F.  Uehara,  J.  A. Nadel, and H.  A.  Boushey.   Lower  threshold and
     greater  bronchomotor responsiveness  of   asthmatic  subjects to  sulfur dioxide.   Am.  Rev.
     Respir. Dis. 122:873-878, 1980.

XD13A/A                                      13-40                                         2-14-81

-------
Sheppard, D. ,  A.  Saisho, J. A.  Nadel,  and H. A.  Boushey.   Exercise increases sulfur dioxide-
     induced  bronchoconstriction in  asthmatic subjects.  Am.  Rev.  Resp.  Dis., May,  1981 (in
     press).

Sim, V.  M. ,  and R. E.  Rattle.   Effect of possible  smog irritants on human  subjects.   J. Am.
     Med. Assoc. 165:1908-1913,  1957.

Snell,  R.  E. , and P.  C.  Luchsinger.   Effects of  sulfur dioxide  on expiratory flow  rates and
     total respiratory  resistance in  normal  human  subjects.   Arch.  Environ.  Health 18:693-698,
     1969.                                                                          ~~

Speizer,  F.  E. , and N.  R. Frank.  A comparison of  changes in pulmonary flow  resistance in health
     volunteers  acutely  exposed to  SO,  by  mouth  and  by nose.   Br.  J.  Ind. Med.  23:75-79,
     1966a.                             <•

Speizer,  F.   E. ,  and  N.  R.  Frank.   The  uptake  and release  of SO, by  the human  nose.   Arch.
     Environ.  Health  12:725-728, 1966b.                            ^

Tomono,  Y.   Effects of  S0»  on  human pulmonary functions.   Sangyo  Igaku 3:77-85, 1961.

Toyama,  T.   Studies on  aerosols.  Synergistic response of the pulmonary  airway  resistance of
     inhaling sodium  chloride  aerosols  and S0? in  man.   Sangyo  Igaku 4:86-92,  1962.

Toyama,  T. ,   and  K.  Nakamura.   Synergistic  response to hydrogen  perixide aerosols and  sulfur
     dioxide  to pulmonary airway resistance.   Ind.  Health 2:34-45,  1964.

Ulmer,  W. T.   Inhalative noxen:  schwefeldioxyd.   Pneumonologie 150:83-96, 1974.

Utell,  M.  J.  , P.   E.  Morrow, and R. W.  Hyde.   Inhaled  Particles.   V.  Pergamon Press,  1981 (in
     press).

von  Nieding,  G. ,  H. M.  Wagner,  H. Krekeler,  H.  Lb'llgen, W.  Fries,  and A.  Beuthan.  Controlled
     studies  of human exposure  to single  and combined  action of  N09, 07  and S09.  Int.  Arch.
     Occup.  Environ.  Health 43:195-210, 1979.                        £    J       *

Weir,  F.  W. , and  P.  A.  Bromberg.   Further investigation  of  the  effects of sulfur dioxide on
     human  subjects.    Annual  Report  Project No.  CAWC  S-15,  American  Petroleum Institute,
     Washington, DC,  1972.

Weir,  F.  W. , and  P.  A. Bromberg.   Effects  of sulfur dioxide on  human subjects exhibiting
     peripheral  airway   impairment.    Project No.  CAWC  S-15,  American  Petroleum Institute,
     September 1973.    pp.  1-18.

Wolff,  R.  K.  , M.   Dolovich, C.  M.  Rossman, and M.  T.  Newhouse.   Sulphur dioxide  and  tracheo-
     bronchial  clearance in man.  Arch. Environ. Health 30:521-527,  1975a.

Wolff,  R. K.,  M.  Dolovich, G.  Obminski, and M.  T.  Newhouse.   Effect of  sulfur dioxide on
     trachiobronchial  clearance at rest  and during exercise.  Inhaled  Particles,  Proceedings
     of the  4th  International  Symposium, Edinburgh,  Scotland,  September 22-26,   1975.   W.  H.
     Walton,  ed.,  Pergamon  Press, London,  England,  1975b.  pp.  321-332.

Yamada,  J.    Untersuchunger iiber die quantitative  Absorption der Dampfe einiger  Sauren  durch
     Tier und Mensch.   Dissertation,  Wiirzburg,   1905.  (See   Lehmann,  K.   B. ,  Arch.   Hyg.
     67:57-98,  1908.)
XD13A/A                                       13-41                                         2-14-81

-------
                      14.   EPIDEMIOLOGICAL STUDIES ON THE EFFECTS OF SULFUR
                          OXIDES AND PARTICULATE MATTER ON HUMAN HEALTH

14.1 INTRODUCTION
     This chapter  evaluates epidemiological  literature  concerning health  effects associated
with ambient  air exposures  to  sulfur oxides  and particulate matter.   The main  focus  of the
chapter  is  on:   (1)  the qualitative characterization of  human  health  effects associated with
exposure to atmospheric  sulfur  dioxide (S0?), related sulfur compounds, and other particulate
matter  (PM);  (2) quantitative delineation of  exposure/effect and  exposure/response relation-
ships for the induction of such health effects; and (3) the identification of population groups
at special risk  for experiencing the health effects at ambient exposure levels.
     The epidemiological  data discussed  here both complement and extend information presented
as part of health effects analyses contained in preceding chapters (11,12,13) of this document.
Those  chapters  focus on  information derived from  animal  toxicology  and controlled  human
exposure studies which offer the advantage of characterizing, under well-controlled laboratory
conditions, differential patterns of respiratory tract deposition and clearance of:  S02; sul-
fates (SO.) and  sulfuric acid (H?SO.); and other particulate matter of  varying size and chemi-
cal  composition.   In  addition,  the animal toxicological  studies provide  evidence for notable
health effects occurring in mammalian species as the result of such respiratory tract deposition
of  sulfur  oxides  and  particulate  matter,  including:   transient  alterations  in  pulmonary
functions;  altered mucociliary  clearance  and other respiratory tract  defense  mechanisms; and
increased susceptibility to infection and morphological damage seen especially after high level
or prolonged exposures.   However, while such results from animal studies are highly suggestive
of  analogous  effects possibly  being induced  in  human beings,  caution must be  exercised in
directly extrapolating  the  findings or associated dose-effect  relationships  to human health.
More direct delineation of quantitative dose-effect or dose-response relationships is possible
through  controlled human  exposure studies, but such  studies  also  have important limitations.
For  example,  whereas  controlled human exposure studies have  demonstrated S0? or PM induction
of  transient  pulmonary  function decrements, altered mucociliary clearance patterns, and symp-
tomatic  effects  consistent  with animal toxicology study findings,  observation of such effects
has  generally been confined to  conditions  involving  single or a  few  repeated  short-term (<3
hrs)  exposures  but not prolonged chronic exposure conditions.   Also  left  unanswered by con-
trolled  human exposure studies  are questions concerning whether  or not  more  severe effects,
e.g.,  increased vulnerability  to  respiratory diseases  or  marked morphological  damage, are
associated with  either short-term or prolonged ambient exposure conditions.
     Epidemiological   studies,  in contrast,  offer several advantages  beyond those  of animal
toxicology  or controlled  human  exposure  studies.   Health effects of both short- and long-term
pollutant exposures  (including  complex mixtures  of pollutants) can be studied and sensitive
members  of  populations  at  special  risk  for particular effects  at ambient  air concentrations

SOX14G/A                                   14-1                                         2-14-81

-------
identified.    Also,  epidemiological  evaluations  allow  for  investigation  of  both  acute  and
chronic  disease  effects   and  associated  human  mortality.    Epidemiological   studies,  then,
together with the results of controlled animal and human exposure studies,  can significantly con-
tribute to more complete understanding of health effects of sulfur oxides and particulate matter,
especially  in  helping to  characterize human health effects associated  with  those pollutants
under ambient conditions.   Despite such advantages, however, important limitations do exist in
regard  to  the conduct, analyses,  interpretation,  and  use of many of  the  available epidemio-
logical studies on the health impact of S0? and PM, as discussed next.
14.1.1  Methodological Considerations
     As  noted by  Lowrence  (1976),  epidemiological  and  other  types  of studies  employed  in
generating  information  relevant  to human risk assessment typically  divide  into four lines of
investigation.  These involve making measurements aimed at:   (1) defining exposure conditions;
(2) identifying adverse effects; (3) relating exposures to effects; and (4) estimating overall
risk.
     In relation to accomplishing  these goals, one important limitation of  most of the epidemi-
ological  studies  reviewed  here  has been less-than-optimum characterization  of community  air
quality parameters used to estimate exposures of population groups to varying atmospheric con-
centrations of sulfur oxides and particulate matter.  Such characterization of air quality  has
generally  involved relatively crude  estimates  of levels of pollutants  present,  allowing  for
only  limited  qualitative  statements to be made  regarding exposure  conditions--e.g.  whether a
given  site  or time period had comparatively  higher  or  lower atmospheric levels of  SOp  or PM
than some other site or time period.   Only very rarely have the epidemiological studies relied
on  measurement  methods  or practical  field  applications   of  those  methods  that  permitted
reasonably  precise determinations  of variations in airborne levels of the pollutants of concern
so  as  to provide quantitative information on S0? or PM levels associated with observed health
effects.  Even when reasonable quantification of community air quality parameters was achieved,
however,  the  use  of  such data  in estimating actual population  exposures  has typically been
further constrained by factors such as siting of air sampling devices in relation to the study
population, frequency  and duration of sampling periods, activity patterns  of study population
members,  and  contributions  of  indoor air  pollution  to overall  exposures of  study groups.
These,  and  other limitations noted, arise in part from the fact that most  of the presently-
reviewed  epidemiological  studies utilized air quality monitoring data  obtained from sampling
networks originally established  for purposes other than health-related research and, therefore,
not  optimally designed to provide the  specific  types or quality of  aerometric data ideally
needed  for  epidemiological  assessment of health  effects  related to  SCL  and  PM.   Thus,  the
aerometric  data utilized thus far  should generally be viewed as yielding, at best, only approx-
imate estimates of actual  study  population exposures.
     Adequate  characterization  of health effects  associated  with  various  S0? and  PM expo-
sure  conditions  has  represented  a  second  major  type  of problem for  many  of  the epidemio-
logical  studies  evaluated in the  present chapter.   A  variety  of health endpoint measurements

SOX14G/A                                   14-2                                         2-14-81

-------
(mortality, morbidity, and  indirect measures of morbidity) have been employed in such studies
and each have their own advantages and disadvantages, as has been discussed in detail in other
reviews (Hill, 1968; Speizer, 1969; Holland, 1970; Goldsmith and Friberg, 1977; Higgins, 1974;
Shy et al., 1978; NRC/NAS, 1978a; NRC/NAS, 1978b; Ferris, 1978; ATS, 1978; Macklen and Permutt,
1979; Fox  et  al.,  1979).   Some  health outcome  measurements  have involved more or less direct
observations of signs and symptoms of disease states or objective indicators typically closely
associated with  the occurrence  of illnesses, e.g.,  patient  visits  to hospitals or clinics or
absenteeism  from school  or  work.   Direct quantification of health effects  has  also included
measurement of  biochemical  or physiological changes in study populations, as in the recording
of  pulmonary  function changes  by spirometry methods.  Indirect measures  or  indices  of health
effects  have also  been  used,  e.g., in  gathering  information  on  frequency and  duration of
respiratory  illnesses by  means  of telephone  interviews,  written  questionnaires,  or  self-
reported  entries in  diaries.   The  validity of such indirect  measurements  of  health effects,
however,  is heavily dependent on  the ability and motivation of respondents to recall  accurately
and  report past or  present health-related events; and this can  be markedly  influenced by
numerous  extraneous factors  such  as age, cultural and educational background, instructions from
experimenters, sequencing of questions, and problems with interviewer variability and/or bias.
Confidence in the results obtained by either direct or indirect measurement methods is greatly
enhanced  if possible  interfering  or biasing factors have been appropriately controlled for and,
especially for  indirect  health  endpoint measurements,  if results have  been validated against
corroborating evidence  such  as  physician or hospital records verifying reported health effect
occurrences.
     Adequately  relating  observed  health  effects to specific parameters  of ambient exposure
conditions  is another objective that has  been very difficult  to  achieve by epidemiological
studies  reviewed below,  such that  relatively  few allow for confident  qualitative  or quanti-
tative  characterization of  S0?  or PM exposure/health effect relationships.  For example, com-
peting  risks, such  as cigarette  smoking and occupational exposures,  may contribute to observed
health  effects  results  and,  therefore usually must be controlled for or taken into account in
order for much confidence to be  placed in reported health effects/air pollution relationships;
however,  numerous  studies on  SO* or  PM  effects have  failed  to control  adequately for such
factors.   Similarly,  the possible  effects  of  other covarying or confounding  factors  such as
socioeconomic status, race,  and  meteorological  parameters have not always been adequately con-
trolled  for  or  evaluated  in relation to study results.   Also, further complicating the evalu-
ation  of the epidemiological  data is the  fact  that exposure parameters  are  not subject to
experimenter  control, with  ambient levels of a  given pollutant  often widely varying over the
course  of a  study.   This has  made it extremely difficult to determine  whether mean concen-
trations,  peak  concentrations,  rapid fluctuations in levels, or other air quality factors are
most  important   as  determinants  of the  reported health  effects.    In  addition,  significant
covariation  between concentrations of  S0?, PM,  and other pollutants  has  often made it very


SOX14G/A                                   14-3                                         2-14-81

-------
difficult  to  distinguish  among their  relative  contributions  to  the health  effects  demon-
strated.
     Estimation of  overall  risk by means of epidemiology studies requires still further steps
beyond  the  delineation of  exposure/effect  relationships  that  define  exposure  conditions
(levels,  durations,  etc.)  associated  with the induction of specific health effects.   That is,
estimation  of risk  also  requires:   (1)  the  identification  of particular population  groups
likely to  manifest  the health effects under  exposure  conditions  of concern;  and (2) ideally,
the  determination of  numbers  or percentages  of  such  individuals  (responders) likely to  be
affected at various exposure or dose levels.   Delineation of the first variable, i.e.,  identi-
fication of  population groups  at special risk  for  being  affected at lower exposure  levels of
SOp  and  PM than  other groups,  has  to  some  extent been accomplished through various  epidemio-
logical  studies  reviewed  here.  However,  epidemiological definition  of  precise quantitative
dose/response (or,  more  correctly,  exposure/response) relationships, which define percentages
of population groups  likely to manifest a given  health effect  at various levels or  durations
of exposure  to  SO^  and PM, has  been  extremely difficult to achieve and is largely lacking at
this time.
     Another  limitation  of the epidemiological information reviewed here  concerns its  useful-
ness  in  demonstrating  cause/effect  relationships  versus  merely  establishing  associations
between  various  health effects and S02 or PM (which may be non-causal in  nature).   The  inter-
pretation  of epidemiological data as an aid in inferring causal  relationships  between presumed
causal agents and  associated  effects  has been  the subject  of discussion by  several  expert
committees  or deliberative bodies  faced with  evaluation  of controversial biomedical  issues
during  the past  several  decades (U.S.  Surgeon General's Advisory  Committee on  Smoking  and
Health,  1964; U.S.  Senate  Committee on Public Works, Subcommittee on Air  and  Water Pollution,
1968).   Among the criteria selected by each group for determination of causality were  many of
those  advocated  by  A.  B.  Hill  (1965), which  included the following:  (1) the strength  of the
association;  (2)  the consistency of the association, as evidenced by its  repeated observation
by  different persons,  in  different places,  circumstances and time;  (3) specificity  of  the
association;  (4) the  temporal  relationship  of  the association;  (5) the  coherence   of  the
association  in  being  consistent with other  known  facts; (6)  the existence  of  a biological
gradient,  or dose-reponse  curve, as revealed by the association; and (7) the biological  plausi-
bility  of the  association.   Hill  further  noted that  strong  support  for  likely  causality
suggested  by an  association  may be derived  from experimental  or semi-experimental  evidence,
where  manipulation  of  the presumed causative agent (its  presense  or  absence,  variability in
intensity, etc.) also  affects  the frequency or intensity of the associated effects.
     It  is important to note that Hill (1965) and the deliberative bodies  or expert committees
alluded  to above were  careful  to emphasize, regardless of the specific set of criteria selected
by each,  that no one  criterion was definitive by itself nor was it  necessary that all  be ful-
filled in  order to support a determination of causality.  Also,  Hill and several of the groups
noted  that statistical methods cannot establish proof  of a causal  relationship in an associ-

SOX14G/A                                   14-4                                         2-14-81

-------
ation nor does  lack of "statistical significance"  of  an association according to arbitrarily
selected probability  criteria necessarily  negate the  possibility  of a  causal  relationship.
That  is,  as  stated  by  the  U.S.   Surgeon  Genera]  Advisory  Committee  on  Smoking  and Health
(1964):   "The causal  significance  of an association is a matter of judgment which goes beyond
any  statement  of  statistical  probability."  Statistical  findings,  nevertheless,  as  well  as
other types  of  observational  and   experimental  information,  are useful  inputs  in helping to
determine likely causal relationships.
14.1.2  Guidelines  for Assessment of Epidemiological Studies
     Taking  into account  the  above methodological  limitations, it appears  to  be  possible to
delineate a  reasonable set of guidelines by which to judge the relative scientific quality of
epidemiological  studies  and their   findings reviewed in  the  present chapter.  Such assessment
guidelines include  consideration of the following questions:
     1.   Was the  quality  of the aerometric data used sufficient to allow for meaningful
          characterization  of geographic or temporal differences in study population pol-
          lutant exposures?
     2.   Were  the study populations well-defined and adequately selected so as to allow
          for meaningful comparisons between study groups or meaningful temporal analyses
          of health effects results?
     3.   Were  the health  endpoint measurements meaningful and reliable, including clear
          definition  of diagnostic criteria utilized  and  consistency in  obtaining de-
          pendent  variable  measurements?
     4.   Were  the statistical analyses employed appropriate  and  properly  performed and
          interpreted,  including accurate  data handling and transfer at various steps of
          analyses?
     5.   Were  potentially confounding  or covarying factors adequately controlled for or
          taken  into  account  in the study design and statistical analyses?
     6.   Are  the  reported  findings  internally consistent,  biologically  plausible, and
          coherent in terms of being consistent with other known facts?
     It  is  recognized that few, if any,  epidemiological studies deal with  each  of  the above
points  in  a completely  ideal fashion;  nevertheless,  these  guidelines  provide benchmarks by
which  to judge  the  relative quality of various  studies and by which to select  the best for
detailed discussion here.
     Detailed  critical analysis of the vast number of  epidemiological  studies  on the health
effects  of  SCL  and PM, especially  in relation to each of the above questions, would represent
an  undertaking  beyond the  scope or purpose of the present  document.  Of  most importance for
present  purposes are  those studies which provide useful quantitative information on exposure/
effect  or exposure/response  relationships  for health  effects associated with  ambient air
levels  of SCL  and PM likely to  be encountered  in  the United  States  over  the  next 5-year
period.  Accordingly, the  following criteria were  employed  in selecting studies for  detailed
discussion in the  ensuing  text:
     1.   Concentrations  of  both   S0?   and PM  were  reported,  allowing  for potential
          evaluation  of their  separate  or combined effects.
SOX14G/A                                    14-5                                         2-14-81

-------
     2.    Study results provide  information  on quantitative relationships between health
          effects and ambient  air S02 and PM levels of approximately 1000 (jg/m  or less.
     3.    Important methodological  considerations were  adequately  addressed,  especially
          (a)  in  controlling  for  likely  potentially  confounding  factors  and  (b)  in
          carrying  out  data collection,  analysis,  and  interpretation so  as  to minimize
          errors  or potential  biases  which  could be  reasonably expected  to  affect the
          results.
     4.    The  study results have been  reported  in  the open literature or  are  in press,
          typically after having undergone peer review.
     In addition,  some  studies not meeting all  of the above criteria are either briefly men-
tioned or discussed in the main chapter text below as appropriate in helping to elucidate par-
ticular points  concerning  the  health  effects of S02 and/or PM.   Additional studies,  including
those mainly providing only qualitative information on S0? and PM health effects are concisely
discussed in Appendices A and B.
     As a starting  point  in the present  assessment,  important  information discussed in Chap-
ters 2 and 3 is summarized with regard to physical and chemical  properties of S0? and particu-
late  matter indexed  by air  quality  measurements employed  in  community  health epidemiology
studies evaluated in this chapter.  The ensuing discussion of community health studies is then
subdivided  into  two main  subsections:  Section 14.3 deals with  studies of acute mortality and
morbidity  effects  most  germane  to  development  of  health  criteria for  possible short-term
(e.g., 24 hr)  ambient air standards;  and Section 14.4 discusses studies of mortality and mor-
bidity effects associated with chronic exposures most pertinent  for development of health cri-
teria  for  long-term  (annual-average)  ambient  air standards.  The last major  chapter section
(14.5) attempts to  provide an integrative summarization and interpretation of the overall pat-
tern of results evaluated in the preceding sections.
     The extensive  presently available  epidemiological  literature on the  effects of occupa-
tional exposures to S0? and PM is not reviewed here for several  reasons:
       1.    Such  literature  generally deals  with the effects of exposures to S0? or PM
            chemical  species at  levels many-fold higher than those  encountered in the
            ambient air by the general population.
       2.    Populations exposed  occupationally  mainly  include  healthy  adults, self-
            selected to some extent in terms of being better able to tolerate exposures
            to  S02  or PM  substances than more  susceptible  workers  seeking alternative
            employment or  other  groups often at  special  risk among  the general public
            (e.g.,  the old,   the  chronically  ill,  young  children, and  asthmatics).
       3.    Extrapolation  of observed  occupational  exposure/health  effects  relation-
            ships (or lack thereof) to the general public (especially population groups
            at  special  risk) could,  therefore,  be potentially misleading  in  terms  of
            demonstrating  health  effects among healthy  workers  at  higher  exposure
            levels  than  would  affect  susceptible  groups  in  the  general  population.

The  occupational   literature  does,  however,  demonstrate  well  links  between  acute  high
level or  chronic lower  level  exposures  to  SCL  or  many different  PM chemical  species and a
variety of health effects, including:   pulmonary function changes; respiratory tract diseases,

SOX14G/A                                   14-6                                          2-14-81

-------
morphological damage  to  the respiratory system; and, especially in the case of silica-related
compounds, certain heavy metals and organic PM species, induction of respiratory tract cancers
or  many  other types  of  carcinogenic  and noncarcinogenic effects.   The  reader  is  referred to
National  Institute of  Occupational  Safety  and Health  (NIOSH)  criteria documents  and other
pertinent  reviews and  assessments  listed  in  Appendix C  for  information on  health effects
associated with  occupational  airborne exposures to S0? and various PM species and recommended
or  implemented  occupational  hygiene guidelines or standards  aimed  at  protecting workers from
such effects.
14.2  AIR QUALITY MEASUREMENTS
     Of  key  importance  for the evaluation of epidemiological studies reviewed here is a clear
understanding  of the physical  and chemical  properties  of S0? and PM  indexed  by  measurement
methods  employed  historically  in  collecting  ambient air  aerometric  data utilized  in those
studies.   Such  information on relevant  air quality  measurement  methods  and their limitations
is  concisely summarized  below  as  background  for  the critical  evaluation  of epidemiological
studies  that  follow.  See  Chapters  2  and 3 for more detailed discussion of measurement methods
and related  information  on physical and  chemical properties of S0?.
14.2.1   Sulfur Oxides Measurements
     Three  main measurement  methods  or variations  thereof have been  employed in generating
data  cited for  sulfur  dioxide  (S0?)  levels in epidemiological  studies  discussed  below:   (1)
sulfation  rate  (lead dioxide)  methods;  (2)  hydrogen peroxide measurements and  (3)  the West-
Gaeke  (pararosanaline) method.
     Sulfation rate methods involve reaction of airborne sulfur compounds with lead dioxide in
a paste  spread over an atmospherically-exposed plate or cylinder.  Rates of reaction of sulfur
                                                                2
compounds  with  surface  paste compounds  are expressed  in  SO^/cm /day.   However, the reactions
are not  specific for  S0?,  and atmospheric concentrations of S0? or other sulfur compounds can-
not be  accurately extrapolated from  the results,  which  are markedly affected by factors such
as  temperature and humidity.  Lead  dioxide gauges were widely used in the United Kingdom prior
to  1960 and  provided aerometric data  reported for  SO™  in some pre~1960s  British epidemio-
 logical  studies;  sulfation rate methods were also used in certain American studies.
     Use of  the hydrogen peroxide  method was  gradually  expanded in the United Kingdom during
the 1950s,  often being coupled in  tandem with apparatus for particulate matter (smoke) moni-
toring.   The  hydrogen  peroxide method  was  adopted  in  the early  1960s  as the  standard S0?
method  used  in the National  Survey of  Air  Pollution throughout the United Kingdom and, as an
OECD-recommended method,  elsewhere  in Europe.   The  method can  yield  reasonably  accurate
estimates  of  atmospheric  S02  concentrations  expressed in  (jg/rn ;  but results  obtained with
routine  ambient air  monitoring  can  be  affected  by  factors  such as  temperature,  presence of
atmospheric ammonia and  titration errors.  Very little quality assurance information exists on
sources  and  magnitudes  of  errors  encountered  in  use  of the  method  in obtaining  S0? data
reported in specific  British or other European epidemiological studies, making it difficult to
assess  the accuracy  and precision of  reported  S0~  values.  Only in the  case  of  the  British

SOX14G/A                                  14-7                                         2-14-81

-------
National Survey has extensive quality assurance information been reported (Warren Spring Labora-
tory, 1961; 1962; 1966; 1967; 1975; 1977; OECD, 1964; Ellison, 1968) for S02 measurements made
in the United Kingdom and used in various British epidemiological studies.
     The West-Gaeke (pararosanaline) method has been more widely employed in the United States
for measurement  of  SCL.   The method involves absorption of S0? in potassium tetrachloromercu-
rate (TCM)  solution,  producing  a chemical complex  reacted  with  pararosanaline to form a red-
purple  color  measured colorimetrically.  The  method,  suitable  for sampling up to  24 hrs,  is
specific for SCL if properly implemented to minimize interference by nitrogen or metal oxides,
but  results can  be  affected  by factors  such as  temperature  variations  and  mishandling  of
reagents.   Only limited  quality assurance  information (Congressional  Investigative Report,
1976) has been reported for some American S0? measurements by the West-Gaeke methods.
     Measurement approaches for  suspended  sulfates  and  sulfuric  acid,  used mainly  in  the
United  States,  include   turbidimetric  and  methylthymol  blue   methods.  The  former  usually
involves collection of  samples  on sulfate-free glass fiber filters by means of high-volume PM
samplers.   Sulfate  is extracted  and precipitated with barium chloride, and turbidity  of  the
suspension  is  determined  spectrofluorometrically.   However, the method does not differentiate
between  sulfates and  sulfuric  acid, and secondary  formation  of  such  products  from SO- in  air
drawn through the filter can affect estimation of atmospheric sulfate  levels.   Similar collec-
tion procedures  and limitations  apply  for the methylthymol  blue method,  which involves reac-
tion of  extracted  sulfate with barium chloride and complexing of the  latter with methylthymol
blue.   Inability to differentiate between sulfates and  sulfuric  acid  limit these two methods
as specific measures of suspended sulfates, but their results can serve as  rough indicators of
atmospheric levels of sulfur-oxide related PM.
14.2.2   Particulate Matter Measurements
     To  be of maximum value, epidemiological  studies  on PM effects must  utilize  air quality
measurement  methods that provide  meaningful  data,  not  only regarding the mass  or amount of
atmospheric  PM,  but also  quantitative  information related to size and chemical composition of
particles  present.   In actual  practice,  however, most  epidemiological studies  on  PM effects
have  relied on  air  quality data  from air  monitoring  instruments of  questionable  sampling
accuracy and  not specifically  designed for  health-related  research.   The  resulting data thus
typically  only  provide  limited  information regarding mass, size or chemical properties of the
PM sampled.
     Three  main measurement  approaches  or  variations  thereof  were  used  to  obtain  PM data
reported in  epidemiological  studies reviewed below:  (1) the British Smokeshade light reflec-
tance method  or variations  used  in the United Kingdom and elsewhere in Europe; (2) the Ameri-
can  Society for Testing  and Materials  (ASTM) filter soiling method based  on  light transmit-
tance  and   used  in the United  States;  and  (3)  the high-volume sampling method  most widely
employed in the United States.
     As  discussed  in  Chapter 3,  the British  Smoke (BS) method and close  variations  of it in
routine  use  have typically  employed standardized monitoring equipment with a D™ cut-point of

SOX14G/A                                   14-8                                         2-14-81

-------
= 4.5  urn at  KPH (McFarland,  1979).   Thus,  regardless  of whether  or not larger coarse-mode
particles were  present  in the atmosphere  during  the sampling period, the BS method collected
predominantly small  particles.   The D5Q of  the  instrument may,  however, shift at higher wind
speeds.  The  BS method  neither directly measures the mass nor determines chemical composition
of  collected particles.   Rather,  it  primarily  measures reflectance  of  light  from  a stain
formed  by  particles  collected  on filter paper, which  is  somewhat inefficient  for collecting
very  fine  particles  (Lui,  1978).  The  reflectance  of  light  from the  stain depends  both on
density  of  the  stain or  amount of  PM  collected in  a standard period of time and optical pro-
perties  of  the  collected materials.  Smoke  particles composed of elemental carbon of the type
found  in incomplete fossil  fuel  combustion  products typically  make the greatest contribution
to  the darkness of the stain,  especially  in urban areas.  Thus, the amount of elemental car-
bon,  but not organic carbon, present  in  the stain tends  to be most highly correlated with BS
reflectance  readings.  Other  non-black, non-carbon particles also have optical properties such
that they can affect  the  reflectance readings (Pedace and  Sansone, 1972).
     Since  highly variable  relative  proportions of atmospheric carbon  and  non-carbon PM can
exist  from  site to site  or  from  one  time to another at the same site, then the same absolute
BS  reflectance  reading  can be  associated  with  markedly different amounts (or mass) of parti-
cles  collected  or,  even, carbon  present.   Site-specific  calibrations  of reflectance readings
against  actual  mass  measurements obtained  by  collocated gravimetric monitoring  devices  are
therefore necessary in  order to  obtain approximate  estimates of atmospheric concentrations of
PM  based on  the BS  method.  A single calibration curve relating mass or atmospheric concentra-
tion  (in ug/m ) of particulate matter to  BS reflectance readings obtained at a given site may
serve  as a  basis for crude  estimates  of PM  (mainly small particle)  levels  at  that site over
time,  so long  as the chemical  composition  and relative  porportions  of  elemental  carbon and
non-carbon  PM do  not  markedly change.
     As  part of  British  National  Survey  and OECD work in the  early  1960s,  site-specific BS
mass  calibration curves  were determined  for numerous  urban areas  in  the  United Kingdom and
Europe and  efforts were  made to  interrelate such curves  (or  normalize  them)  against certain
standard curves.   Two standard calibration  curves were adopted:   (1) a British standard smoke
curve  that  defines  relationships  between  PM  mass  and  BS  refectance  readings  for London's
                                                                                3
atmosphere  in 1963, which was  used to yield BS concentration estimates (in (jg/m ) reported in
many  published  British  epidemic logical health  studies; and (2) an international standard OECD
smoke  curve,  against which smoke reflectance measurements made  elsewhere in Europe were com-
pared  to yield  smoke  concentration  estimates (in ug/m ) reported in various European epidemio-
logical  studies on PM effects.   Of crucial importance for evaluation of  such  studies is the
fact  that  the  actual mass  or smoke  concentration  present at  a particular site  may differ
markedly from  the  corresponding  mass or concentration  (in  (jg/m ) associated  with  a given
reflectance  reading on  either of the  two  standard curves; and, great care must be applied in
interpreting  exactly  what any reported BS value  in  \ig/m  means at  all.  Further complicating
interpretation  of smoke  data-used  in most epidemiological studies  is  the  lack of reporting of

SOX14G/A                                   14-9                                          2-14-81

-------
specific quality assurance information for the cited aerometric measurements.  Such information
has only  been  reported in general  terms  for United Kingdom National  Survey data utilized in
numerous  British  studies (Warren Spring  Laboratory 1961,  1962, 1966,  1967,  1972,  1975; OECD
1964;  Moulds, 1962; Ellison, 1968).
     The  ASTM or  AISI  light transmittance method  is  similar  in approach to the British smoke
technique.  The instrument has a D,-n cut-point of =5 urn and utilizes an air flow intake apparatus
similar to  that  used for the BS method,  depositing collected material on a filter paper tape
periodically  advanced  to allow  accumulation of  another  stain over  a standard  time  period.
Opacity of  the stain  is  determined by  transmittance of light  through  the  deposited material
and filter  paper,  with results expressed  in terms of optical density  or coefficient  of haze
(CoHs)  units per  1000  linear feet  of air  sampled (rather  than mass units).  Thus,  CoHs read-
ings  roughly  index  the  soiling  capacity  of PM  in  the  air and,  like BS  readings,  are most
strongly  affected  by fine-mode  elemental  carbon particles.   CoHs readings,  however, are some-
what  more markedly  affected  by  non-carbon  particles  than  BS  measurements.   The ASTM method
does  not  directly  measure  mass  or  determine  chemical  composition  of  the PM  collected.
                                    o
Attempts  to ever relate CoHs to ug/m  would  require site-specific calibration of CoHs readings
against mass measurements determined by a collocated gravimetric  device,  but the accuracy of
such  'nass pstimates  could b
-------
Numerous factors  other  than wind speed, as discussed in Chapter 3, can affect PM measurements
by hi-volume  sampling  techniques;  however, quality assurance information for TSP measurements
reported  in  most American  epidemic logical studies  is  largely  lacking,  except for extensive
information on U.S.  Environmental Protection Agency CHESS Program data (Congressional Investi-
gative Report, 1976).
     One consequence of the broader size range of particles sampled by the hi-vol method versus
the  BS  or ASTM  methods  are  severe  limitations  on  intercomparisons or  conversions  of PM
measurements  by  those methods  to  equivalent  TSP  units or  vice versa.  As  shown  by several
studies, no consistent relationship typically exists, for example, between BS and TSP measure-
ments  taken  at  various  sites  or  even during various  seasons  at the  same  site (Commins and
Waller,  1967; Lee,  1972;  Ball  and  Hume, 1977;  Holland  et al.,  1979).   The  one exception
appears  to be that,  during severe  London air pollution episodes when  low  wind speed condi-
tions  resulted  in   settling out  of  larger  coarse-mode  particles  and fine-mode particles
markedly  increased  to  constitute nearly 100 percent of the PM present, then TSP and BS levels
(in  excess of = 500 |jg/m  ) tended to converge  as  would be  expected when  both methods are
essentially sampling only fine-mode particles (Holland et al., 1979).
     Taking  into account  the  foregoing   information  on SOp and  PM measurement methods and
factors  affecting the quality  of  results obtained with routine  field monitoring,  aerometric
data  cited in various epidemiological  studies  must  generally be viewed as  providing at  best
only  very approximate estimates  of atmospheric  levels  of sulfur dioxide,  other sulfur  com-
pounds,  or other PM associated with reported health effects.   Further, to the extent that the
aerometric data  cited  are derived from use of techniques  with limited specifity for the  sub-
stance^)  purportedly  measured or the  relative contributions  of  sulfur  oxides  or  PM to
observed  health  effects  cannot be distinguished from  each  other or from the effects of other
covarying  pollutants, then  the aerometric  data and associated health effects reported might be
more  appropriately  viewed as relatively non-specific indicators of the effects of overall air
pollutant  mixtures containing sulfur oxides and PM.
14.3 ACUTE SOx/PM EXPOSURE  EFFECTS
14.3.1 Mortality
14.3.1.1   Acute  Episode  Studies—Detailed  study of  the human  health  effects associated  with
episodes  of  severe  air pollution spans a  period of less than 50 years.  The earliest reliable
documentation  of such  episodes describes  an  incident  in the  Meuse Valley of Belgium in 1930.
     An  intense  fog covered the Meuse Valley from Liege to Huy (Firket, 1931) from December  1
to 5,  1930, and  was accompanied by an  anticyclonic high pressure area with low winds and  large
amounts of PM.   Sixty deaths associated with the fog occurred among residents of the Valley on
December  4 and 5.  The people who  died were  sick for only a short time.  Although there  were
no other  immediate  deaths,  several persons affected by the fog died much later  from complica-
tions  associated with fog-induced injuries.  The death rate in the area was 10.5 times normal.
The illnesses  abated rapidly when the  fog  dispersed.
     A similar but smaller  event later occurred in Donora, Pennsylvania (Shrenk  et  al., 1949':
Donora was blanketed by a  dense fog  during October  1948, which adversely affected 43 per v
SOX14G/A                                   14-11                                         »-i4-81

-------
of the population of approximately 10,000 people.   Twenty persons, mostly adults with preexist-
ing cardiopulmonary  diseases,  died during  or  shortly after the  fog  due  to cardiorespiratory
causes; and  10  percent of the population was  classified  as being severely affected.  No pol-
lution measurements were made during the incident but SO™, its oxidation products, and PM were
undoubtedly  significant  contaminants.   During  subsequent inversion periods, presumably not as
severe in  terms  of pollutant elevations as the one  in October 1948,  daily averages of SO,, as
high  as  0.4 ppm  (-1140  (jg/m3) were  recorded  (NAPCA).   Cioco  and Thompson  (1961)  found in-
creased mortality  rates  and morbidity effects  (e.g.,  heart  disease,  asthma,  high blood pres-
sure,  chronic bronchitis)  during  an 8-year follow-up  period  for  Donora residents who had re-
ported acute illness during the 1948  episode  in  comparison to those reporting  no  acute ill-
ness.
     As seen in  Table 14-1, a series  of  episodes  were documented in  London between 1952-1975
(Ministry  of Health,  London, 1952; Martin  and Bradley,  1960; Lawther,  1963;  Clifton  et al.,
1960; Wilkins, 1954; Wilkins, 1954; Logan, 1953; Waller,  1978; Apling  et al.,  1977;  Holland et
al., 1979).  Excess mortality reported during those episodes occurred  mainly among the elderly
and chronically  ill adults.  Various factors have been discussed which might help explain some
of  the excess mortality (Holland et  al.,  1979),  including  possible influences not  only of
increased  air pollution, but also of high humidity (fog) and low temperatures.  Regardless of
the  relative contributions of  these different factors, one  clear conclusion  from these major
London episodes  is  that increases in  mortality  were associated with  air  pollution episodes
when concentrations of both S02 and BS exceeded 10QO ug/m3 (Rail,  1974;  NAPCA, 1969; Goldsmith
and  Friberg, 1977; Higgins, 1974; Shy et al.,  1978; Holland et al., 1979; Higgins and Ferris,
1979;  Speizer and Ferris, 1978;  NRC/NAS, 1978a,b; WHO, 1979; Shy, 1979).   The available data,
however, do  not  allow  for  clear delineation of the effects of specific pollutants acting alone
or  in  combination.  Qualitative  studies of milder  episodes  in  the 1950's (Gore and Shaddick,
1958;  Burgess and  Shaddick, 1959)  showed similar correlations of mortality with air pollution.
               TABLE  14-1.  EXCESS DEATHS AND POLLUTANT CONCENTRATIONS DURING SEVERE
                           AIR POLLUTION EPISODES IN LONDON (1948-75)
Maximum 24-hr pollutant




Date
Nov.
Dec.
Jan.
Dec.
Jan.
Dec.
Dec.
1948
1952
1956
1957
1959
1962
1975

Duration,
days
6
4
4
4
6
5
2
Deviation from
X of total
excess deaths
750
4000
1000
750
250
700
100-200**
concentration, ug/m3
Smoke
(BS)
2780
4460*
2830
2417
1723
3144
546
S02
(H202 titration)
2150
3830
1430
3335
1850
3834
994
             *Note that peak and 24-hr BS levels were likely much higher than 4460
                ug/m  due to rapid saturation of filter paper by collected PM.
            **Excess mortality during the 1975 London episode may be attributable in
                part to a concurrently occurring strike affecting medical care.
SOX14G/A                                   14-12                                          2-14-81

-------
     Episodes of  acute air pollution  have  also occurred in the  United  States  since the 1948
Donora episode, but  no single event has reached the proportions of the major London episodes.
Some studies suggest however, that slight increases in excess deaths and morbidity were associ-
ated  with  severe episodes   in  New York  City  (see  Table  14-2).   The  estimates  of  excess
mortality  reported  from the  New York  episodes were derived by comparing  daily deaths  during
periods of  high  air  pollution with daily deaths  for  the same period in the years immediately
before or  following  the episode (Glasser and  Greenburg,  1971)  or by calculating daily devia-
tions from  a 15-day  moving average of daily deaths (McCarroll  and Bradley, 1966).  Studies of
the New York episodes  listed in Table  14-2  controlled for meteorological  variables and found
an independent influence of the pollutants (McCarroll  and Bradley, 1966;  Glasser and Greenburg
1971).  During at least one of the episodes  (December,  1962),  the increased death rates were
predominantly  in  the  45  to 64 and  65 years  and older  age  groups.   During the episodes in
January,  1963,  some  days did not  have an excess mortality.  The episode  between January and
February  1963  involved a peak death rate apparently  superimposed upon an elevated death rate
average due  to the present of influenza virus  in the community.   There was one other period of
excess  mortality  (April, 1963) which  did  not show sharp  increases  in air  pollutants.   The
above studies  appear to yield a pattern of results indicative of small increases in mortality
                                                                                     o
among older adults  occurring  in  New  York  City when  S0? levels exceeded  1000  ug/m   in the
presence  of simultaneously  elevated  PM concentrations measured in the range of 5.0 to 7.0 CoH
units.  The numbers of  excess  deaths  detected;  however, were  very low in  comparison  to the
large total  population of New York and the  numbers of episode-related excess deaths observed
in London  (vida supra).  Direct, precise comparisons of the pollution data from the London and
New York  episodes, as  has been noted (Holland  et al.,  1979), cannot be made because of differ-
ences in  methods  used  for measuring PM concentrations.  However, even rough comparisons of the
results obtained  by  the different (BS, CoHs)  approaches  suggest  that the pollution must have
typically  been much  greater in London.
     When  a marked  increase  in air pollution is  associated with a sudden  rise  in the death
rate  or  illness  rate that  lasts for a few  days and both return  to normal shortly thereafter
(as  documented in the above studies), a causal  relationship  is strongly suggested.   Sudden
changes in weather,  however,  which may have  caused the air pollution incidents, must also be
considered  as  another  possible  cause of the death  rate increase.   On the other hand, the con-
sistency  of  the above  associations between S0?  and particulate matter elevations  and increases
in mortality render  it extremely unlikely that  weather changes alone provide an adequate expla-
nation  for  all such observations.   This view is  further reinforced by (1)  the  fact that at
least some episodes  were not accompanied by sharp  falls  in temperature; and (2)  other weather
changes  of  similar  magnitudes  to  those  accompanying the  above pollution episodes  are not
usually associated  with  such dramatic increases  in  mortality in  the absence  of greatly in-
creased levels of SOy, particulate matter, or  other pollutants.  In summary, the above London
episode studies appear to provide clear evidence for substantial  increases in excess mortality
SOX14G/A                                   14-13                                         2-14-81

-------
                                TABLE 14-2.   ACUTE AIR POLLUTION EPISODES IN NEW YORK CITY
         Location
Date
Reference
  Estimated
excess deaths
          24 Hour
  pollutant concentrations
S02, max        participates,
|jg/m3              CoHs
New York City   Dec. 1962


New York City   Jan 1963
       McCarroll and
        Bradley, 1966

       McCarroll and
        Bradley, 1966
                     90
New York City   Jan-Feb 1963   Glasser and Green-
                                burg, 1971

New York City   Feb.-Mar.  1964 Glasser and Green-
                                burg, 1971
                               405-647**


                                  50
                                 1890 (0.72 ppm)    5-6.5


                                 1830 (0.7 ppm)      6.0


                                 1570 (0.6 ppm)      7.0


                                 1570 (0.6 ppm)      5.0+
 *Specific numbers of excess deaths not clearly reported in published paper.
**Influenza outbreak also present.

-------
when S0   exceeded  1000 (jg/m3 in the  presence  of PM over 1000 ng/m3 (BS).  Certain of the New
       2
York studies  yield  some evidence for small increases in excess mortality at simultaneous ele-
vations of 1000 (jg/m3 S02 and PM in the range of 5.0 - 7.0 CoHs.
14.3.1.2   Mortality Associated  with  Non-Episodic  Variations  in  Pollution—A number of reports
have investigated  relationships between mortality and air pollution in England during periods
with no  unusual  air pollution  episodes (Weather ly and Waller, in press; Martin, 1964; Waller,
1969;  Gore,  1958;  Burgess,  1959;  Scott,  1963;  Martin, 1960;  Riggan  et al.,  1975; Lawther,
1963;  Clifton et al., 1960).  For most of  these studies, 15-day moving averages were construc-
ted  and  the  effects of pollution were  assessed  in terms of daily deviations from these base-
lines.   Increases  in daily deaths during  the winter  of 1958-59 were found (Lawther, 1963) to
                                                 3                  3
be associated with  concentrations of BS >750 (jg/m  and S02 >715 ug/m  (0.25 ppm) during a long
(59-day)  period  of thick fog.  Increases  in  daily deaths  were not associated with pollutants
at  lower concentrations during 1958-59; nor did they occur at similar pollutant levels during
the  prior winter  having  only  8 days  of  fog.   Similar studies in  Sheffield  (Clifton et al.,
1960)  did not  yield  confirmatory  results; that  is,  while- increases  in  deaths  appeared to
possibly  be  associated with very high  concentrations  of  pollutants,  random variations in the
number of deaths were so  large  that firm conclusions could not be drawn.
     Among the most important British studies bearing on acute health effects of sulfur oxides
and  particulate  matter at  levels below 1000  ug/m  are those of Martin and Bradley (1960) and
Martin (1964).   The first  of these  studies related daily mortality from all  causes and from
bronchitis and  pneumonia  to the level of  S02 and  smoke in London during the winter of 1958 to
1959.   The authors  found a considerable  number  of coincident  peaks  in pollution  level and
daily  mortality.  The correlation of mortality from all causes with pollutants measured on the
 log  scale was 0.613 for smoke (BS) and 0.520 for S02-  Martin and Bradley (1960) reported that
neither  temperature nor  humidity  was significantly correlated with  London mortality studied
during the winter of 1958-59,  noting a very low correlation coefficient (r = -0.030) for tem-
perature   and deaths for the  entire 1958-59 winter  and the  occurrence  of several  peaks in
mortality during November and  December, 1958, when temperatures were substantially over 38°F.
They further noted that  a  range of 30-38°F is characteristic of most winter fogs and tempera-
tures  consistently below 30°F  (when temperature effects on mortality can be expected) are the
exception.
     Though  the  authors emphasized the relationship between change  in pollution level and num-
ber  of deaths  and lack  of meteorological effects, an influenza epidemic  during  part of the
study  may have  influenced  some of  the  results.   The  authors,  however,  reported  number of
deaths,  smoke levels,  and  S02 levels from November 1, 1958  to February 28,  1959.   A further
analysis  of  these data  was  performed by Ware et al. (1981) but excludes the month of  February,
in  which an  epidemic of  Type A influenza  also  significantly influenced daily mortality.  For
the  remaining 92 days,  the  deviations of daily mortality from the 15-daymoving average (trun-
cated  at each end  of the series) was computed and appeared to show a consistent and signifi-
cant trend of  increasing mortality with  increasing  BS and  S02.   Change  in  mean  deviations

SOX14G/A                                    14-15                                          2-14-81

-------
occurred between 500-600  ug/m3  BS and 300-400 ug/m3 S02  as  levels above which small positive
increases  in  mortality over  the  moving average were  seen,  although this is  not  intended to
suggest  a  threshold for  response.   In fact,  it  is  unclear  at what  level significant excess
mortality  first occurred,  but the analysis suggests  that notable  increases occurred somewhere
in the  range  of  500-1000 ug/m3 BS and  S00  and most  likely when both  pollutants  exceeded 750
    3
ug/m .    Although  temperature  and humidity  were not  correlated   with daily  mortality,  both
pollution  level and  daily mortality  increased throughout the period  of  study, and the possi-
bility  of  other  extraneous  seasonal  variables contributing  to   this association  cannot  be
ignored.
     An  analysis similar  to that  used by Martin and Bradley  (1960)  was  carried out by Martin
(1964)  for the winter  of 1959-60.   This winter  had  fewer incidents of high  pollution.   The
significant positive correlation  between  mortality and pollution  was, however,  still  present
although the  coefficients were somewhat  lower  than  in the previous year.   The  Martin (1964)
results  were  based on  analyses  combining high pollution days  from  1958 to  1959  and  1959  to
1960, after excluding  days on which  pollution had fallen from a previously higher  level.   The
                                                                o
mean deviation was positive for every BS level above  500-600  ug/m   and S09  level  above  400-499
    3
ug/m ,  but  no clear  threshold  for  significant  increases  in  mortality could  be  clearly
delineated although  the  most  marked  increases occurred for BS  levels  over 1200 ug/m  and S0?
                         3
levels exceeding 900 ug/m  .  Considerable covariation in levels  of  the two  pollutants,  however,
preclude  attribution  of  the  apparent mortality  effects to  either  one  alone.   Bronchitis
mortality  was  also  significantly,  though  less strongly, correlated with pollution level,  but
pneumonia  mortality was  not  correlated  with  pollution.   Based   on  the  above analyses,  it
appears  that  small  increases  in mortality may have occurred  in London during 1958 to  1960 in
                                                                                            3
association with  covarying increases  in  BS  and  S09  levels   in the  range of  500-1000 ug/m ,
respectively.   Holland  et al.  (1979),  however, suggest that  the increases  in  excess mortality
most clearly  occurred  when particulate levels exceeded 750 ug/m   (BS) in  the presence of S09
                    3
levels over 710 ug/m .
     A  number  of   investigators  have  also  reported  on  relationships  in the  United States
between mortality and daily variations in air pollution during non-episodic periods (Greenburg
et  al.,  1967; Schimmel   and  Greenburg,   1972;  Schimmel  and  Murawski,  1975;  Schimmel  and
Murawski,  1976;  Hodgson,  1970; Buechley  et al.,  1975;  Buechley,  1977;  Lebowitz,  1973a,b).
These studies  mainly provide, at  most, qualitative evidence  linking  mortality effects to air
pollution  (see Appendix  A).   For  example, Hodgson (1970)  used  multiple  regression methods to
examine  the relationships between deaths  and air pollution concentrations on a monthly basis
in New York City.   His correlations between excess deaths and S0?  or particulate matter (CoHs)
were significant.   Buechley (1975, 1977) used similar models  to relate daily  deaths in the New
York/New Jersey metropolitan  area (1962 through 1972)  to  SOp  measured at a  single monitoring
station; he  showed  significant correlation  coefficiences as  well,  and showed  a  relation of
residual mortality to levels of S02>   Lebowitz (1973a,b) utilized  a stimulus-response model to
study daily air pollution  exposures,  meteorology, and daily mortality in New  York (1962-1965),

SOX14G/A                                   14-16                                         2-14-81

-------
Philadelphia (1963-1964), Los Angeles (1962-1965), and Tokyo (1966-1969).  Adverse temperature
and  humidity  changes were shown  to  be  important, but cannot  account  for mortality increases
which were  closely  associated with increases of air pollution.  In each case no specific pol-
lutant  levels  were  clearly  shown to be  associated with  significant  increases in mortality.
     In  another  study,  possibly  yielding  useful  quantitative  information,  Glasser  and
Greenberg (1971) carried out an analysis of daily mortality in New York City during the 5 year
period  1960 to  1964, using  only data from  the months October  through March.   Deaths  were
analyzed  both  as deviations  from a  15-day  moving average and as  deviations  from the 5-year
average  for each day.  Results from  the  two analyses were said to  be qualitatively similar.
Twenty-four  hour average pollution  data  were  based  on hourly  S0? and  bihourly  smoke shade
(CoH)  readings.   The results  are adequately  summarized  by  the unadjusted  analysis,  which
suggests  a  trend in mortality over the full  range of S00 and  smoke  shade  (CoH) levels,  with
                                                                                            3
marked  positive mean deviations  above  5.0-5.9  CoHs and  S0?  levels above  786-1048 ng/m  .
Variations  in  the  two pollutants, however,  are  markedly confounded due to their colinearity,
not  allowing one to  discern  the  relative contributions of each to  reported excess mortality
effects.   In cross-tabulation of  daily mortality by  S02 and  smoke  shade  level, however,  S02
was  reported to  be  more  strongly  related to mortality and was used as  an index of pollution in
some analyses;  and, in a multiple regression  analysis  with  temperature and rainfall, S0« was
reported  to be  more strongly associated  with  mortality  than  either  weather  variable.   This
association  persisted  in  analyses   of  bimonthly  periods.    Although  the  observations  are
dependent,  Glasser  and Greenberg computed standard errors for the mean deviations by assuming
independence.  As in  the case of  other  New York non-episode mortality  studies listed above
(e.g.,  Greenburg et al., 1967; Schimmel and Greenberg,  1972, etc.), the results of this study
are  open  to  question  on  the basis  of  data  from only a single monitoring station  in central  New
York having been  used to generate  exposure estimates  for the  entire metropolitan area,  but
arguments  can  be made for those  data possibly  being  reasonably representative  for the entire
city under  markedly elevated pollutant conditions  (see Appendix A).
14.3.1.3  Morbidity—Morbidity studies of  acute or short-term air pollution exposures are much
 less common  in the  epidemiologic  literature  than  morbidity studies of  chronic or long-term air
pollution  exposures.   This  reflects the  dual  complications  of the  difficulty  of having
adequate  estimates  of pollution exposure as well  as the  statistical analytical problems of the
health  data  being  collected.   The  main  focus  here  is  on  studies providing  information on
quantitative relationships or associations between ambient air concentrations of SO^ or parti-
culate  matter and acute  exposure  morbidity health  effects.
      Several  British  studies  have been  published on health  effects  associated with acute or
short-term  exposures  of  adults to  sulfur oxides and particulate matter which appear to provide
useful  information  on  quantitative dose-effect relationships.
      Illness  data  were  obtained  in  many  of the  early severe pollution  episodes discussed
above;  this information did little more  than  support the mortality results reported  in those
 SOX14G/A                                    14-17                                          2-14-81

-------
studies.   There was evidence, however, that increases in illness occurred along with increases
in deaths,  although the  effects  were  less  sudden.   Waller and Lawther  (1955),  for example,
reported that  when  smoke  (BS) concentrations in London increased tenfold during the course of
2 hours, there was  a deterioration in the clinical  condition of some patients with bronchitis
or asthma.   On this day,  peak smoke (BS) concentration may have reached 6500 |jg/m .   SO,, also
increased  to   a  maximum  of about  2860  ug/m  (1.0  ppm)  but H2$04  did not,  on the  basis  of
washings from  impactor slides.  Most of the mass of  particulate matter was determined by micro-
scopic studies to consist of particles less than 1 |jm in diameter.
     Lawther (1958)  studied  associations  between daily variations in  smoke  and S0£ pollution
and the self-indicated health status in 29 British patients with chronic bronchitis.   Patients
maintained  diaries  on which  their daily  condition  was  indicated in  relation  to  their usual
condition.   The  alternatives were  "better,"  "same,"  "worse,"  and "much  worse."   Figure 14-1
shows graphically the  effects of  high pollution levels observed in  the 29 bronchitic patients
studied in January 1954.  During the month  of  January 1954, an  episode of relatively high pol-
lution resulted  in a  sharp  increase in  the number of  patients whose condition  worsened  as
                                                        o
24-hour smoke  (BS) increased from about 400 to 2000  |jg/m  and 24-hour SO- increased from about
450 ug/m3 (0.15 ppm) to -1300 ug/m3 (0.20 ppm).
     In the winter of 1955, the study was extended to include 180 patients in the London area.
The  prevalence of exacerbation of  preexisting  illness was related  more  closely  to  pollution
than  to  temperature or  humidity  during the  winter months, and the  relationship  disappeared
when the levels  of  pollution decreased in the spring.   Actual  numerical  data are not given  in
the  report, but  inspection of the figures  indicate  that  exacerbation of illness increased  as
smoke (BS)  increased  to  about 300-350 ug/m  and  S0?  to  about  500-600 ug/m .  The data suggest
that  during the  winter  months,  SOp was  associated  more closely with  variations  in  health
status;  however, in  the  spring  of the year,  when pollution  concentrations  were  no  longer
associated  with  health  status,  SO- continued to  occur  in  intermittent peak concentrations  as
high as  those  associated  with increased illness  during  the  winter.   However,  the association
between pollution and  illness decreased when smoke  (BS)  concentrations  fell  to a fairly con-
                                                     o
sistent  24-hour  concentration of  less  than 250  ug/m  .   The few short higher  peaks  in smoke
(BS)  after  this time  had little  effect  on illness status.   These   investigators  noted that
worsening of subjects'  conditions  were  more likely  associated  with  markedly higher short-term
peaks in pollution rather than the 24-hr average levels noted above  and that the results are not
necessarily indicative of causal relationships,  but  rather that the  measurements of smoke (BS)
and S0? may only be indicators of whatever is the cause.
     A later report by Lawther et al.  (1970) gave  the results of further  extension of these
studies into the winters of 1959-60 and 1964-65.  The techniques used were similar except that
the  patients  now reported  on health status  in relation  to the previous day  rather than  in
relation to usual  conditions.   These studies supported the  results  in previous years in that
the  worsening  of health  status  was  associated  clearly with increases in  air  pollution.  The
authors  stated that, although exact  relationships  between the responses of  patients and the

SOX14G/A                                   14-18                                         2-14-81

-------

 45


 40


 35




2.0


1.8


1.6
   in*
   *
   O
       1.0

       0.8

       0.6


       0.4
{2  S
2  0^
u-  oc
O  uj
                                        A
                                        REL. HUMIDITY
                                        TEMPERATURE
                                        SMOKE
                                       . so.
                                                 \
                       \
                        \
                         \
        /    ••
        I
        I   '
I __•_ • •  .
                                                                                  100


                                                                                  90


                                                                                  80


                                                                                  70


                                                                                  60
                                                                           0.5

                                                                           0.4


                                                                           °'3
                                                                           0.2

                                                                           0.1

                                                                           0
               16         17         18         19

                                         JANUARY
                            20
                                                          21
                                                22
                                                            (-
                                                            5
                                                            S
                                                            i
                                                            J
                                                            ui
                                                            ff
                                                                                       I
                                                                                       
-------
concentrations of  smoke  and  SOp could not be determined,  the minimum pollution leading to any
significant response was  about 500 ug/m3 (0.17 ppm)  SOp,  together  with about 250 ug/m  smoke
(BS).   Lawther et  al.  (1970) also emphasized that these  responses  may reflect the effects of
brief  exposures  to  maximum  concentrations  several   times  greater  than  the  24-hour  average
(i.e., presumably  in excess of 1000 ug/m3  for both BS  and S02 levels).   As  in  the  earlier
studies, the results appear to relate more closely during  the first  part of the winter  and, in
some  instances,  there  was little reponse to higher  concentrations  of  pollutants  near  the end
of the winter.  Although the concentrations of smoke  and S02 closely correlate, examination of
the data  again  suggests  that often higher concentrations of  S02 near  the end  of  the  winter,
occurring  with  generally lower  concentrations  of  smoke,  produced less response  in  the  study
subjects than did the same concentrations of S0? earlier in the winter, when smoke was  higher.
There  was  some  evidence  for  a loss of interest by participants.   When  the  association  between
exacerbations and S02 concentrations were compared in the  two winters,  the  impression was of a
slightly  reduced  and  less  consistent,  but definite  effect during the  second winter.   The
                                             o            o                     33
declines in concentrations were from 342 ug/m  to 129 ug/m  BS and from 299 ug/m  to  264 ug/m
SOp  (Lawther  et  al.,   1970).   These studies  among chronic  bronchitis  patients  in  London
continued  into  the 1970s as  the frequency of periods of  high pollution declined.  There were
no  sharp  increases reported  in illness scores in the winter of 1969-70 (Lawther,  1970) nor in
the winter of 1974-75 (Waller,  1971).
     Martin (1964) examined applications for hospital admissions for the winter of 1958-59 and
found  for men ages  45-79 (after  adjustment  for day of  the week  and correction for  15-day
moving average)  significant  correlations  for  both  cardiovascular  and respiratory conditions
with  smoke (r =  0.46)  and sulfur dioxide (r = 0.40).  Analogous significant correlations were
found  for  the same male age group for such conditions in relation to both smoke (r =  0.41) and
SOp  (r =  0.43)  for the winter of  1959-60.  The  average deviations  associated with increasing
SOp  and  smoke levels during  both winters are summarized  in Tables  14-3 and 14-4.  As  seen in
those  tables, whereas  no clear threshold for the onset  of mean positive deviations across the
exposure  ranges  can  be distinguished, very marked increments  in the positive mean deviations
can be discerned starting at 800-899 ug/m3 for S02 and 1100-1510 ug/m3  for PM (BS).  Presenta-
tion  by  the  authors  of  their results separately  in relation  to SOp and BS  (and  the  present
summarization  in Tables  14-3  and  14-4)  is  not meant  to  imply that  the  relative individual
contributions  of  S02  and  BS  alone  to  the  observed   effects  can  be  ascribed  to  the
concentrations listed, in view of considerable covariation in S0? and BS levels during  the two
winters studied.
      In  addition  to  the  above  British  and  European  studies,  several American  studies may
provide  useful  information  on  the effects of  acute (24  hr) exposures to  sulfur dioxide and
particulate matter.
     For  example,  McCarroll  and  colleagues  (Mountain et  al., 1968;  Thompson et  al.  "1970;
Cassell  et al., 1969, 1972;  Lebowitz et al., 1972;  Lebowitz,  1977) demonstrated significant
SOX14G/A                                   14-20                                         2-14-81

-------
                       TABLE 14-3.   AVERAGE DEVIATION OF RESPIRATORY AND
                          CARDIAC MORBIDITY FROM 15-DAY MOVING AVERAGE,
                                BY S02  LEVEL (LONDON, 1958-1960)
                S02  level                      Number                         Mean
                 (|jg/m3)                     of days                      deviation
                 400-499                        9                            2.2

                 500-599                        6                            5.1

                 600-799                        9                            6.9

                 800-899                        6                           12.8

                900-1280                        5                           12.8
                   TABLE 14-4.   AVERAGE DEVIATION OF RESPIRATORY AND CARDIAC
                              MORBIDITY FROM 15-DAY MOVING AVERAGE,
                             BY SMOKE LEVEL (BS) (LONDON,  1958-1960)

Smoke level
(Ijg/m3, BS)
500-599
600-699
700-799
800-1099
1100-1510
Number
of days
9
6
9
8
7
Mean
deviation
3.2
-0.7
2.4
4.9
12.9
SOX14G/A                                   14-21                                         2-14-81

-------
multiple  correlations  between acute  respiratory  symptoms and air  pollution,  controlling for
season,  weather,  and  social  class, when  seasonal  SO,  means  in the  range of  0.10-0.24 ppm
               o                                       ^
(-280-700  ug/m )  seasonal  smoke shade  means  in  the  range of  1.56-3.15  CoHs.   Initially,
multiple  regression  analyzes  showed  conflicting  findings  in  that  the  pollutants  were
occasionally  absent  from or negative in their  regressions.   This  led to a  separation  of the
combined  meteorological  and air  polluant  conditions  into categories of:   (1)  stormy weather
(low  temperatures,  occasional  precipitation,  high  wind speed)  when the pollutants  were low;
(2) stagnation periods (low wind speed,  moderate temperatures) when SOp and TSP were high; (3)
periods  of  change in  pollutant  levels  during  the  fall  through  spring periods;  and  (4) high
photoxidant conditions in the summer.  This analysis revealed significant correlations between
the  pollutants and acute  symptoms  for  1800 individuals studied weekly  in  New York (1962-65)
during  stagnation periods  and significant  correlations of the same acute respiratory symptoms
(predominately common  colds)  with meteorological  conditions during stormy  periods.   They also
found  a lag  of  one  to  three  days   in  symptoms  and corresponding  increases in  school  absen-
teeism.  Some  individuals (mostly under  the age of 10) were found to have reacted consistently
and  frequently to  increases in the pollutants, and their respiratory symptoms  were  of greater
duration and  severity than "nonsensitive"  individuals  (Lebowitz  et al.,  1972).   Those who were
sensitive during  the  first part of the  period under study were  found to be sensitive later on
in  the study.  The  attack rates per person  year  were about double for the "sensitive",  and
occurred  predominately  in  the winter period.  Additional  qualitative studies  demonstrating
effects  of  acute  exposure  to SOp and PM on the health of children and other sensitive groups,
e.g.,  asthmatics, are summarized in Appendix B.
      In  summary,  studies on  acute  exposure  effects  tend to suggest that  the  elderly,  those
with  chronic  cardiorespiratory diseases,  children, and  asthmatics  may  constitute populations
at  risk for  manifesting  morbidity  effects  in  response to acute exposure  to  elevated  atmos-
pheric  levels of  sulfur dioxide and particulate  matter.    Lawther's  studies  in London,  for
example,  appear  to  demonstrate  worsening  of  health  status among  bronchi tic  patients  to  be
                                                            3
associated  with  acute  24-hr exposures to BS of 250-500 ug/m  in  the presence of S00 levels in
                           3
the  range of  500-600  ug/m  or peak 1-hr exposures to  each of  the pollutants  at levels pre-
sumably  in excess  of  1000 ug/m .    In  contrast,  no  effects on  bronchitics  appeared  to  be
detectable  at 24-hr  BS levels below 250 ug/m  in  the presence  of  24-hr SO,  levels below 500
    3
ug/m  .   Also,  increased applications by adults aged 45-79  for admissions  to London hospitals
for  cardiac and  respiratory morbidity most clearly occurred, based on  Martin's studies, when
24-hr  BS  and  SOp levels approached or exceeded 900-1000 ug/m ;  and Martin's data suggest that
such effects  may have occurred at somewhat lower levels down to  500 ug/m3 for both S0? and BS.
Insufficient  epidemiological  information  exists,  however,  by  which  to   determine  specific
quantitative  acute  exposure  levels at  which  the  health  of other  sensitive  groups,  e.g.,
children and  asthmatics, might be adversely affected.
SOX14G/A                                   14-22                                         2-14-81

-------
14.3.2  Chronic SO^/PM Exposure Effects
14.3.2.1  Mortality
     Numerous  studies  have been  performed comparing  general  or cause-specific  mortality in
areas of lowest-to-highest pollution concentrations.  Most of these studies do not account for
cigarette smoking,  occupation,  social  status, and/or mobility differences between areas, thus
making  it difficult to define accurately any quantitative relationships between mortality and
air  pollution  parameters.    Many  such  qualitative  studies  are  summarized  in  Appendix B.
Essentially  no  epidemic logical  studies are presently well-accepted as providing valid quanti-
tative  data  relating  respiratory disease mortality of chronic  (annual  average)  exposures to
sulfur  oxides or particulate matter.
     Certain studies have more specifically attempted to relate lung cancer mortality to chronic
exposures to sulfur oxides,  particulate matter undifferentiated by  chemical  composition, or
specific  particulate matter  chemical  species.   However,  little  or no  clear  epidemiological
evidence  has been  advanced  to date  to  substantiate hypothesized  links between  S0? or other
sulfur  oxides  and  cancer.   Nor does  there presently  exist  credible  epidemiological evidence
linking increased  cancer rates to  elevations  in  PM as a class,  i.e.,  undifferentiated as to
chemical  content.    Some  epidemiological  studies   (e.g.,  of occupationally exposed workers)
do  provide  evidence of increased cancer risk associated with exposure to some types of parti-
culate  matter,  e.g., certain organic compounds or metals, often found in the fine- and coarse-
mode particulate fractions of many  urban aerosols (see Appendix C).   However, no well-accepted
basis  currently exists by  which to  quantitatively define  any  consistent relationships con-
cerning relative  contributions  or levels of  such  PM components  to  possible  carcinogenic
effects of PM  pollution as a whole.
14.3.2.2  Morbidity
14.3.2.2.1   Respiratory effects  in  adults.  Several extensive studies on associations between
air pollution  and chronic respiratory  disease have  been conducted on European populations, but
few provide  more  than qualitative  information on possible SOp or PM effects, as summarized in
Appendices A and B.
      In one  of  the  few English studies possibly yielding useful quantitative data, Lambert and
Reid  (1970)  surveyed  nearly  10,000 British postal  workers (age  35  to  59)  for respiratory
symptoms  indicated  by response  to a  self-administered MRC  questionnaire.   Concurrent air
pollution data during  1965 were  used  to  determine  associations with symptoms where possible.
However,  the areas  from which such  data  were available included only about 30 percent of the
study  group.  Consequently,  an  index of  pollution developed by Douglas  and  Waller in 1952,
from  domestic  coal  consumption,  was used as well.  The areas covered by the index included 88
percent of   the study  group.   The  results  summarized  in  Table  14-5,  adjusted  for  age and
smoking habits but not  as  well  for socioeconomic  status,  appeared   to  show relationships
between health effects  and air  pollution indices  for  both males  and females.   That is,   a
greater prevalence  of cough and phlegm was  found to occur in more polluted areas, where annual
SOX14G/A                                   14-23                                          2-14-81

-------
mean BS  concentrations exceeded  100 |jg/m  and  S02  150
                                                               tnan  in  areas where annual BS  or
SOp  concentrations were  less than  100 tig/m   (based on concentrations  for the  30  percent of
study areas actually  monitored).   These investigators also developed  data showing that smoking
was  an  important factor  in  acquiring chronic bronchitis  and  that the  combined  effect of
smoking  and  pollution  exceeded  the  sum of  the  individual   effects.   However,   failure to
consider  socioeconomic  status  might  have  affected  the  results,  (Holland  et al.,  1979),
although  this   is not   very  likely  since  the  entire  population  consisted  of a  single
occupational  group (Higgins,  1974; WHO, 1979).

        TABLE 14-5 rrMVTOM-FKCVAUNCS RATIOS (rtWimXT  COUCH AND FHUGM) STANDARDISED F0> AC! AND SMOKING IT A«-
                                                 INDICES
CMccnfntfea
(HC./CJB4
<100 	
M^ •• •• ••
IS»- 	
JOO+ 	
y.»*fct
AUk. | Fcouki
nun
lll(M)
ll«(J7)
134 (M)
«
-- »
Sulphw dioiid*
MaUt
n an
9t an
120 
9\an
»7
115 WO
          FitWM I" iulic frf* <>»* oburved numben of tyaipiom-paiiiivc teipaadcr.li. Smoke uid uilphur dioud* conccnuaiwnt in bitcd on vilun M
         mUmtU uu> ia Muck. IMS (>UlMnil Air PoUiMiM SuryeyX
         From: Lambert and Reed, 1970.

      Impairment  of  pulmonary function  is likely to  be  one of the  effects of  exposure to air
pollution since  the pulmonary system includes the tissues that receive  the initial impact when
toxic materials  are inhaled.   Acute and chronic changes in  function may be  significant bio-
 logical  responses  to  air pollution exposure.   A number of studies  have been  conducted in an
effort  to  relate  pulmonary function  changes  to  the presence  of  air  pollutants  in various
European, Japanese, and American communities.   However,  very few provide more than qualitative
evidence relating  pulmonary  function  changes to elevations in SOp  or PM (see Appendices A and
B).
      A series of studies,  reported on from the early 1960s to the  mid-1970s were conducted by
Ferris,  Anderson,  and  others.   The initial  study  involved comparison  of  three areas within a
pulp-mill  town   in northern  New Hampshire.   In the  original  prevalence  study  (Ferris  and
Anderson,  1962;  Anderson  et  al.,  1964),  no  association was  found  between  questionnaire-
determined symptoms and lung function tests in  the three areas with differing pollution levels
after standardizing for cigarette  smoking.  The  authors  discuss  why residence  is a  limited
indicator for exposure (Anderson  et  al.,  1964).   The  study  was  extended  to  compare Berlin,
New  Hampshire,  with the  cleaner city of  Chilliwack,  British Columbia  in  Canada (Anderson and
Ferris,  1965).   Sulfation  rates (lead candle method) and dustfall  rates were higher  in Berlin
than in Chilliwack.   The prevalence of  chronic respiratory disease was greater in Berlin, but
the  authors concluded  that this difference was due  to the  interaction between age and  smoking
habits  within  the  respective  populations.   Higher  levels  of  respiratory function in  some
cigarette-smoking  groups in  the cleaner  area were  observed,  but this  difference could be due
to  socioeconomic  and ethnic differences as well as  air pollution.  Ethnic differences could
also have been  a confounding factor (Higgins, 1974).
SOX14G/A
                                            14-24
                                                                                            2-14-81

-------
     The Berlin, New  Hampshire,  population was followed  up  in 1967 and again in 1973 (Ferris
et al., 1971,  1976).   During the period between 1961 and 1976, all measured indicators of air
pollution fell.   In the  1973 follow-up,  sulfation  rates nearly doubled  from  the  1967 level
(0.469 to 0.901  mg S03/100 cm2/day) while TSP values fell from 131 to 80 ug/m3.   Only limited
data  on  SO,, was available (the mean of  a series  of 8-hr,  samples  for  selected weeks) (WHO,
1979).  During the 1961 to 1967 period,  standardized  respiratory symptom rates decreased and
there  was an indication that lung  function  also  improved.   Between the period  1967  to 1973,
age-sex  standardized  respiratory   symptom rates  and  age-sex-height standardized  pulmonary
function  levels  were  unchanged.   Given that  the  same set  of investigators,  using  the same
standardized procedures,  conducted  the  symptom surveys and pulmonary  function  tests  over the
entire course  of these studies, it  is  unlikely that the  observed improvements in Berlin were
due  to variations   in  measurement  procedures,  but  rather  appear  to  be  likely  associated with
                                            3
decreases in TSP levels from  180 to  131 ug/m .   The relatively small changes observed, however,
argue  for  caution in  placing  much weight  on these  findings  as quantitative  indicators  of
observed effect/no  effect  levels for TSP-induced health changes.
      Becklake  et al.  (1979) used pulmonary spirometric and closing volume function tests (and
symptom reporting)  in  three areas of Montreal, Canada and did not find significant differences
in  children or adults (other than  in closing  capacity)  that were associated with TSP levels.
In  the three areas studied,  ambient SO,  was  reported  to  be 15,  123,  and  59,  and annual mean
                                                 3
high-volume  TSP  values were 84, 95, and 131 ug/m , respectively, for the low-, intermediate-,
and  high-pollution areas,  but  there was  a  large  overlap  between  areas.    In  a later report
(Aubry et al.,   1979)  discriminant  analysis  was  utilized  to control  for  smoking,  after which
differences  in health  variables were not significant.  This study, however, cannot be taken as
showing  lack of  effects at the  listed  S0? and TSP levels because  the power of the study was
too  low to  expect  an effect to be seen with the small number of subjects studied.
14.3.2.3  Respiratory  Effects in Children—Several British  studies  have  reported quantitative
relationships  between  respiratory  disease  incidence  in  children   and  elevations  in  sulfur
dioxide and particulate matter  (BS).   In  one  of the best known  and frequently cited investi-
gations,  Douglas and  Waller  (1966)  studied a  cohort of  a national sample of children born in
the  United   Kingdom during  the first  week  in March  1946.   They prospectively  examined  the
occurrence  of  respiratory  illness  in the children in relation to  the  estimated intensity of
air  pollution  in  the  area of  their residence.   The  areas  in which  the  children  lived were
assigned  to one  of four pollution groups  on the basis of estimates derived from domestic coal
consumption  in 1951-52.  An effort to validate the index  later, on the basis of measured smoke
(BS)  and  S0? measurements in 1962 and  1963, indicated that the categorization of study groups
by  estimated pollution level was  reasonably  good.   At the time  of  the  1962-63 measurements,
                               3
SO,  varied  from about 90 ug/m  (0.03  ppm) in representative  low-pollution areas  sampled to
               3
about  250 ug/m  (0.09 ppm) in  representative  high-pollution  areas  actually sampled, as shown
in  Table  14-6.   Also, BS varied  from  about  67  ug/m   to  205 ug/m   in  comparable  areas.
Information on respiratory  illness and  symptoms was obtained from the children
                           t
SOX14G/A                                   14-25                                         2-14-81

-------
when they were  6,  7, and 11 and,  if  they had lived the  first  11 years of their lives in the
same area,  similar  information  was gathered when they were  15,  20,  and 25 years  of age.  No
significant  relationship was  observed between  upper respiratory  tract  infections  and in-
creasing  air pollution  levels,  in contrast to  a highly significant  and  clear dose/response
relationship  between increasing air  pollution  indices and  lower respiratory  tract infection
prevalence  rates seen  in Table  14-6,  as indexed by virtually all  of  the health measures used.
It  has  been  noted  that:   "Higher  illness  rates  were  noted in all  higher pollution classes"
(NRC/NAS, 1978); and "Socio-economic  status was important in the  study but a relationship...
still existed within separate  social  classes"  (WHO,  1979).  These results appear  to  provide
qualitative  evidence  linking the occurrence of  lower respiratory tract infection  in children
under age 11 to long-term exposures to polluted air containing  elevated levels of  SO,,  and PM.

                TABLE 14-6.   FREQUENCY OF LOWER  RESPIRATORY TRACT  INFECTIONS OF
                            CHILDREN IN BRITAIN  BY POLLUTION LEVELS,  %
1962-1963
Mean annual pollution level

Lower respiratory
tract infections
First attack in first 9 months
At least one attack in first two years
More than one attack in first two years:
Boys
Girls
Middle class
Manual working class
Admission to hospital in first five years:
Lower respiratory infection
Bronchitis
Pneumonia
Very low
Smoke: 67
S0£: 90
7.2
19.4
4.3
5.7
2.9
3.0
5.1

1.1
0.0
1.1
Low
132
133
11.4
24.2
7.9
8.1
7.7
4.0
10.8

2.3
0.9
1.4
Moderate
190
190
16.5
30.0
11.2
10.9
12.1
7.7
13.9

2.6
1.0
1.6
3
s , |jg/m
High
205
251
17.1
34.1
12.9
16.2
9.7
9.3
15.4

3.1
1.4
1.8

    From Douglas and Waller (1966).

     It  is  impossible, however,  (based  on the  above reported results)  to  estimate specific
quantitative  levels  of S02  or PM that may  be  associated with the observed  health  effects in
the study.   Douglas  and Waller (1966) suggested that  these  children probably were exposed to
higher pollution concentrations  in their early  lives  than suggested by the measurements made
in  1962-63  because  of  the  improvement  that followed the 1956 United  Kingdom  Clean Air Act.
Furthermore,  attempting  to   retrospectively  estimate  past  pollutant  exposure   levels  from
limited  (1-2  yrs)  data  following known or  suspected marked changes  in  study  area pollutant
SOX14G/A
14-26
2-14-81

-------
concentrations  usually tends  to  invalidate or  substantially  decrease  confidence  in study
findings, at  least  concerning quantitative  air pollution/health effects relationships.  Thus,
fundamental  deficiencies  preclude the  use  of  the aerometric  data  quantitatively, e.g., the
lack  of  data  for  all  study  areas and  apparent  failure to  have  used site-specific calibra-
tions for BS readings  in all areas.
      Further  study  of  the Douglas and Waller  population at 20 years of age indicated  that in
the  then now young  adults,  cigarette smoking had the greatest effect  on  respiratory  symptom
prevalence, followed by a history  of  lower respiratory tract illness under 2 years of age.  At
this  time  of their lives, social  class  and  air pollution had  little effect.  The standardized
prevalence rate  (percent), however, was  higher among the group  who had lived in high-pollution
areas (11.51)  than  in  those who  had lived  in the  low-pollution  area (10.20) but the difference
was  not  significant.   This study  would  appear to  indicate that the effects of exposure to air
pollutants in  high  concentrations  during the first 11 years of  life had disappeared by  age 20,
unless  there was a  history  of  lower  respiratory illness before age  2.   However,  no specific
information  is provided in the report to indicate the concentration of pollutants to which the
children were  exposed  after 1957 when they were 11 years old.
      A final  survey, when the study population was 25 years old, confirmed the observation made
5  years  earlier.  At  this time, Kiernan et  al. (1976) reported that smoking continued  to have
the  greatest effect on  respiratory symptoms and  lower  respiratory  illness.   The association
with  air  pollution was  again   a  positive  one and  stronger  than had  been observed  5 years
earlier, but  was not statistically significant.
      An  association between  air pollution and lower respiratory tract illness in children was
also  observed by Lunn et al.  (1967).   These investigators  studied  respiratory  illness in 5-
and  6-year-old schoolchildren living in four areas of Sheffield, England.   Air pollution con-
centrations  showed a  gradient   in 1964  across  four study  areas for  mean  24-hour smoke (BS)
                            3            3
concentrations  from 97 ug/m  to 301  (jg/m   and the same gradient for  annual  mean 24-hour S0?
                             33
concentrations  from 123  ng/m  to  275 ug/m .  The  following year, the annual concentrations of
 smoke  were about 20 percent  lower  and  SCL about 10 percent higher, but the gradient was pre-
 served for each pollutant.   In  high-pollution areas, individual 24-hour mean smoke concentra-
 tions  exceeded 500 (jg/m   30  to  45  times in 1964 and 0 to 15 times in 1965 for the lowest and
 highest  pollution  areas,  respectively.   S0? exceeded 500 ug/m  11 to 32 times in 1964 and 0 to
 23  times  in  1965  for  the lowest and  highest pollution  areas,  respectively.   Information on
 respiratory  symptoms  and  illness was obtained by  questionnaires completed by the parents, by
 physical  examination,   and by tests of pulmonary  function  (FEV~ ?I-  and FVC).   Socioeconomic
 factors  (SES) were considered  in the  analyses,  but home  heating  systems  were  not.   Although
 certain  differences  in SES between areas  were  noted,  the gradients between areas would exist
 even when  the groups were divided  into social  class,  number of children  in  house,  and so on
 (1977).  Positive  associations  were found between air pollution concentrations and both upper
 and  lower  respiratory   illness.    Lower  respiratory  illness  was  33 to 56 percent more frequent
SOX14G/A                                    14-27                                          2-14-81

-------
in the  higher  pollution areas than in the low-pollution area (p <0.005).   Also, decrements in
lung function  as  measured by spirometry tests were  closely  associated with the occurrence of
respiratory disease symptoms.
     The  authors  of the  study  (Lunn et  al.,  1967)  highlighted the following  points  in dis-
cussing their results:
            "The respiratory measurement findings showed no association with area, social
       class,  children  in the house,  and sharing of  bedrooms,  although Attercliffe, the
       area  of highest pollution,  showed reduced F.E.V.n JC- and F.V.C.  ratios.   On the
       other hand,  very clear evidence  of reduced F.E.V.Q?5  ratios emerged where there
       was a past  history of pneumonia and bronchitis, persistent  or  frequent cough,  or
       colds going to the chest.   It must be stressed that these findings  relate to first
       year  infant  schoolchildren  and that measurements were made during  the summer term
       when  pollution  levels were  low  and  acute  respiratory  infections  few  and  far
       between.  In  other words,  a pattern of respiratory disability  had appeared at an
       early  age  and  was sufficiently  established  to persist  although  the  factors  of
       pollution and infection were temporarily absent or at  a low level."
     In a  second  report,  Lunn et al. (1970) gave  results for 11-year-old children studied in
1963-64 that were similar to those provided earlier  for  the younger group.   Upper  and lower
respiratory  illness  occurred more  frequently  in children exposed  to  annual  average  24-hour
mean  smoke (BS) concentrations  of  230 to  301 ug/m   and 24-hour mean SO,  concentrations of
             o                                                    33
181-275 ug/m   than  in  children  exposed to smoke  (BS)  at  97  ug/m  and  S02 at 123 ug/m .  This
report also provided additional  information obtained in 1968  on 68 percent of the children who
were  5  and  6  years in 1963-64.   By 1968, tlie  concentrations of smoke  (BS)  were  only about
one-half  of  those  measured in 1964, and  S0» concentrations  were about 10 to 15 percent below
those measured in 1964.   By 1968  the  pollution  gradient no longer existed,  so  the combined
three higher pollution areas were compared with the single original  low-pollution area.  Lower
respiratory illness prevalence measured as "colds going to chest" was 27.9 percent in the low-
pollution  area  and  33.3 percent  in the combined  high-pollution  areas,  but the difference was
not statistically  significant (p  >0.05).   (Ventilatory function results were similar.)  Also,
the  9-year-old children  had less  respiratory  illness than  the  11-year-old group  seen pre-
viously.   Since  11-year-old  children  generally  have  less  respiratory  illness  than  do
9-year-olds, this  represented an  anomaly that the authors suggested may  have been the result
of improved air quality.  It should be noted that these Lunn  et al.  (1967, 1970) findings have
been  widely  accepted (Rail,  1974;  Higgins, 1974;  Holland and Bennett  et al. ,  1979; National
Research  Council,  1978a;  National  Research Council, 1978b; WHO, 1979)  as being valid, and, on
the basis  of  the  results reported  it  appears that increased  frequency  of lower respiratory
symptoms  and decreased lung  function in children  clearly occur with  long-term exposures to
annual BS  levels  in the range of 230-301  ug/m3  and S02 levels of 181-275 ug/m3.  Also, based
on the  1968  follow-up  study results, it  appears  to  be warranted to conclude that no observed
effect  levels  were  demonstrated  by the study  for  BS levels  in  the  range of 48-169 ug/m  and
                                      o
SO- levels in the range of 94-253 ug/m .
SOX14G/A                                   14-28                                         2-14-81

-------
     Rudnick  (1978),  as part  of  a well-designed  and  methodologically-sound study, collected
information by a  self-administered  questionnaire on respiratory  symptoms  and disease in 3805
children, 8  to 10  years  old,  living  in  three communities in Poland with  differing air pol-
lution  concentrations.    The  questionnaire  sought  information   on  respiratory  symptoms  and
symptoms of asthma during the previous 12 months.  Mean pollutant concentrations in the higher
pollution area for the years 1974 and 1975 were 108 to 148 ug/m3 for S00 (OECD) and 150 to 227
   .3                                                                                    3
ug/m  for  smoke  (OECD).   The  low pollution areas had SO, concentrations of 42 to 67 ug/m  and
                                     3
smoke concentrations of 53 to 82 ug/m .  Most symptoms of respiratory illness in both boys and
girls  occurred more  frequently  in the  high  pollution  area but  the  differences were,  in
general,  nonsignificant.   There  was  a  higher  prevalence of  breathlessness,   sinusitis  and
asthma  attacks  in boys  living  in the  high  pollution  area but only "runny nose in the last 12
months" occurred  more frequently in girls in the same area.  There were no significant differ-
ences  between the  frequencies  of  nonchronic  cough,  attacks  of  breathlessness,  shortness of
breath,  or  multiple cases of pneumonia associated with the different pollution levels.  These
results,  however, cannot be taken  as  indicative  of  no-effect levels at above  S0? and  smoke
concentrations due to ambiguities concerning the measurement methods used, e.g., whether site-
specific calibrations were employed in generating the mass estimates for smoke rather than the
OECD standard curve, and given  that at least some weak indications were reported for increased
symptomatology in the high pollution areas.
     In  the  United  States,  a  retrospective survey  conducted  by  Hammer (1976, 1977) regarding
the  frequency of lower respiratory  illness  in children  was undertaken in  1971  in  two south-
eastern  cities,  using  similar questionnaire sampling as employed in certain other EPA "CHESS"
program  studies  (Hammer  and  Miller  et al.,  1976; French and  Lowrimore,  1975).   Data  were
obtained  by  questionnaire from parents of about 10,000  children  aged 1 to 12 years.  The two
communities  represent  intermediate  and high particulate exposures  (annual  averages of 74-112
    3                   3
ug/m   and 133-169  ug/m  TSP,  respectively,  for 1960 to  1971),  with  low  annual  average S09
                    3
exposures  (<25 ug/m  in both  communities).   The analysis  of  data  indicated  that  in the high
exposure  community  (Birmingham)  there was  significantly  increased respiratory  disease  over
that  for the lower exposure community (Charlotte), based on statistically significant results
obtained  on 10 of  17  measures  of  respiratory  morbidity.  This  included  more  pneumonia and
croup  among blacks and more lower  respiratory disease,  bronchitis and croup among whites in
Birmingham  than  in  Charlotte.   There was also  a consistent trend for the association of more
illness  and  hospitalization  with higher pollution  to become stronger in older children.   This
suggests  that the effect increased with extended  exposure.   The  investigators concluded that
differences  in  parental recall, questionnaire  reliability, family size, crowding, or parental
smoking  habits  were not  likely explanations  for  the excess  morbidity  in  the high-pollution
areas,  since these factors were not statistically significantly different between communities.
The  results,  therefore, were  taken to be indicative of associations  between increased lower
respiratory  disease  rates  in children and exposure to  moderately elevated particulate matter
SOX14G/A                                   14-29                                         2-14-81

-------
levels  in  the  presence of low S02 levels.  Asthma rates clustered in families, were higher  in
male children and female parents, and were comparable to other studies.   Significant increases
of  lower  respiratory disease were also  reported  for asthmatic children  in  the high exposure
community.  The  above  aspects  of the Hammer  (1976,  1977)  study appear to provide a basis for
arguing that it demonstrates, at least qualitatively, that significant respiratory effects  in
children are associated with elevated particulate matter air concentrations in the presence  of
very low  levels of SCL.
     Certain  other  aspects  of  the  study, however,  argue  for caution  in  fully accepting its
reported  findings  and  conclusions.   The investigators  assumed  that  cigarette-smoking  for
children  under  age  13  in the South was minimal, equally distributed, and did not affect their
results.   Also, although  the  response rates  were  excellent  in  both communities,  they were
significantly  lower  in  Charlotte  (88 percent) than  in Birmingham  (95 percent)  and signifi-
cantly  lower  for Blacks  (84 percent) than  for Whites (89  percent) within  Charlotte.   Such
small  differences  in  response  rates  in  absolute terms may  be unlikely to  have  affected the
overall  study  results  but  the  possibility  cannot  be completely  discounted;  nor can  the
possible  confounding effects of smoking  be ruled out  completely.   Nor  were the questionnaire
results  checked for test-retest  reliability  to verify accuracy  and consistency  of parental
recall  of  illnesses  for  their  children  or  validated against doctor  or  hospital  records.
Furthermore, major reservations  exist regarding the extent to  which the  reported air quality
data are  accurate  and  adequately representative of  the respective study population exposures;
most notably,  exposures  over much of the  lifetimes  of the  older  children (i.e.,  over 4 years
of  age)  were  estimated using monitoring data  from  a  single  site  or at best  a few sites that
were not located directly in the residential  areas being studied.*
     In  another  American study,  possible  pulmonary  function  decrements  were  studied  in
Cincinnati  schoolchildren  in 1967-1968  by Shy et  al. (1973).   Children  from schools  in an
industrial  valley of Cincinnati  were  compared with children  from  schools in a non-industrial
river  valley  on the  east side of the metropolitan  area.   Two each upper-middle white,   lower-
middle  white,  and  lower-middle  black  schools were  selected  from  each valley.   Air monitoring
stations within  three  blocks of the  schools  showed  that  7-month  average TSP values were from
18  to  32  ug/m  higher  in the industrial  valley than in the non-industrial valley, but  little
or  no  differences existed  in  corresponding   levels  for S09.   Arithmetic  averages  over  the  7
                                                        3
months  of  the  study  ranged  for TSP from  96  to 114  ug/m  in the more polluted industrial area
and  from  77 to 82 ug/m  in  the  cleaner  areas.   The 7-month average for S09 ranged from 39 to
        3                                                 3
51  ug/m   in  the polluted areas  and from 40 to 45  ug/m   in  the  clean  areas.   Ventilatory
function was measured  as the forced expiratory volume at  .75 second (FEV -,,-) on a Stead-Wells
*Note that the health effects results described here for the Hammer (1976; 1977) dissertation
 study were based on analysis of unvalidated computerized data tapes.   Recent realysis of the
 data based on validated  data tapes, however, has produced results very close to those reported
 in the Hammer dissertation and the results are in the process of being prepared for peer review
 and publication.

SOX14G/A                                   14-30                                         2-14-81

-------
water-filled spirometer once weekly on each child during  each  of  the  study months.   The  better
of two satisfactory forced expiratory maneuvers obtained  on  each  test  day was  used  for all  com-
putations.   Height,  sex, and  race  were  used to make  adjusted FEV -,,- comparisons.   The  study
was  confined to  394  second graders  who participated  in weekly measurements during November
1967, February 1968, and May 1968.  These students  represented 93  percent of second  graders  in
the  classrooms  selected.   Mothers were  interviewed to obtain  socioeconomic data.   The  educa-
tional attainment of  fathers was similar for corresponding  schools in the industrial and non-
industrial valleys.
     The  Shy et al.  (1975) data  showed  that average height  adjusted  FEV 75 in "clean" schools
exceeded  that  in "polluted" schools  in  all 3 months for  lower-middle  class whites and in 2  of
3  months  for  upper-middle  whites.    Blacks  consistently had  lower FEV  75  values,  and a pol-
lution  effect was  seen  among  blacks  during only  one of three  study periods.   The absolute
differences  in average FEV -,,.  were  roughly  40-120  ml   (<10  percent)  in  most  cases.   A  multi-
variate  analysis  of  variance  was  applied  which  allowed   for  testing  of  community effects
adjusted  for a  possible  month effect  and  for  the covariates  height,  sex,  race,   and  social
class.  The  dependent variable for each child  was  his vector of  three monthly average  FEV  -,^
values.   However, the authors  reported  that no association  existed between acute exposures  to
24-hr  TSP levels and pulmonary function test  results  obtained on the same or following  days,
making  it difficult to ascribe the relatively weak observed differences in pulmonary function
between  the study  areas  to the  very small differences  in annual average  TSP  levels  in  the
respective  study areas.
      In  summary, one  set of  the above  studies, by  Lunn et  al.  (1967, 1970)  in  Sheffield,
England,  provides clear evidence for significant pulmonary  function  decrements  and  increased
respiratory  disease  illnesses  in  children being associated with  chronic exposure  to  SCL  and  PM
in the ambient air.  Two American  studies (Hammer, 1976, 1977;  Shy et al., 1975) also provide
suggestive  but  controversial (mainly  qualitative) evidence indicative  of possible increases  in
lower  respiratory tract diseases  and  pulmonary  function decrements in  children being associat-
ed with elevations  in  ambient  air PM  in  the absence of marked  elevations in S0?  levels.
14.5  CHAPTER  SUMMARY  AND CONCLUSIONS
      Some of the epidemiological  studies reviewed above appear to  provide meaningful  quantita-
tive information  on  health  effects associated  with  ambient  air  exposures to  PM and S0?.
Others,  however, do not meet  as  fully  the various objectives discussed earlier  under Section
14.1.2  or ambiguity  exists regarding clear  interpretation of  their reported results.  Only
some of  the study  results can, therefore,  be  accepted  with  a relatively high degree  of
certainty or confidence, whereas others may  be seen as providing,  at best, only  suggestive
evidence  for the reported  associations between air pollutant parameters  and health  effects.
The main  focus of the present section  will  be on  summarizing results and conclusions derived
from selected key studies  having a  relatively  high degree  of certainty associated with their
findings.
 SOX14G/A                                    14-31                                         2-14-81

-------
     In general, the epidemiological studies reviewed above provide strong evidence for severe
health effects,  such  as  mortality and respiratory diesease,  being  induced in certain popula-
tions at  special  risk by marked elevations at atmospheric levels of sulfur dioxide and parti-
culate matter.   Those  populations at special risk for such effects appear to include, mainly,
the  elderly  and adults  with  chronic  pre-existing  cardiac  or  respiratory diseases  (e.g.,
bronchitics).   Increased  lower  respiratory  tract  illnesses  and  more  transient  (likely
indicator)  effects, e.g.,  decrements in  pulmonary function,  also  appear  to be associated for
children  with  lower chronic  exposures to sulfur dioxide  and  PM.   Also,  some qualitative epi-
demiological evidence suggests that asthmatics may be a susceptible population at special  risk
for experiencing pulmonary function decrements in response to  elevations  in SO,, and PM.
14.5.1  Health Effects Associated with Acute Exposures to Sulfur Oxides and Particulate Hatter
     As  noted  earlier  in  the  present   chapter,  it  is  widely  accepted  that  increases  in
mortality occur  when  either  S09 or particulate matter  levels increase beyond 24-hr levels of
          3
1000 |jg/m .   Such increased mortality, mainly in the elderly or chronically ill, may logically
also be most directly attributed to very high short-term peak levels in  the pollutants,  which
at times  increased to several  thousand ug/m  during certain major pollution episodes.
     Much more  difficult to  establish are  to what extent significant increases  in mortality
and morbidity are associated with exposures to S0? and/or particulate matter levels below 1000
    3
ug/m .  Concisely summarized  in Table 14-7 are several  key studies that  appear to demonstrate
with  a  reasonably high  degree  of certainty,  mortality and morbidity  effects  associated  with
acute exposures  (24 hrs)  to  these  pollutants.   The first two  studies  cited, by  Martin and
Bradley (1960) and Martin (1964), deal with a relatively small body of data from London in the
late 1950s.   No  clear "threshhold"  levels were revealed by their analyses regarding S0?  or BS
levels  at which significantly  increased  mortality  began to occur.  Based  on  their findings,
there appears  to be  little  question that  mortality in  the  elderly  and  chronically  ill was
elevated  in  association with exposure to  ambient air containing simultaneous S09 and BS levels
                                        3
somewhere in the  range of 500-1000 ug/m  .  Greatest certainty applies for levels in excess of
700-750 ug/m .   Much   less certainty is   attached  to lower estimates  possibly  derived  from a
reanalysis  of  the  same data  set  by  Ware  et al.  (1981), which applies to  mortality data from
very brief  periods  during the two  London winters.   It  seems  more likely  that  levels  well  in
excess  of 500 ug/m   BS  and  S02  are typically  necessary in  order  to induce  mortality  among
highly susceptible elderly or chronically ill individuals.
     Only very  limited data  exist by which to  attempt  to delineate any specific physical and
chemical  properties  of  PM associated with  the  observed increases  in  mortality.   Based  on
information  noted  earlier  (Section  14.2),  it would  seem  that marked  increases  in  small
particles to levels above 500-1000  ug/m   appear to  be  most clearly associated with increased
mortality,  based on  the BS  aerometric   measurements  reported,  although  contributions  from
larger coarse-mode particles  cannot be completely ruled out.   Nor is it possible to state with
certainty specific PM chemical species associated with the increases in mortality.  We do know
SOX14G/A                                   14-32                                         2-14-81

-------
                   TABLE  14-7.   SUMMARY OF QUANTITATIVE CONCLUSIONS FROM EPIDEMIOLOGICAL  STUDIES  RELATING  HEALTH
                              EFFECTS OF ACUTE  EXPOSURE TO S02 AND  PARTICULATE MATTER TO AMBIENT AIR  LEVELS
Type of study
Mortality
Effects studied
Likely increases in daily
24-hr average pollutant level (pg/m )
particulate matter
CoH BS TSP S02
>1000 - >1000
Reference
Martin and
                          total mortality above a
                          15-day moving average during
                          winter 1958-59 among persons
                          with existing respiratory
                          or cardiac disease  in London.
                                                                                   Bradley (1960)
CO
GO
Slight indication of likely
increases in daily total
mortality above a 15-day
moving average during winters
of 1958-59 and 1959-60 among
persons with existing respira-
tory or cardiac disease in
London.
                                                                    750-1000
                   710-1000
                     Martin (1964)
    Morbidity
Likely worsening of health
status among a group of
chronic bronchitis patients
250-500
500-600
Lawther et al.
(1958, 1970)
                          No  apparent  response or
                          worsening  of health status
                          among  a  group of chronic
                          bronchitis patients
                                            <250
                    <500
                     Lawther et al.
                     (1970, 1975)

-------
that  large  amounts of  pollutants  (e.g., elemental  carbon,  tarry organic matter,  etc.) from
incomplete combustion of coal were present in the air,  but no single  component or combinations
of  particulate  pollutants can clearly  be  implicated.   Nor can the  relative  contributions of
S02 or particulate matter be clearly separated based on these study results or possible inter-
active effects with  increases  in humidity (fog)  completely ruled  out;  but temperature changes
do not appear to be important in explaining the mortality effects  observed in  Martin's studies.
     A study  by  Glasser and Greenberg  (1971), not  listed in the  table,  similarly  appears to
suggest,  with  less  confidence,  that slight mortality increases were  associated with increases
in  S02 above  786-1048 ug/m3 and in CoHs levels of 5.0-7.0.   These latter levels likely corre-
spond  to  concentrations in excess  of 570-720  pg/m3 BS equivalent units  based  on  calibration
studies by  Ingram alluded  to  above.    Again  specific  particulate chemical species  cannot be
clearly implicated nor the relative contributions of S02 and particulate matter separated.   It
should be noted  that, whatever,  the causal  agents,  only very small  increases  in mortality may
have been detected at the above pollutant levels  in New York City.
     Similar  analysis of Lawther morbidity  studies  listed  in Table  14-7  suggests  that acute
                                                                   O
exposure to elevated  24 hr PM levels in  the  range  of  250-500 ug/m  (BS)  in  association with
24-hr  S02  levels of  500-600 ug/m3 were  likely  associated with the induction  of  respiratory
disease symptoms  in  chronically ill  London  bronchitis patients.   Again,  little can  be said,
however,   in  terms of specifying physical or  chemical  properties of  PM associated  with  the
observed effects beyond the comments noted above  in relation to Martin's studies on mortality.
     In regard to  chronic  exposure  effects  of S0?  and  particulate matter, the best pertinent
epidemiclogical health studies are summarized in  Table  14-8.   The  Lambert and  Reid  (1970) study
suggests  that  respiratory disease  symptoms  (cough  and phlegm) are  associated  with long-term
(annual-average) exposures of  adults  to PM levels in the range of 100-200 ug/m  (BS) or above
in  association with  S0? levels in the range of 150-200 ug/m  or above.   The studies by Ferris
et al. (1973,  1976) suggest that lung function decrements may occur in  adults  at TSP levels in
                   o
excess of 180  ug/m  in the presence of  relatively low  estimated SCL  level, whereas no effects
were observed by the  same investigators  at TSP levels below 130 g/m  or by other investigators
(Holland and Stone, 1965; Deane et al.,  1965; Comstock  et al., 1973)  at TSP levels  in the range
of  70-163  ug/m ,  based  on  surveys of  chest illness and symptoms prevalence.   Other studies
listed in Table 14-8  suggest that significant respiratory effects  occur in children in associ-
ation with  long-term  (annual  average)  PM levels  in the range of 230-301 ug/m  (BS) in associ-
                                       3
ation  with  S09 levels  of  181-275 ug/m .  No  effects  were  seen for children,  however,  at PM
                                    "\                                       \
levels in  the range  of 48-169  ug/m  (BS)  or at S02  levels of 94-253 ug/m  .   One study, by
Hammer suggested  possible respiratory effects in children  at an  annual  average TSP  level of
135-169 ug/m in the  presence  of  very low S02  levels,  but controversy  and questions regarding
the conduct of the study, data analysis, and aerometric measurements  cloud its interpretation.
SOX14G/A                                   14-34                                         2-14-81

-------
I
co
01
     Cross-sectional
     (5 cities)
                            TABLE 14-8.  SUMMARY OF QUANTITATIVE CONCLUSIONS FROM EPIDEMIOLOGICAL STUDIES
                                  RELATING HEALTH EFFECTS OF CHRONIC EXPOSURE TO S0? AND PARTICULATE
                                                     MATTER TO AMBIENT AIR LEVELS
Type of study
Cross-sectional
(4 areas)
Cross-sectional
(4 areas)
Cross-sectional
(4 areas)
Longitudinal
and cross-
sectional
Longitudinal
and cross-
sectional
3
Annual average pollutant levels (HQ/ro )
parti cul ate matter
Effects studied CoH BS TSP S02
Greater prevalence of cough - 100-200+ - 150-200+
and phlegm in areas of elevated
BS and S0? pollution, observed
in survey of 10,000 British
postal workers.
Likely increased frequency - 230-301 - 181-275
of lower respiratory symp-
toms and decreased lung
function in children
No observed effect on res- - 48-169 - 94-253
piratory symptoms and lung
function in children
Apparent improvement in - - 180
lung function of adults
in association with decreased
PM pollution in Berlin, N.H.
Apparent lack of effects - - 80-131
and symptoms , and no
apparent decrease in lung
function in adults
Reference
Lambert and Reid
(1970)
Lunn et al .
(1967)
Lunn et al .
(1970)
Ferris et al.
(1973, 1976)
Ferris et al .
(1973, 1976)
No apparent evidence of
increased symptom pre-
valence or chest illness
among telephone plant
workers
70-163
Holland and
 Stone (1965)
Deane et al.
 (1965)
Comstock et al.
 (1973)

-------
     Again,  no  specific  particulate  matter  chemical  species  can clearly  be implicated  as
causal agents associated with the effects observed in  those  studies listed in Table 14-8.   Nor
can potential contributions  of  relatively large inhalable coarse mode particles  be ruled out
based on these  study  results;  and,  it should be remembered,  that various  occupational  studies
listed  in   Appendix   C  at  least qualitatively suggest  that  such  sized particles  of  many
different  types  of  chemical   composition  can  be   associated   with  significant  pulmonary
decrements, respiratory tract pathology,  and morphological damage.
     It  should  also   be  noted  that  certain  studies  not listed  in Tables 14-7  and 14-8  but
discussed  in  Sections 14.3  and  14.4,  or Appendices A and B, suggest that respiratory  effects
(usually pulmonary  function  decreases)  may occur  in association with  lower annual  average
exposure levels that those seen in Tables 14-7  and 14-8.   Particular  features of most of those
studies  or ambiguities about their  results, however, preclude  acceptance  of their findings
with much confidence at this time.
SOX14G/A                                 14-36                                           2-14-81

-------
14.6  REFERENCES


Anderson,  D.  0.,  and  A.  A.  Larsen.   The  incidence of  illness  among young  children  in  two
     communities  of  different air quality:   A  pilot study.   Can.  Med.  Assoc.  J.  95:893, 1966.

Anderson,  D.  0.,  and B. G. Ferris, Jr.   Air  pollution  levels and  chronic  respiratory disease.
     Arch. Environ.  Health  10:307-311, 1965.

Anderson,  D.  0.,  B.   G.   Ferris,  Jr.,  and  R.   Zinkmantel.   Levels  of  air  pollution  and
     respiratory  disease  in  Berlin,  New Hampshire.  Am.  Rev.  Respir.  Dis. 90:877-887,  1964.

Angel, J.  H. , C.  M. Fletcher,  I.  D.  Hill, and C.  M.  Finker.  Respiratory  illness  in factory
     and office workers.  Br. J. Dis. Chest 59: 66-80,  1965.

Apling, A. J. , A. W. C. Keddie,  and M.L.  P. M.  Weatherby  et  al.  The  high  pollution  episode in
     London,  December,  1975.   Report LR  263  (AP).  Stevenage, Warren Spring  Laboratory, 1977.

ATS.  Epidemiology  Standardization Project.   Am.  Rev. Res. Dis.  118(6,pt.2),  1978.

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.

Ball, D. J. ,  and  R.  Hume.   The  relative  importance  of vehicular  and domestic  emissions of dark
     smoke in Greater London in the  mid-1970's,  the significance  of  smoke  shade  measurements,
     and  an  explanation  of  the  relationship of  smoke shade to  gravimetric measurements  of
     particulate.   Atmos. Environ. 11:1065-1073,  1977.

Bates,  D.  V.  Air  pollution  and  chronic bronchitis.   Arch. Environ.  Health 14:220,  1967.

Bates,  D.  V.  The  fate of  the  chronic bronchitic:  A  report of the ten-year  followup  in the
     Canadian Department of  Veterans Affairs  Coordinated Study  of  Chronic Bronchitis.   Am.
     Rev.  Res. Dis.  108:1043, 1973.

Bates,  D.  V., C. A. Gordon,  G.  I.  Paul, R.  E. G.  Place,  D.  P.  Snidal, and C.  R.  Woolf. (with
     special  sections contributed by  M.  Katz, R.  G.  Fraser,  and  B. B. Hale)  Chronic bronchitis.
     Report  on the  third and fourth  stages  of the  Coordinated  Study of Chronic  Bronchitis in
     the  Department of  Veterans  Affairs.  Canada.   Med. Serv. J. Can. 22:5, 1966.

Bates,  D.  V.,  C.  R. Woolf,  and G.  I.  Paul.   Chronic  bronchitis:  A report on the  first two
     stages  of the  Coordinated  Study  of  Chronic Bronchitis in the  Department of Veterans Affairs.
     Canada.   Med.  Serv. J. Can. 18:211,  1962.

Becklake,  M.  R. , F. Aubry, J.  Soucie, F. White,  J.  Swift, E. Ghezzo, and  W.  G.  Gibbs.  Health
     Effects  of  Air Pollution in the  Greater  Montreal  Region: A Study  of  Selected Communities.
     Final  Report.   Dept. of  Epidemiology and Health, McGill  University, 1975.   See  also Aubry,
     F., W.  G. Gibbs, and M.  R.  Becklake, Arch. Environ.  Health  34:5, 360-368,  1979.

Bennett,  A.   E. ,  W.  W.  Holland,  T.   Halil,  and A.  Elliot.   Lung  function and  air  pollution.
     Chronic  inflammation of  the bronchi.   Prog.  Respir.  Res. 6:78-89,  1971.

Bennett.  1973

Biersteker,  K.  Polluted Air Causes, Epidemiological  Significance,  and Prevention  of Atmos-
     pheric  Pollution.   Assen,  Netherlands,  Van Gorcum  and  Co.,  pp.  21-23  (in  Dutch), 1966.

Biersteker,  K.,  and P. van Leeuwen.   Air pollution and  peak flow rates of  schoolchildren in
     two districts  of Rotterdam.  Arch.  Environ.  Health  20:382-384,  1970.
SOX14D/B                                      14-37                                        2-18-80

-------
Biersteker, K. ,  and  P.  van Leeuwen.  Air pollution, bronchitis prevalence and peak  flow rates
     of schoolchildren  in  two districts of Rotterdam  (Netherlands).   In:   2nd  Int.  Uean Mir
     Cong.  Proc.  Washington,  D.C., December  1970.   H.  M.  England and W.  T.  Berry  (ed. ;.  new
     York, Academic Press,   p. 209-212.

Bouhuys,  A.,  G.  J.  Beck, and J.  B.  Schoenberg.   Do present  levels  of air pollution  outdoors
     affect respiratory health?  Nature 276:466-471, 1978.

Buck,  S.  F.,  and A.  D. Brown.  Mortality from Lung Cancer and Bronchitis in Relation  to Smoke
     and  Sulfur  Dioxide  Concentration,  Population Density, and  Social  Index.    Research Paper
     No.  7.   London, Tobacco Research Council.  1964.

Buechley, 1975.

Buechley, et al., 1975.

Buechley,  R.   W.   S0?  Levels,  1967-1972  and  Perturbations  in  Mortality.    Contract  No.
     ES-5-2101.   Report  available  from  National  Institute of  Environmental  Health  Sciences,
     Research Triangle Park, N.C., 1977.

Buechley, R. W.,  W.  B.  Riggan, W.  Hasselblad,  and J. B. Van Bruggen.  SO, levels  and  perturba-
     tions  in  mortality.   A  study  in  New York-New Jersey metropolis.  7\rch.  Environ.  Health
     27:134-137,  1973.

Burgess,  S.   E. , and  C.   W.  Shaddick.    Bronchitis and  air  pollution.   R.  Soc.  Health  J.
     79:10-24, 1959.

Burn, J.  L. ,  and J.  Pemberton.   Air pollution bronchitis and lung cancer in Salford.   Int.  J.
     Air Water Pollut.  7:5-16, 1963.

Burrows, B., A.  L. Kellogg, and J. Bushey.  Relationship of symptoms of chronic  bronchitis and
     emphysema to weather and air pollution.  Arch.  Environ.  Health 16:406-413,  1968.

Carnes, 1964.

Carnow, B. W.  Sulfur  oxides  and particles.   Effects  on  health.  Proceedings of the  National
     Academy  of   Science  Conference  on  Health  Effects  of  Air  Pollution.    U.S.  Government
     Printing Office, Washington, DC.  Stock No.  5270-02105,  1973.  pp. 263-291.

Carnow,  B.  W. ,  and P.  Meier.   Air  pollution and  pulmonary  cancer.   Arch.  Environ.  Health
     27:207-218,  1973.

Carnow,  B.  W. ,  M.  H.  Lepper, R.  B.  Shekelle, and J.   Stamler.   Chicago  air pollution  study.
     Arch. Environ.  Health 18:768-776, 1969.

Carroll,  R.  E.   Epidemiology of  New Orleans  epidemic   asthma.   Am.  J.  Public Health  58:1677,
     1968.                                                                             —

Cassell,  E.  J. ,  and M. D.  Lebowitz.  The Utility of  the  Multiplex Variable in  Understanding
     Causality.   Perspect.  Biol.  Med. 19(3):338-341, 1976.

Cassell,  E. J. ,  M.  D.  Lebowitz, and J.  R. McCarroll.   The Relationship Between  Air  Pollution,
     Weather,  and Symptoms in  an  Urban  Population.    Am. Rev.  Res.  Dis.  106:677-683,  1972.

Cassell,  E. J. ,  M.  D.  Lebowitz,  I.  M.  Mountain,  H. T. Lee,  D. J. Thompson, D.  W. Wolter, and
     J.  R.  McCarroll.   Air Pollution,  Weather,  and Illness  in  a  New  York Population   Arch.
     Environ.  Health 18:523-530, 1969.
SOX14D/B                                     14-38                                         2-18-80

-------
Cederlof,  R.   Urban  factor  and  prevalence of  respiratory  symptoms  and  "angina  pectoris."
     Arch. Environ. Health  13:743-748,  1966.

Chapman,  R.  S. ,   C.  M.   Shy,  J.  F.  Finklea, D.  E.  House,  H.  E.  Goldberg,  and C.  G.  Hayes.
     Chronic  Respiratory Disease in Military  Inductees and Parents  of  School Children.   Arch.
     Environ.  Health 27:138,  1973.

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.

Cioco and Thompson, 1961.

Clifton,  M.,  D.   Kerridge,  J.   Pemberton,  W.  Moulds,  and  J.  K.   Donoghue.   Morbidity  and
     mortality from bronchitis  in  Sheffield in four periods  of  severe pollution.   I_n:   Proc.
     1959 Int. Clean Air Conf.   London,  National  Society for Clean Air.  1960.   p.  189.

Col ley,  J.  R.  T.,  and D.  D.  Reid.   Urban and social  origins of childhood bronchitis in England
     and Wales.   Br. Med. J.  2:213-217,  1970.

Colley,  J.  R.  T.,  and W.  W.  Holland.   Social and Environmental Factors  in Respiratory Disease.
     Arch Environ.  Hlth.  14:157, 1967.

Collins, J.  J. ,  H. S.  Kasap, and W. W.  Holland.   Environmental  factors in child mortality in
     England  and  Wales.   Am.  J.  Epidemiol.  93:10,  1971.

Commins, B.  T. ,  and R.  E.  Waller.  Observations  from  a  ten-year study of pollution at a site
     in  the  city  of London.   Atmos.  Environ.  1:49-68,  1967.

Comstock,  G.  W. ,  R. W.  Stone,  Y.  Sakai, T.  Matsuya, and J.  A. Tonascia.   Respiratory findings
     and urban living.   Arch. Environ.  Health 27:143,  1973.

Cowan,  D. W.,  H.  J. Thompson, et al.   Bronchial asthma associated with  air pollutants from the
     grain  industry.  J.  Air Poll.  Contr.  Assoc.  13:546,  1963.

Deane,  M. ,  J. R.  Goldsmith,  and D. Tuma.   Respiratory  conditions in outside workers.  Report
     on  outside  plant  telephone  workers  in San  Francisco and  Los Angeles.   Arch.  Environ.
     Health  10:323,  1965.

Derrick, E.  H.  A  comparison between the density of  smoke in the Brisbane air and the preva-
     lence  of asthma.   Med.  J.  Aust.  11:670-675, 1970.

Dohan,   F.  C.   Air pollutants  and  incidence  of  respiratory  disease.   Arch.  Environ.  Health
     3:387-395,  1961.

Dohan,  F.  C. , and  E. W.  Taylor.  Air Pollution and Respiratory Disease, A Preliminary Report.
     Am. J.  Med.  Sci. 240:337,  1960.

Douglas  and  Waller,  1952.

Douglas, J.  W.  B. , and  R.   E.  Waller.   Air pollution and  respiratory infection in children.
     Br. J.  Prev.  Soc.  Med.  20:1-8, 1966.

Ellison, J.    The  estimation of particulate air  pollution from  the soiling of filter paper.
     Staub  Reinhalt,  Luft 28:28, 1968.

Emerson, P.  A.   Air pollution,  atmospheric conditions  and  chronic airway obstructions.  J.
     Occup.  Med.  15:635-638,  1973.
 SOX14D/B                                      14-39                                        2-18-80

-------
Environmental  Protection Agency.   Air Quality  Criteria  for  Sulfur Oxides.   U.S.  Department of
     Health,  Education,  and We]fare,  (Publ. AP-50),DC, 1969.

Environmental  Protection Agency.   Air Quality  Criteria  for  Particulate Matter.   U.S.  Depart-
     ment  of  Health,  Education, and Welfare,  (Publ. AP-49),  DC,  1969.

Fairbairn, A.  S. ,  and D.  D. Reid.  Air pollution  and  other local  factors  in respiratory disease.
     Br. J. Prev.  Soc. Med. 12:94, 1958.

Ferris,  B.  G. , Jr.   Health Effects of Exposures  to Low  Levels of Regulated Air Pollutants:  A
     Critical  Review.  JAPCA 28:482-497,  1978.

Ferris,  B.  G., Jr.,  and  D. 0.  Anderson.   The prevalence of chronic respiratory  disease  in a
     New Hampshire town.   Am. Rev. Respir. Dis.   86:165-177,  1962.

Ferris,  B.  G. , Jr.,  Burgess, W.  A.,  and J.  Worchester, J.   Prevalence of  chronic respiratory
     disease  in a pulp mill and  a paper  millin the United States.  Br. J.  Ind.  Med.,  24:26-37,
     1967.

Ferris,  B. G.,  Jr., H. Chen, S. Puleo, and R. L.  H. Murphy,  Jr.   Chronic  non-specific respira-
     tory  disease in  Berlin,  New Hampshire,  1967-1973.   A  further  follow-up  study.   Am.  Rev.
     Respir.  Dis.  113: 475-485, 1976.

Ferris,  B.  G. , Jr.,  I.  T. T. Higgins, M. W.  Higgins, J. M.  Peters,  W. F. Van  Guase,  and M. D.
     Goldman.   Chronic non-specific  respiratory  disease, Berlin,  New Hampshire,  1961-67:  A
     cross section study.  Am.  Rev. Respir. Dis.  104:232-244, 1971.

Ferris,  B.  G. , Jr.,  I.  T. T.  Higgins,  M. W.  Higgins, and  J.  M.  Peters. Chronic non-specific
     respiratory  disease  in Berlin, New Hampshire, 1961-67.  A follow-up  study.   Am.  Rev.  Respir.
     Dis.  107:110-122, 1973.

Ferris,  B.  G.,  Jr.,  I.   T.  T.  Higgins,  M. W.  Higgins,  and J.  M.  Peters.   Sulfur oxides  and
     suspended  particulates,  possible  effects  of chronic  exposure.   Arch.  Environ.  Health
     27:179-182,  1973.

Ferris,  B. G.,  Jr., J. R.  Mahoney, R. M.  Patterson, and  M. W. First.   Air quality, Berlin,  New
     Hampshire, March 1966 to December 1967.  Am.  Rev. Respir. Dis.  108:77-84,  1973.

Firket,  J.   Sur   les  causes  des  accidents  survenus dans  la   valee de  la Meuse,  lors  des
     brouillards  de Decembre, 1930.   Bull. Acad.  R. Med. Belg. 11:683-741,  1931.

Fletcher,  C.  M. ,  R.  Peto, C.   M. Tinker, and F.  E.   Speizer.  The Natural   History of  Chronic
     Bronchitis  and Emphysema  ( an eight year  study  of  early chronic obstructive lung disease
     in  working men in London). Oxford University  Press, 1976.

Fox  et al., 1979.

French and Lowrimore,  1975.

Friedman,  G.  D.   Primer of Epidemiology.  McGraw-Hill  Book Company,  a  Blakiston Publication,
     New York,  1974.

Fujita,  S., T. Motoichi,  K. Shoji, Y. Ichiro, F.  Takashi, S.  Seigo,  K. Tatsuo,  and M. Michiko.
     Studies  on chronic bronchitis  epidemiological survey (2nd  report).   Teishin Igaku 21:13,
     1969.

Gervois, M. ,  G.  Dubois,  S.  Gervois,  J. M.  Queta,  A.  Muller,  and C.  Vorsin.   Atmospheric
     pollution  and acute respiratory disease.  Denoin  and Quavrechoin epidemiological study.
     Rev. Epidemiol.  Sante Publique   25:195-207,  1977.


SOX14D/B                                      14-40                                          2-18-8C

-------
Glasser,  M.,  and  L.  Greenburg.    Air  pollution  and mortality  and weather,  New York  City,
     1960-64.   Arch. Environ. Health  22:334-343,  1971.

Glasser,  M.,  L.  Greenburg,  and  F.  Field.   Mortality  and Morbidity During a Period  of  High
     Levels  of  Air   Pollution,   New  York,   November   23-25,   1966.   Arch.   Environ.   Health
     15:684-694, 1967.

Goldsmith, J.  R., and  L. T.  Friberg.  Effects  of  Air Pollution  on Human Health.   In:   Air  Pol-
     lution .   II.  A.  C.  Stern,  ed., Academic Press, New York,  1977.   pp.  458-610.

Goldstein,  I.  F.,  and  G.  Block.   Asthma  and air  pollution in two inner city areas in New  York
     City.  J. Air  Pollut. Control  Assoc. 24:665-670, 1974.

Goldstein,  I.,  and  L.  Landowitz  (Letter to editor).  J.  Air Pollut.   Control Assoc.  25:1195,
     1975.                                                                             ~~

Goldstein,  I.  F. and  L.  Landovitz.  Analysis  of  air pollution  patterns in New  York City--I.
     Can  one  station  represent  the  large   metropolitan area?   Atmos.  Environ.   11:47-52,
     1977a.

Goldstein,  I.  F. and  L.  Landovitz.   Analysis  of  air pollution  patterns in New  York  City--ll.
     Can   one   aerometric   station   represent the  area  surrounding   it?   Atmos.   Environ.
     11:53-57, 1977b.

Gore,  A.  T. , and C. W.  Shaddick.   Atmospheric  pollution  and mortality in the County of London.
     Br.  J. Prev. Soc.  Med.  12:104-113. 1958.

Gorham, E.  Bronchitis and the  acidity  of urban precipitation.   Lancet  2:691,  1958.

Gorham, E.  Pneumonia  and  atmospheric sulphate deposit.   Lancet  2:287,  1959.

Greenburg,  L., C. Erhardt, F.  Field,  J. I.  Reid,  and N.  S. Seriff.   Intermittent air  pollution
     episode  in  New York City,  1962.  Public Health Rep.  78:1061-1064,  1963.

Greenburg,  L. , F. F. Field,  J.  I.  Reed, and C.  L.  Erhardt. Air  pollution and morbidity in New
     York City.  J.  Am.  Med. Assoc.  182:161-164,  1962.

Greenburg,  L. ,  F.  Field,  J.  I.  Reed,  and  C.   L.  Erhardt.   Asthma and  temperature change.   An
     epidemiological   study  of emergency clinic  visits  for asthma in  three  large   New  York
     Hospitals.  Arch.  Environ. Health  8:642,  1964.

Greenburg et al., 1967.

Gregory,  J.  The  influence  of climate and atmospheric  pollution on exacerbations of chronic
     bronchitis.  Atmos.  Environ.  4:453-468, 1970.

Hagstrom,  R.   M.,  H.  A.  Sprague,  and  E.  Landau.   The  Nashville air  pollution  study.   VII.
     Mortality  from cancer  in relation  to air pollution.  Arch. Environ.  Health 15:237-248,
     1967.

Hammer,  D. I.   Respiratory  Disease  in  Children  Exposed to Sulfur Oxides  and  Particulates.
     EPA-600/1-77-043, U.S.  Environmental Protection Agency,  Research Triangle Park,  NC, 1977.

Hammer, D.  I.,  F.  J.  Miller,  A.  G.  Stead,  and C.  G. Hayes.   Air Pollution and Childhood Lower
     Respiratory Disease.    I.  Exposure  to Sulfur Oxides and Particulate  Matter in  New York,
     1972.  _In:   Clinical  Implications  of Air Pollution Research.   A. J.  Finkel   and  W.  C.
     Duel,  edT,  Publishing Sciences Group,  Inc.,  Acton,  MA, 1976.  pp.  321-337.
 SOX14D/B                                      14-41                                        2-18-80

-------
Hammer, D.  I.   Frequency of lower respiratory disease  in children:  Retrospective survey of two
     southeastern communities,, 1968-1971.  Ph.D. Dissertation,  Harvard,  Univ.,  1976.

Heimann, H.   Episodic  air pollution  in metropolitan  Boston.   A  trial epidemiologic  study.
     Arch.  Environ. Health 20:230-251, 1970.

Hewitt, D.   Mortality  in the London boroughs,  1950-52,  with special  reference to respiratory
     disease.   Br. J. Prev. Soc. Med. 10:45, 1956.

Higgins,  I.  T.   T.    Epidemiology   of  Chronic  Respiratory  Disease:   A  Literature  Review.
     EPA-650/1-74-007, U.S. Environmental Protection Agency,  DC, 1974.

Higgins, 1978.

Higgins and Ferris. 1978.

Higgins and Ferris, 1979.

Higginson,  J.   Present trends in cancer epidemiology.  Proc. Can.  Cancer  Conf.  8:40-75,  1969.

Hill,  A.  B.  The Environment and Diseases:  Associations  and  Causation.  In:   Proceedings  of
     the Royal Society of Medicine (Occ. Med.) 58:272, 1965.

Hill,  1968.

Hodgson, A., Jr.   Short-term  effects of air pollution  on mortality  in New  York  City.   Environ.
     Sci. Technol. 4:589-597, 1970.

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. Epidemiol. 110(5):525-659,  1979.

Holland, W.  W.,   and D.  D.  Reid.   The Urban Factor in Chronic  Bronchitis.   Lancet  1:445-448,
     1965.

Holland, W. W. ,  and R. W. Stone.  Respiratory disorders in United  States  East  Coast telephone
     men.  Am. J.  Epidemiol.  82:92-101, 1965.

Holland, W.  W. ,  ed.   Data Handling in Epidemiology.  Oxford University Press,  London,  1970.

Holland, W.  W.,  H.  S.  Kasap,  J.    R.  T.  Colley, and  W.   Cormack.   Respiratory  symptoms  and
     ventilatory  function:  A family study.  Br. J. Prev.  Soc.  Med.  23:77-84, 1969.

Holland, W.  W. ,  T.  Halil, A.  E.  Bennett,  and  A. Elliot.   Factors influencing  the  onset  of
     chronic respiratory disease.  Br. Med. J. 2:205-208,  1969.

Holland, W. W. ,  T. Halil, A. E. Bennett, and A. Elliot.   Indications for  measures to be taken
     in  childhood to  prevent chronic respiratory disease.   Milbank Mem.  Fund  0  47-215-227.
     1969.                                                                          —'

Hrubec,  Z.,  R.   Cederlof,  L. Freberg,  R.  Horton, and  G. Ozolins.   Respiratory symptoms  in
     twins.  Arch. Environ. Health 27:189-195, 1973.

Ingram, W.   Smoke Curve Calibration.  PHS Contract PH-86-68-66,  New York University, New York,
     NY, 1969.

Ingram, W.  T. , and J.  Golden.   Smoke curve  calibration.  J. Air Pollut.  Control Assoc  23-110,
     1973.                                                                             " —'
SOX14D/B                                      14-42                                         2-18-80

-------
Ipsen,  J.,  M.  Deane,  and  F.  E.  Ingenito.    Relationship  of  acute  respiratory  disease  to
     atmospheric  pollution and meteorological  condition.   Arch.  Environ.  Health  18:462-472,
     1969.                                                                           —

Irwig,  L. ,  D.  G.  Altman,  R. J.  W.  Gibson,  and C. Du  V.  Florey.   Air Pollution:  Methods  to
     study  its Relationship to Respiratory Disease  in  British  Schoolchildren.   Proceedings  of
     the Intermath Symp on  Recent Advances with Asses,  of the Health  Effects of Environ.  Pol.,
     Luxembourg:   Commission of the  European  Communities,  Vol 1,  1975 pp.  289-300.

Ishikawa, S. ,  D.  H.  Bowden, V. Fisher,  and J.  P. Wyatt.  The  "emphysema  profile"  in two mid-
     western cities in North America.  Arch.  Environ. Health 18:660,  1969.

Jacobs,  C. , and  B.  Langdoc.   Cardiovascular deaths and air  pollution  in Charleston,  South
     Carolina.  Health Services Reports  87:623-632,  1972.

Joosting,   P.  E.   Air  Pollution   Permissibility  Standards   Approached   from  the   Hygienic
     Viewpoint.   Ingenieur,  79(50):A739-A747, 1967.

Kagawa,  J. , and  T.  Toyama.  Photochemical Air Pollution.   Arch.  Environ.  Health  30:117-122,
     1975.

Kagawa  et al., 1975.

Kagawa,  J., T.  Toyama,  and M.  Nakaza.   Pulmonary function tests  in children exposed to air
     pollution.   In:  Clinical  Implications of  Air Pollution Research.  A.  J.  Finkel  and  W.  C.
     Duel,  ed.,  Publishing Sciences  Group,  Inc.,  Acton,  MA,  1976.  pp.  305-320.

Kalpazanov,  Y. ,  M. Stamenova,  and G. Kurchatova.  Air pollution and the  1974-1975  influenza
     epidemic  in  Sofia.  Environ.  Res. 12:1-8,  1976.

Kevany,  J. , M.  Rooney,  and J. Kennedy.  Health  effects of air  pollution  in Dublin.  Ir.  J.
     Med. Sci. 144:102-115,  1975.

Kiernan,  K. E. ,  J. R.  T.  Col ley, J.  W.  B.  Douglas, and D. D.  Reid.  Chronic cough  in  young
     adults in relation to  smoking  habits, childhood environment and chest illness.   Respira-
     tion 33:236-244, 1976.

Lambert,  P. M. ,  and  D.  D.  Reid.  Smoking,  air  pollution  and  bronchitis  in  Britain.   Lancet
      K853-857,   1970.

Lave,  L. B., and  B. P. Seskin.  Air  pollution and human health.   The  quantitative effect, with
     an estimate  of  the  dollar  benefit of  pollution  abatement  is  considered.    Science
      169:723-733,  1970.

Lave,  L.  B. ,  and B. P.  Seskin.   Air pollution,  climate,  and  home  heating:  Their effects  on
     U.S. mortality rate?   Am.  J.  Public Health  62:909-916. 1972.

Lave,  L.  B.,  and B. P.  Seskin.   Air Pollution  and Human Health.  Baltimore, The Johns Hopkins
     University  Press.   1977.

Lawther, P. J.   Climate, air pollution and chronic bronchitis.   Proc. R.  Soc.  Med.  51:262-264,
     1958.

Lawther, et al.,  1958.

Lawther,  P. J.  Compliance  with  the Clean Air Act:  Medical  aspects.  J.  Inst.  Fuel  36:341,
     1963.
SOX14D/B                                      14-43                                        2-18-80

-------
Lawther, P.  J.,  A.  G.  F.  Brooks, P.  W.  Lord, and R. E. Waller.  Day-to-day  changes  in ventila-
     tory function  in relation  to  the environment.   Part  I.   Spirometric values.   Environ.
     Res. 7:24-40,  1974.

Lawther, P.  J. ,  A.  G.  F.  Brooks, P.  W.  Lord, and R. E. Waller.  Day-to-day  changes  in ventila-
     tory function  in relation  to  the environment.   Part  II.   Peak expiratory flow values.
     Environ. Res.  7:41-53, 1974.

Lawther, P.  J. ,  A.  G.  F.  Brooks, P.  W.  Lord, and R. E. Weller.  Day-to-day  changes  in ventila-
     tory function  in relation  to the environment.   Part  III.   Frequent measurements of peak
     flow.  Environ.  Res. 8:119-130. 1974.

Lawther, P.  J. ,  P.  W. Lord, A.  G.  F.  Brooks,  and R.  E. Waller.   Air pollution  and pulmonary
     airway resistance:  A pilot study.  Environ. Res. 6:424-435, 1973.

Lawther et al.,  1975.

Lawther,  P.  J. ,  R.   E.  Waller,   and M.  Henderson.   Air  pollution  and exacerbations  of
     bronchitis.  Thorax  25:525-539, 1970.

Lebowitz, M. D.  A comparative analysis of the  stimulus-response relationship between morta-
     lity and air pollution weather.  Environ.  Res.  6:106-118, 1973.

Lebowitz, M.  D.  A Critical  Examination  of  Factorial Ecology  and Social  Area  Analysis  for
     Epidemiological  Research.   Ariz. Acad. of Science 12(2):86-90, 1977.

Lebowitz, M.  D.  Methodology  of SOX/TSP  Health Effects Research  in Humans,  EPA,  in press,
     1980.

Lebowitz, M. D. , E.  J. Cassell, and J. D.  McCarroll.  Health and the Urban Environment.   XV.
     Acute  Respiratory Episodes as  Reactions  by  Sensitive  Individuals  to Air Pollution  and
     Weather.  Environ. Research 5(2):135-141,  1972.

Lebowitz, M., P. Bendheim, G. Cristea, D.  Markovitz,  J. Misiaszek, M. Staniec,  and  D.  Van Wyck.
     The  effect of  air  pollution  and weather  on lung function in exercising  children  and
     adolescents.  Am. Rev. Respir.  Dis. 109:262-273, 1974.

Lae,  R.  E.   Jr., J.  S. Caldwell, and  G.  B.  Morgan.   The evaluation  of  methods for measuring
     suspended particulates in air.   Atmos. Environ.  6:593-622, 1972.

Lepper,  M.  H.,  N.  Shioura, B.   Carnow,  S.  Andelman,  and L.   Lehrer.  Respiratory  disease in an
     urban environment.  Arch.  Indust.  Med. 38:36, 1969.

Levy, D., M. Gent,  and M. T. Newhouse.   Relationship between acute respiratory  illness and air
     pollution  levels  in an industrial city.  Am. Rev. Respir. Dis. 116:167-175,  1977.

Lindeberg, W.  Correlations between air pollutant concentrations and death  rates  in Oslo.   In:
     Air Pollution in  Norway.  III.   Oslo, Norway, Smoke Damage Council,  1968.              ~

Linn, W.  S. , J.  D.  Hackney, E.  E.  Pedersen,  P.  Breisacher, J. V. Patterson, C.  A.  Mulry, and
     J.  F.  Coyle.   Respiratory  function and  symptoms in urban office workers  in  relation to
     oxidant air pollution exposure.  Am.  Rev.  Res. Dis. 114:477, 1976.

Logan, W.  Mortality  in the London fog incident.   Lancet 1:336-338, 1953.

Lowrence,   W.   W.     Of   Acceptable  Risk.   Science  and   Determination  of  Safety    Los
     Altos, William Kaufman, 1976.                                                    *'

Lui, 1978.


SOX14D/B                                     14-44                                         2-18-80

-------
Lunn, J.  E.,  J.  Knowelden, and A. J. Handyside.   Patterns  of  respiratory illness in Sheffield
     infant schoolchildren.  Br. J.  Prev. Soc. Med.   21:7-16,  1967.

Lunn, J. E., J. Knowelden, and J. W.  Roe.   Patterns  of  respiratory  illness in Sheffield junior
     schoolchildren.  A follow-up study.  Br. J.  Prev.  Soc.  Med.  24:223-228,  1970.

Macklem,  P. T. ,  and  S.   Permutt.   The  Lung in  the Transition Between  Health and  Disease.
     Marcel Dekker, Inc.,  New York,  1979.

Manfreda,  J. ,  N.  Nelson,  and  R.  M.   Cherniack.   Prevalence of respiratory abnormalities  in  a
     rural  and an urban community.   Am.  Rev.  Respir.  Dis. 117:215-226,  1978.

Martin, 1960.

Martin,  A.  E.   Mortality  and  morbidity  statistics and air  pollution.    Proc.  R.  Soc.  Med.
     57:969-975, 1964.

Martin, A.  E. ,  and W. H.  Bradley.   Mortality, fog and  atmospheric  pollution--An investigation
     during the  winter  of  1958-59.   Mon.  Bull.  Minist.  Health  Public Health  Lab.  Serv.
     19:56-72, 1960.

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.

McCarroll,  J. R., E.  J. Cassell, W.  T.  Ingram, and D. Wolter.   I.   Health and the Urban Environ-
     ment.  Am. J.  Public  Health 56:266-275,  1966.

McCarroll,  J., E. J.  Cassell, D. W.  Woeter, J. D.  Mountain,  J.  R. Diamond,  and I.  M.  Mountain.
     Health and the Urban  Environment.   Arch. Environ Health 14:178-1967.

McFarland,   A.   R. ,   and   C.   E.    Rodes.    Characteristics  of  Aerosol  Samplers   Used  in
     Ambient  Air Monitoring.   Presented  at 86th National Meeting.   American Institute  of
     Chemical Engineers, Houston, TX, April 2, 1979.

McEuen,   D.  Daniel,  and   J.  L.  Abraham.   Particulate  concentrations in  pulmonary  alveolar
     proteinosis.   Environ. Res. 17:334-339,  1978.

Melia,  et al., 1977.

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.

Ministry  of Health.   Mortality and  Morbidity During the  London Fog of December 1952.   London,
     Her  Majesty's  Stationery Office.   1954.

Ministry  of Health, 1952.

Ministry  of  Pensions and  National   Insurance.   Report on  an Enquiry into  the  Incidence  of
     Incapacity  for  Work.   II.   Incidence  of   Incapacity  for  Work  in  Different Areas and
     Occupations.   London,  Her Majesty's Stationery  Office, 1965.

Mork,  T.    A  comparative  study of respiratory disease   in  England  ,  Wales,  and  Norway.
     Norwegian University  Press, Oslo,  1962.

Morris, S.  C. , M. A.  Shapiro, and J.  H.  Waller.   Adult  mortality in two communities with widely
     different air  pollution  levels.  Arch. Environ.  Health 31:248-254, 1976.
SOX14D/B                                      14-45                                         2-18-8C

-------
Moulds, W.  Some  instrumental  variations arising in routine air pollution measurements.   Int.
     J. Air Water Pollut.  6:201-203, 1962.

Mountain, I. M., E.  J. Cassell, D.  W. Wolter, and J. D. Mountain.  Health and the  Urban  Environ-
     ment.  VII.  Air Pollution  and Disease Symptoms  in  a Normal Population.  Arch.  Environ.
     Health 17:343-352, 1968.

NAS.   Proceedings of the Conference on Health Effects of Air Pollutants, prepared  for  the  Com-
     mittee on  Public Works, U.S.  Senate, Committee  Print,  Serial  no. 93-15, U.S.  Government
     Printing Office, Washington, DC, 1978.

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.

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.

Neri,  L.  C., J. S. Mandel, D. Hewitt, and D.  Jurkowski.  Chronic obstructive pulmonary disease
     in  two cities  of contrasting  air  quality.   Can.   Med.  Assoc.  J.  113:1043-1046,  1975.

NAPCA

Nobuhiro, T. ,  M.  Yozo, T.  Yoshizo, K. Kiroyuri,  H.  Masamichi, K. Tachachiro, H. Teruo,  and  H.
     Ken'ichi.    Concerning  air pollution and  chronic bronchitis in  Ako City.   Report of the
     Environment  Pollution  Research  Institute  of  Hyogo Prefecture,  Japan.   1:25-35,  1970.

Organization for  Economic  Co-operation and  Development.    Methods of  Measuring Air  Pollution.
     Paris, France, 1965.

Organization for Economic Co-operation and Development, 1964.

Pedace, E. A.,  and E.  B. Sansone.  The relationship between "soiling  index" and suspended  parti-
     culate matter concentrations.   J. Air Pollut.  Control Assoc. 22:348-351, 1972.

Pemberton, J.,  and C. Goldberg.  Air polution and bronchitis.  Br. Med. J.  2:557,  1954.

Petrilli, F. L. ,  G.  Agnese, and S. Kanitz.   Epidemiologic studies of air pollution  effects  in
     Genoa, Italy.  Arch.  Environ.  Health 12:733-740, 1966.

Phelps, H.  W.   Follow-up  studies in Tokyo-Yokohama respiratory disease.  Arch. Environ.  Health
     10:143, 1965.

Prindle,  R. A.,  G.  W. Wright, R. 0. McCaldin,  S. C. Marcus, T. C. Lloyd, and W. E.  Bye.   Com-
     parison of  pulmonary  function  and  other  parameters  in two  communities  with widely  dif-
     ferent air pollution levels.  Am. J. Public Health 53:200, 1963.

Rail,  D.  P.  A Review of the Health Effects of Sulfur Oxides.  National Institute of  Environ-
     mental Health Sciences,  NIH,  Research  Triangle  Park,  NC, 1973,  Environ.  Hlth. Perspect.
     8:97-121,  1974.

Ramaciotti, D., M. Bahy, B. Voinier, and P.  Rey.   The S0?  pollution level and the  incidence  of
     bronchitis.  Medicine sociale et preventive 22:189-190, 1977.

Ramsey, J. M.   The relationship of urban atmospheric variables to asthmatic bronchoconstriction.
     Bull. Environ.  Contam. Toxicol. 16:107-111,  1976.
SOX14D/B                                     14-46                                         2-18-80

-------
Rao, M. ,  P. Steiner, Q. Qazi, R. Padre, J.  E.  Allen,  and  M.  Steiner.   Relationship of air pol-
     lution to attack rate of asthma  in children.   J.  Asthma Res.  11:23,  1973.

Reichel,  G.  Effect of air pollution  on the prevalence of respiratory  diseases  in West Germany.
     In:    Proceedings  of  the  Second International  Clean Air Congress, Washington,  DC,  1970.

Report of  the International Joint Commission, United  States  and  Canada, on the  Pollution  of
     the Atmosphere  in the Detroit River  Area.   International  Joint Commission (United States
     and Canada), Washington/ Ottawa, 115  pp.  1960.

Riggan, et al., 1975.

Riggan, W.  B. , J.  B. Van  Bruggen,  L. E. Truppi,  and M. B.  Hertz.   Mortality models:   A policy
     tool, EPA-600/9-76-016, pp. 196-198,  July 1976.

Rudnik, J.  Epidemiological  Study  on  Long-term Effects on Health of Air Pollution.   Probl. Med.
     Wieku Rozwojowego 7a(suppl):1-159, 1978.

Sawicki,  F.    Air  pollution  and prevalence of non-specific chronic respiratory  disease.   In:
     Ecology  of  Chronic Non-Specific Respiratory  Diseases.   Z. Brzezinski,  J.  Kopczynski, and
     F. Sawicki. ed., Warsaw, Panstwowy Zaklad Wydawnictw Lekarskich.   1972.  p.  3-13.

Sawicki,  F.   Chronic non-specific  respiratory disease in the city of  Cracow.   X.   Statistical
     analysis  of air pollution  by  suspended particulate matter and sulfur dioxide.   Epidemiol.
     Rev.  23:221,  1969.

Sawicki,  F.   Chronic non-specific  respiratory disease in the city of  Cracow.   XI.   The cross-
     section  study.  Epidemiol.  Rev.  23:242, 1969.

Sawicki,  F. ,  and P.  S.  Lawrence, eds.  Chronic Non-specific Respiratory Disease in the City  of
     Cracow--Report  of  a  5 year Follow-up  Study Among Adult Inhabitants of the  City of Cracow.
     National  Institute of Hygiene, Warsaw, Poland, 1977.

Schimmel,  H. , and  T.  J.  Murawski.  S02--Harmful  pollutant or air quality  indicator?   J. Air
     Pollut.  Control Assoc.  25:739-740, 1975.

Schimmel,  H.,  and  T. J. Murawski.   The relation of air pollution to mortality.   J.  Occup.  Med.
     18:316-333, 1976.

Schimmel,  N. , and L.  Greenburg.   A study  of  the  relationship of  pollution  to  mortality,  New
     York  City, 1963-1968.   J.  Air Pollut.  Control  Assoc.   22:607-616, 1972.

Schoettlin,  C. E. ,  and E.  Landau.   Air  pollution and  asthmatic  attacks in  the  Los Angeles
     area.  Public Health  Reports  76:545,  1961.

Schrenk,  H. H. , H.  Heimann,  G.  D.  Clayton,  W.  Gafafer, and H.  Wexler.   Air Pollution in Donora,
     Pennsylvania.   Epidemiology of the Unusual  Smog Episode of October  1948.   Public Health
     Bulletin  306,  U.S.G.P.O. Washington,  DC,  1949.

Scott,  J.  A.   Fog and deaths  in  London,  December 1952.   Pub. Health Rep.  68:474-479, 1953.

Scott, J.  A.   The  London  fog of December,  1962.   Med.  Off.  109: 250-252,  1963.

Shy et al., 1975.

Shy,  C.   M.    Epidemiologic  Evidence and   the  United  States Air  Quality Standards.   Am.  J.
     Epidemiol. 110:661-671, 1979.
SOX14D/B                                      14-47                                        2-18-80

-------
Shy, C. M. ,  J.  R.  Goldsmith, J. D. Hackney, M. D. Lebowitz, and D. B. Menzel.  Health  Effects
     of Air  Pollution.   American  Thoracic Society, Medical  Section  of American  Lung Associa-
     tion, 1978.

Shy, C. M. , V. Hasselblad, R. M. Burton, C. J.  Nelson, and A. Cohen.   Air Pollution  Effects  on
     Ventilatory Function of U.S.  Schoolchildren.   Results of Studies in Cincinnati, Chattanooga,
     and New York.   Arch. Environ. Health 27:124-128, 1973.

Speizer,  F.   E.    An  Epidemiological  Appraisal  of  the  Effects  of Ambient  Air  on   Health:
     Particulates  and Oxides  of   Sulfur.   J.   Air Pollut.  Control   Assoc.  19:647-655,  1969.

Speizer,  F.  E., and  B.  G.  Ferris,  Jr.    Exposure  to automobile  exhaust.   I.   Prevalence  of
     respiratory symptoms and disease.  Arch.  Environ. Health 26:313, 1973a.

Speizer, F. E., and B. G. Ferris,  Jr.  Exposure to automobile exhaust. II.  Pulmonary function
     measurements.   Arch. Environ. Health 26:319,  1973b.

Speizer and Ferris, 1978.
Sprague,  H.  A., and  R.  M.  Hagstrom.   The Nashville  air  pollution study:   Mortality multiple
     regression.  Arch.  Environ. Health 18:503-507, 1969.

Stebbings, J.  H. ,  Jr.,  and  D.  G.  Fogleman.   Identifying a  Susceptible  Subgroup:   Effects  of
     the  Pittsburgh Air  Pollution Episode Upon Schoolchildren.  Am.  J.  Epidemiol.  110:27-40,
     1979.

Stebbings, J. ,  and C.  Hayes.   Panel  Studies  of  acute  health effects  of  air pollution.   I.
     Cardiopulmonary  symptoms  in  adults,  New York, 1971-1972.   Environ.  Res. 11:89-111,  1976.

Sterling, J.  D. , J. J. Phair, S. V. Pollack, D. A. Schumsky, and I. De Grout.  Urban Morbidity
     and Air Pollution.   A First Report.  Arch. Environ.  Health 13:158-1966.

Sterling, J.  D. ,  S.  V.  Pollack, and J. J. Phair.   Urban Hospital Morbidity and Air  Pollution.
     A Second Report.   Arch Environ Health 15:352-1967.

Stocks, P.   Air Pollution and Cancer Mortality in  Liverpool Hospital Region and  North Walls.
     Inter. J. Air Pollut. 1:1-13, 1958.

Stocks, P.  Cancer and bronchitis mortality in relation to atmospheric deposit and smoke.  Br.
     Med. J.  1:74, 1959.

Stocks, P.   On  the relations between atmospheric  pollution  in urban and rural localities and
     mortality   from   cancer,  bronchitis  and   pneumonia   with   particular   reference   to
     3:4-benzopyrene,  beryllium, molybdenum, vanadium, and arsenic.   Br.  J. Cancer 14:397-418,
     1960.                                                                         ~

Stocks,  P.,   and  R.   I.  Davies.   Epidemiological evidence  from  chemical  and spectrographic
     analyses that soil  is concerned  in the causation of cancer.   Br. J.  Cancer 14:8-22,  1960.

Sultz, H. , J.  Feldman,  E. Schlesinger, and W.  Mosher.  An effect  of  continued exposure to air
     pollution  on  the incidence of chronic childhood allergic disease.   Am  J   Public Health
     60:891-900, 1970.

Suzuki, T. ,  N.  Ishinishi,  R.  Yoshida,  Y.  Tsunetoshi, M.  Hitosugi,  S.  Tominaga,  K. Fukutomi,
     and  A.  Nozoe.   The  Relationship Between  Air Pollution and  the Respiratory  Symptoms and
     Functions  of  Housewives.  Japan Public  Health  Society Foundation,  Tokyo,  Japan,  1978.

Thompson, D.  J. ,  M.  D.   Lebowitz,   E.  J.  Cassell,  D.   Wolter, and J.  McCarroll.  Health  and the
     Urban Environment.   VIII.   Air  Pollution, Weather,  and  the  Common Cold   Am  J   Public
     Health 60(4):731-739, 1970.


SOX14D/B                                     14-48                                         2-18-80

-------
Toyama, T.   Air pollution and  its  health effects in Japan.   Arch.  Environ.  Health 8:153-173,
     1964.

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.

Tsunetoshi,  Y. , T.  Shimizu,  H.  Takahashi,  A.  Schenosowa,  M.  Ueda,  N. Nakayama, Y.  Yamagata,
     and  A.   Ohshino.    Epidemiologic  study of  chronic  bronchitis with  special reference  to
     effects of  air  pollution.   Int. Arch.  Arbeitsmed.   29:1-27,  1971.

U.S.  Congress.   Committee  on Public Works,  U.S.  Government Printing Office, Washington, DC,
     1968.   Air  Quality  Criteria Staff  Report,  90th Congress,  2d  Session,  1968.

U.S.  Department of  Health,  Education  and  Welfare.   Air  Quality Criteria for  Sulfur  Oxides.
     Washington, D.C., U.S. Government  Printing Office.   1970.  178  p.   National Air Pollution
     Control Administration Publication No.  AP-50.

U.S.  Environmental  Protection  Agency.   Health  Consequences  of Sulfur Oxides:  A  Report  from
     CHESS,  1970-71.   EPA-650/1-74-004.   May 1974.

U.S.  Environmental Protection Agency.    Scientific and  Technical  Issues Relating to Sulfates.
     Ad Hoc  Panel  of the Science Advisory Board.,  Washington,  DC,  1975.

U.S.  House of Representatives.   Committee  on Science and Technology.  The  Environmental  Pro-
     tection Agency's  Research  Program with  Primary   Emphasis  on  the  Community   Health and
     Environmental  Surveillance System  (CHESS):   an Investigative Report.   Government Printing
     Office, Washington, DC,  November  1976.

U.S. Surgeon General's Advisory Comm.  on Smoking and  Health,  1964.

Ulmer,  W. T. ,  G.  Reichel, A.  Czeike,  and  A.   Leuschner.   Regional  incidence  of  nonspecific
      respiratory diseases.  IV.   Communication,  Int.  Arch.  Arbeitsmed.  27:73, 1970.

Van der  Lende,  R.  Epidemiology  of Chronic Non-Specific  Lung Disease  (Chronic Bronchitis).
     Assen,  Royal  Van  Gorcum,  and Springfield,  111.,  Charles  C. Thomas.   1969.

Van der Lende,  R., C.  Huygen,  E.  J.  Jansen-Koster, S.  Knijpstra,  R.  Peset, B. F. Visser,  E.  H.
      E. Wolfs,  and N. G. M.  Orie.   A temporary  decrease  in  ventilatory  function  of  an  urban
     population during  an  acute  increase  in air  pollution.   Bull.  Physiopathol.  Respir.
      11:31-43,  1975.

Van der  Lende,  R. ,  G.  J. Temmeling, B.  F.  Visser,  K.   de  Vries,  J.  Wever-Hess, and N.  G.  M.
     Orie.   Epidemiological  investigations  in  the Netherlands into the  influence  of  smoking
     and   atmospheric  pollution  on  respiratory symptoms  and  lung  function  disturbances.
     Pneumonologie 149:119-126,  1973.

Van der  Lende, R. ,  J.   P.  M.  de  Kroon,  G.  J.  Tammeling,  B.   F.  Visser,  K. de  Vries,  J.
     Wever-Hess,  and N.  G.  M.  Orie.    Prevalence of chronic  non-specific  lung disease  in a
      non-polluted  and  an air  polluted  area of  the Netherlands.   Jn:   Ecology   of  Chronic
     Non-Specific  Respiratory  Diseases.   Z. Brzezinski,  J.  Kopczynski,  and F.  Sawicki,  ed. ,
     Warsaw, Panstwowy Zaklad Wydownictw Lekarskick.  1972.   p.  27-33.

Verma,  M. P., F.  J.  Schilling and W.  H. Becker.   Epidemiological Study of Illness  Absences in
     Relation to Air Pollution.   Arch  Environ Health  18:536-543,  1969.

Waller, 1971.
 SOX14D/B                                      14-49                                        2-18-80

-------
Waller  R.   E. ,   A.  G.  F.  Brooks,  and  M.  W.  Adler.    Respiratory  Symptoms  and  ventilatory
     capacity  in a  cohort  of  Londoners  born in  1952-53.   Proceedings  of  the  International
     Symposium  on  recent advances  in the  assessment  of the  health  effects of  environmental
     pollution, Paris, June 1974.

Waller, 1978.

Waller, R.  E. ,  and P. J. Lawther.  Some observations on London fog.  Br. Med. J.  1:1356-1358,
     1955.

Waller, R.  E. ,  P.  J.  Lawther,  and  A.  E.  Martin.   Clean air and health  in London,   Jji:   Proc.
     Clean  Air Conf.,  Part  I.   London, National  Society  for  Clean  Air.    1969.   p.  71-78.

Ware, J., and F. Speizer, et al.  Assessment of the Health Effects of Sulfur  Oxides  and  Parti-
     culate  Matter:   Analysis  of the Exposure-Response  Relationship.  Research Triangle Park,
     NC, U.S. Environmental Protection Agency, in press, 1980.

Ware et al., 1981.

Warren  Spring  Laboratory.   Accuracy and representativeness of  the National   Survey  data.   In:
     National  Survey of  Air  Pollution,  1961-1971.   Volume  5.   Scotland,  Northern  Ireland,
     Accuracy of data,  Index.   Warren Spring Labotory,  Stevenage, England, January  1975.   pp.
     111-119.

Warren  Spring  Laboratory.   Measurement  of  Atmospheric  Smoke  and  Sulphur Dioxide:  Reproduci-
     bility  of  Results.   RR/AP/70,  Warren Spring Laboratory, Stevenage,  England,  August 1962.

Warren  Spring  Laboratory.   National Survey of Smoke and Sulphur Dioxide: Instruction Manual.
     Warren  Spring Laboratory,  Stevenage, England, 1966.

Warren   Spring   Laboratory.     The   Investigation   of   Atmospheric   Pollution   1958-1966.
     Thirty-second Report.  Her Majesty's Stationary Office, London, England, 1967.

Warren  Spring  Laboratory.   The  National   Survey  of  Air  Pollution.   The   Use   of  the   Daily
     Instrument for Measuring  Smoke and Sulphur Dioxide.  Warren Spring  Laboratory,  Stevenage,
     England, December 1961.

Warren  Spring Laboratory.   The National  Survey of Smoke and Sulphur Dioxide-Quality Control
     Tests  on  Analyses  of Samples, October 1975  to February 1977.  Warren Spring Laboratory,
     Stevenage, England, 1977.

Watanabe,  H.  Air pollution  and its  health  effects  in Osaka.  Presented  at the 58th  Annual
     Meeting of Air Pollution  Control Association, Toronto, Canada, June  20-24, 1965.

Watanabe,  H.   Health effects  of  air  pollution  in  Osaka  City.   J.  Osaka  Life Hyg.  Assoc.
     10:147-157(in Japanese),  1966.

Watanabe,  H. ,  and F. Kaneko.   Excess  death study of air pollution.   In:  Proceedings  of  the
     Second International  Clean  Air  Congress.  H.  M.  Englund  and W.  T. Beery   ed    Academic
     Press,  New York, 1971. pp. 199-200.

Weatherley,  M.  L. ,   and  R.   E.  Waller.   High  pollution  in  London,  December  1975.   Atmos.
     Environ.,  in press.

Wedding,  J. B. , A.  R.  McFarland,  and J.  E. Cermak.   Large particle collection characteris-
     tics  of ambient  aerosol samplers.  Environ. Sci. and Technol.  11:389-390,  1977.
SOX14D/B                                     14-50                                         2-18-8C

-------
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.

WHO.   Environmental  Health  Criteria  (8):    Sulfur  Oxides and  Suspended Particulate  Matter.
     WHO, Geneva, 1979.

Wicken,  A.  J. , and  S. F. Buck.   Report on  a  study of environmental factors  associated  with
     lung cancer  and bronchitis deaths  in  areas of northeast England.   Research  Paper No.  8.
     London, Tobacco Research  Council.   1964.

Wilkins,  E.   Air pollution  and  the  London  Fog  of  December,  1952.   J.  Roy.  Sanit.  Inst.
     64:1-21, 1954a.

Wilkins,  E.  Air  pollution aspects of  the London Fog of December,  1952.   Roy.  Meterol.  Soc.  J.
     80:267-271,  1954b.

Winkelstein, W.   Utility  or futility of  ordinary  mortality  statistics  in  the  study  of  air
     pollution  effects.   In:   Proceedings  of  the  Sixth Berkeley  Symposium on  Mathematical
     Statistics  and Probability.   L.  LeCam,  J. Newyman, and  E.  Scott,  eds. , University  of
     California Press,  Berkeley, CA, 1972.   pp.  539-554.

Winkelstein, W.,  and M. Gay.   Suspended particulate air pollution.   Relationship  to mortality
     from cirrhosis  of the liver.   Arch. Environ.  Health  22:174-177,  1971.

Winkelstein, W.,  and  S.  Kantor.   Stomach  cancer.  Arch.  Environ.  Health   14:544-547,  1967.

Winkelstein,  W. ,  Jr., and  S. Kantor.   Respiratory symptoms and air  pollution  in an  urban
     population of northeastern United States.   Arch.  Environ. Health 18:760,  1969.

Winkelstein,  W. ,  S.  Kantor,  E.  Davis,  C.  Maneri,  and  W.  Mosher.   The  relationship  of  air
     pollution  and  economic   status  to   total  mortality  and  selected  respiratory  system
     mortality  in men.  I.  Suspended particulates.   Arch.  Environ. Health  14:162-170,  1967.

Winkelstein,  W. ,  S.  Kantor,  E.  Davis,  C.  Maneri,  and  W.  Mosher.   The  relationship  of  air
     pollution  and  economic   status  to   total  mortality  and  selected  respiratory  system
     mortality  in man.   II.   Oxides  of  Sulfur.    Arch. Environ.  Health.  15:401-405,  1968.

Yashizo,  T.  Air  pollution and chronic bronchitis.   Osaka Univ.  Med.  J.  20:10, 1968.

Yoshida,  R., K. Motomiya,  H. Saito, and  S.  Funabashi.   Clinical  and  epidemiological  studies on
     childhood  asthma  in air  polluted areas   in Japan.   J_n:   Clinical  Implications  of  Air
     Pollution Research.   Acton, Massachusetts,  Publishing Sciences  Group, Inc.,  1976.

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.

Zapletal, A., J.  Jech,  T.  Paul, and M. Samanek.  Pulmonary function  studies  in children living
     in  an air polluted area.   Am.  Rev.  Respir.  Dis.  107:400-409,  1973.

Zeidberg, L. D.,  R.  A.  Prindle, and E. Landau.   The  Nashville air  pollution  study.   I.   Sulfur
     dioxide and  bronchial  asthma.   A preliminary  report.  Am.  Rev. Res.  Dis.  84:489, 1961.

Zeidberg,  L.  D. , R.  J.  M.  Horton, E.  Landau, and  V.  Raymond.   The  Nashville  air pollution
     study.  Mortality and  diseases  of the  respiratory system  in relation  to air  pollution.
     Arch. Environ.  Health 15:214-224, 1967.
SOX14D/B                                      14-51                                        2-18-80

-------
                                                  Appendix A -  Chapter 14 PM/SOX
                                APPENDIX A
                  ANNOTATED COMMENTS ON COMMUNITY HEALTH
                 EPIDEMIOLOGICAL STUDIES NOT DISCUSSED IN
                    DETAIL IN MAIN TEXT OF CHAPTER 14.
SOXGR3/G                                A-l                               2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOX








                               APPENDIX A








     Numerous community health epidemiological  studies have been cited during the



past 10 to 20 years as providing quantitative evidence for particular atmospheric



levels of sulfur oxides and/or particulate matter being associated with mortality



or morbidity effects.   In the course of the present assessment,  close examination



of such studies and published evaluations or reinterpretations of their findings



have led to the conclusion that methodological  considerations or published



results reported for many of them substantially limit or preclude their usefulness



in helping to define quantitative air pollution/health effects relationships



especially at levels below 1000 ug/m .   Based on this, many were excluded from



detailed discussion or consideration in the main text of Chapter 14 or mentioned



only briefly in support of certain points made  in the chapter.  Provided below



are annotated comments addressing limitations of various studies for helping



to quantify the health effects of sulfur oxides and particulate  matter and



exposure levels at which such effects occur.   Many of the studies listed,



however, do provide qualitative evidence helpful in characterizing sulfur



oxides and particulate matter health effects and are therefore cited as such



either in the main text of Chapter 14 or in tables summarizing qualitative



studies in Appendix B.
SOXGR3/G                                A-2                               2-14-81

-------
                                                  Appendix A  -  Chapter  14  PM/SO
                                                                               .X
A.  STUDIES OF MORTALITY EFFECTS OF ACUTE EXPOSURES


1.  British, European, and Japanese Studies

     The following studies all concern early  (1950s-60s)  severe air pollution

episodes in England, when atmospheric concentrations of particulate matter

(BS) and sulfur dioxide markedly exceeded 1000 ng/m :
     Burgess, S. E. , and C. W. Shaddick.  Bronchitis and  air pollution.
          R. Soc. Health J. 79:10-24, 1959.

     Clifton, M., D. Kerridge, J. Pemberton,  W. Moulds, and J. K. Donoghue.
          Morbidity and mortality from bronchitis  in Sheffield in four
          periods of severe pollution.   Ijr.   Proc. 1959 Int. Clean Air
          Conf.  London, National Society for Clean Air.  1960.  p. 189.

     Gore, A. T., and C. W. Shaddick.  Atmospheric pollution and mortality
          in the County of London.  Br.  J. Prev. Soc. Med. 12:104-113,
          1958.

     Logan, W.  Mortality in  the London  fog incident.  Lancet 1:336-338,
          1953.

     Scott, J. A.  Fog and deaths in  London,  December 1952.  Pub. Health
          Rep. 68:474-479, 1953.

     Scott, J. A.  The London fog of  December, 1962.  Med. Off. 109:
          250-252, 1963.

     Ministry of Health.  Mortality and  Morbidity  During  the London Fog of
          December 1952.  London, Her Majesty's Stationery Office.  1954.

     Wilkins, E.  Air pollution and the  London Fog of December, 1952.  J.
          Roy. Sanit. Inst. 64:1-21,  1954a.

     Wilkins, E.  Air pollution aspects  of the London Fog of December,
          1952.  Roy. Meterol. Soc. J. 80:267-271, 1954b.


These  studies are mainly useful in being indicative of mortality effects

occurring at BS/SOp levels well in excess of  1000  [jg/m  and are widely accepted

as  such, regardless of particular methodological flaws or limitations associated

with each.

     Biersteker  (1966) also reported  the following study  of a  high  pollution

episode in Rotterdam in December 1962:

     Biersteker, K.  Polluted Air Causes, Epidemiological Significance,  and
          Prevention of Atmospheric Pollution.  Assen, Netherlands, Van
          Gorcum and Co., pp.  21-23 (in  Dutch), 1966.

SOXGR3/G                                 A-3                                2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOX
During the episode, 24-hr mean concentrations were recorded for participate
matter and sulfur dioxide at about 500 ug/m  and 1000 \ig/m , respectively
(OECD smoke /sulfur dioxide methods), together with increased hospital admissions
for the elderly (over 50 years old) with cardiovascular diseases and weak
indications of increased mortality.  However, these results were observed only
once in Rotterdam and could have been due to other causes and do not provide
evidence of a strongly convincing statistical relationship between observed
mortality and hospital admissions and the air pollution levels reported.   Nor
is it possible to determine precisely what the reported smoke levels (in
(jg/m ) mean in terms of actual particulate matter mass present in Rotterdam at
the time.
     A Japanese study, on relationships between mortality and air pollution in
Osaka was reported by Watanabe:
     Watanabe, H.  Health effects of air pollution in Osaka City.  J.  Osaka
          Life Hyg. Assoc. 10:147-157(in Japanese), 1966.

Increases in mortality (about 20%) appeared to occur when daily concentrations
of particulate matter (as measured by a light scattering method) exceeded 1000
ug/m  (4-day average) in association with S02 (probably sulfation method)
                  3
levels of 250 [iq/m .  Low temperatures present may have contributed to the
effects and it is not possible to assess with confidence the statistical
relationship between observed mortality and the reported pollutant levels
which were apparently based on data from a single monitoring station.   Nor is
it possible to interpret the exact meaning of the reported suspended particulate
matter measurement results as to how they might relate to fine-particulate
mode, inhalable coarse-mode, or total suspended particulates levels.
2.  American Studies
     The following series of studies, employing mainly regression analysis
techniques attempted to define relationships between daily mortality and
SOXGR3/G                                A-4
                                                                          2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx

variations in particulate matter and S02 in New York City during the periods

of the 1950s, 1960s, and 1970s:

     Greenburg, L. , M.  B. Jacobs, B. M. Droletti, F. Field, and M. M.
          Braverman.  Report of an air pollution incident in New York City,
          November, 1953.  Public Health Rep. 77:7-16, 1962.

     Glasser, M.,  L. Greenburg, and F. Field.  Mortality and Morbidity
          During a Period of High Levels of Air Pollution, New York, November
          23-25, 1966.  Arch. Environ. Health 15:684-694, 1967.

     Glasser, M.,  and L. Greenburg.  Air pollution and mortality and weather,
          New York city, 1960-64, Arch. Environ. Health 22:334-343, 1971.

     Schimmel, N., and L. Greenburg.  A study of the relationship of pollution
          to mortality, New York City, 1963-1968.  J. Air Pollut. Control
          Assoc.   22:607-616, 1972.

     Schimmel, H., and T. J. Murawski.  The relation of air pollution to
          mortality.  J. Occup. Med. 18:316-333, 1976.


Among the disadvantages of these studies is the fact that only data from a

single air pollution station in Manhattan was used in attempting to correlate

changes in air pollution with mortality in the entire city, raising questions

regarding how representative those aerometric measurements are of exposures

for the entire study population.  Goldstein and Landowitz (1977a,b) found that

most correlations  between pollutant levels recorded at any two New York City

monitoring stations were <0.40 and concluded that use of aerometric data from

any single station generally did not adequately represent pollutant levels for

the entire city.   A possible exception to this may occur during severe air

pollutant episodes when markedly increased pollutant  levels at all stations

may tend to approach a common ceiling elevation.  Lastly, many criticisms have

been advanced regarding specifics of the statistical approach employed (e.g.,

some correlations  likely to be significant by chance alone from among a very

large number run)  and some of the same and other investigators have since

reinterpreted these studies as generally not providing evidence of any association

between mortality  and S0? levels and only very weak associations- with particulate

matter levels.  Generally speaking, then, little evidence can be derived from


SOXGR3/G                                A-5                               2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOX

these studies for excess mortality having been associated with either elevated

S02 or participate matter levels in New York City, with the possible exception

of during severe pollution episodes.

     Several other American studies of New York or other United States cities

utilized primarily multiple regression analysis techniques that mainly allow

only for qualitative statements to be made regarding possible associations

between daily mortality and SCu or particulate matter levels.  These studies

i nc1ude:

     Buechley, R. W., W. B. Riggan, W. Hasselblad, and J. B. Van Bruggen.
          SCL levels and perturbations in mortality.  A study in New
          York-New Jersey metropolis.  Arch. Environ. Health 27:134-137,
          1973.

     Buechley, R. W.  S02 Levels, 1967-1972 and Perturbations in Mortality.
          Contract No. ES-5-2101.  Report available from National Institute
          of Environmental Health Sciences, Research Triangle Park, N.C.,
          1977.

     Hodgson, A., Jr.  Short-term effects of air pollution on mortality
          in New York City.  Environ.•Sci. Technol. 4:589-597, 1970.

     Lebowitz, M., P. Bendheim, G. Cristea, D. Markovitz, J. Misiaszek,
          M. Staniec, and D. Van Wyck.  The effect of air pollution and
          weather on  lung function in exercising children and adolescents.
          Am. Rev. Respir. Dis. 109:262-273, 1974.


     One other American study reported on possible mortality effects associated

 with a 1975  episode in Pittsburgh, Pennsylvania:

     Riggan, W.  B., J. B. Van Bruggen, L. E. Truppi, and M. B. Hertz.
          Mortality models:  A policy tool.  EPA-600/9-76-016, 196-198,  1976.

 This report  concerned an analysis of excess mortality associated with the same

 air pollution episode studied by Stebbings et al. (1976).  Only 20 excess

 deaths were  noted and these were associated with extremely high peak 1-hour
                                           Q
 air pollution concentrations over 1000 ug/m .   Also, this report has not

 undergone peer review.
SOXGR3/G                                A-6                                2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx
B.   MORBIDITY EFFECTS AND ACUTE EXPOSURES
1.    British, European, and Japanese Studies

     Comments on certain individual acute exposure morbidity studies are as

follows for each.

     FOR  Carne, S.  Air pollution study.  Proc. R. Soc. Med.
          57:30-34, 1964.

This study of general practicioners records of  illness during the winter of

1962-63 in London provides evidence of morbidity effects among elderly patients

during the December, 1962, pollution episode when  levels of smoke and SO^
                        3
markedly exceed 1000 g/m .  However, the health effects results cannot be

reliably linked quantitatively to specific pollutant  levels.

     FOR: Angel, J. H., C. M. Fletcher, I. D. Hill, and C. M. Finker.
          Respiratory illness in factory and office workers.  Br. J. Dis.
          Chest 59:66-80, 1965.

This study of acute respiratory illness attack and prevalence rates in a

working population of London correlated such rates with weekly peaks of pollu-

tion measured at several nearby sites.  No clear conclusions were stated by

the authors regarding pollutant levels associated with notable illness increases.

Based on the reported data only some apparent increase seems to occur, generally,

when smoke and SOp levels exceed 1000 pg/m .

     FOR: Gervois, M., G. Dubois, S. Gervois, J. M. Queta, A. Muller, and
          C. Vorsin.  Atmospheric pollution and acute respiratory disease.
          Denoin and Quavrechoin epidemiological study.  Rev. Epidemiol.
          Sante Publique  25:195-207, 1977.

     This article, in French, gives little methodology information and especially

about the quality of aerometry or health measurements.  A positive association

was reported between pollution concentration and acute respiratory disease

within one town (Quavrechoin) but not another (Denoin), although there were  no

clear differences in pollutant levels between the  towns.  Use of this study  is

limited because of uncertainty about its validity  and also because  insufficient

information was given to allow conclusions to be drawn about quantitative

relationships.

SOXGR3/G                                A-7                               2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SO
     FOR:  Van  der  Lende,  R.   Epidemiology of Chronic Non-Specific Lung
          Disease  (Chronic  Bronchitis).   Assen,  Royal  Van Gorcum, and
          Springfield,  111.,  Charles  C.  Thomas.   1969.

          Van  der  Lende,  R.,  J.  P.  M.  de Kroon,  G.  J.  Tammeling, B.  F.
          Visser,  K.  de Vries,  J.  Wever-Hess,  and N.  G.  M.  Orie.  Prevalence
          of chronic  non-specific  lung disease in a non-polluted and an
          air  polluted  area of  the Netherlands.   In:   Ecology of Chronic
          Non-Specific  Respiratory Diseases.   Z.  Brzezinski,  J.  Kopczynski,
          and  F.  Sawicki, ed.,  Warsaw, Panstwowy Zaklad Wydownictw Lekarskick.
          1972.   p. 27-33.

          Van  der  Lende,  R.,  G.  J.  Temmeling,  B.  F.  Visser, K.  de Vries,
          J. Wever-Hess,  and N.  G.  M.  Orie.   Epidemiological  investigations
          in the  Netherlands into  the influence  of smoking and atmospheric
          pollution on  respiratory symptoms  and  lung function disturbances.
          Pneumonologie 149:119-126,  1973.

          Van  der  Lende,  R.,  C.  Huygen,  E. J.  Jansen-Koster,  S.  Knijpstra,
          R. Peset, B.  F. Visser,  E.  H.  E. Wolfs,  and  N.  G.  M.  Orie.   A
          temporary decrease in ventilatory  function of an urban population
          during  an acute increase in air pollution.   Bull.  Physiopathol.
          Respir.  11:31-43, 1975.

     Studies  in the Netherlands reported by  van  der Lende and colleagues (van

der Lende et al.,  1969, 1972,  1973, 1975) compared lung function in  a large

population group  in 1969 and again in 1972.   In  a more polluted area, age-,

health-, and  smoking-adjusted FEV, n  values  in men increased from the first to

the second survey rather than decreasing with age as expected.   This was

associated with a concurrent decrease in air pollution concentrations.  The

investigators  considered other possible causes of the  improved pulmonary

function but  concluded that the most plausible was the effect of reduced air

pollution, but little hard  evidence was advanced to support this hypothesis.

In fact, the  changes  over time in PFT test results may be likely due to different

experimenters  performing the tests from the  earlier to later years.

2.  American  and Canadian Studies

     Comments  on several American (United States) and one Canadian acute

exposure morbidity studies  are as follows for each.

     FOR: Cassell, E. J., M. D. Lebowitz, I. M.  Mountain, H.  T.  Lee, D.
          J.  Thompson,  D. W. Wolter,  and J.  R. McCarroll.  Air Pollution
          Weather, and Illness in a New York Population.   Arch  Environ
          Health 18:523-530, 1969.
SOXGR3/G                                A-8                                 2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SO
                                                                               X

          McCarroll,  J.  R.,  E.  J.  Cassell, W. T. Ingram, and D. Wolter.
          I.   Health  and the Urban Environment.  Am. J. Public Health
          56:266-275, 1966.

          Mountain, I.  M.,  E.  J.  Cassell, D.  W. Wolter, and J. D. Mountain.
          Health and  the Urban Environment.  VII.  Air Pollution and
          Disease Symptoms  in a Normal Population.   Arch.  Environ.  Health
          17:343-352, 1968.

          Thompson, D.  J.,  M.  D.  Lebowitz, E. J. Cassell,  D. Wolter, and
          J.  McCarroll.   Health and the Urban Environment.   VIII.  Air
          Pollution,  Weather,  and the Common Cold.   Am. J.  Public Health
          60(4):731-739, 1970.

     These reports from the Cornell study gave results for correlations of

CoHs and S0? levels with numerous health endpoint measurements.  Many of the

effects measured, such as tearing, are of modest health significance.  Also,

numerous analyses are reported, predominantly multiple regression analysis;

and coefficients frequently change sign and magnitude as variables are added

and deleted, making it difficult or impossible to quantify health effects/air

pollution relationships from these qualitative studies.

     FOR: Greenburg,  L., F.  F.  Field, J.  I. Reed, and C. L. Erhardt.  Air
          pollution and morbidity in New York City.  J. Am. Med. Assoc.
          182:161-164, 1962.

          Greenburg,  L., C.  Erhardt, F. Field, J. I. Reid, and N. S.
          Seriff.  Intermittent air pollution episode in New York City,
          1962.  Public Health Rep. 78:1061-1064, 1963.

          Greenburg,  L., F.  Field, J. I.  Reed, and C. L. Erhardt.  Asthma
          and temperature change.  An epidemiological study of emergency
          clinic visits for asthma in three  large New York Hospitals.
          Arch. Environ. Health 8:642, 1964.

     Peak pollution levels during these studies were often much higher than

1000 ug/m , especially when 1-hour values are considered.   Also, methods of

analyses preclude clear quantitative statements on pollutant/health  effect

relationships.

     FOR: Carnow, B.  W., M.  H.  Lepper, R. B.  Shekelle, and J.  Stamler.
          Chicago air pollution study.  Arch. Environ. Health  18:768-776,
          1969.

     No particulate matter concentrations were given, and  individual exposures

to S0? were estimated from air pollution monitoring  network data in  combination


SOXGR3/G                                A-9                               2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx

with assumptions about individual activity patterns.  Positive associations

between SCL levels and health effects were restricted to seriously ill elderly

patients over age 55 with grades 3 and 4 bronchitis.  Subject attrition was

high during the course of the study.

     FOR:  Levy, D.,  M. Gent, and M.  T. Newhouse.  Relationship between
          acute respiratory illness and air pollution levels in an industrial
          city.  Am. Rev. Respir. Dis. 116:167-175, 1977.

     This Canadian study related hospital admissions records for acute respira-

tory conditions to changes in average weekly levels of an air pollution index

(combining CoH and SCL measurements) and found significant correlations even

after effects of temperature were taken into account.   However, no clear

quantitative associations between specific CoH or SCL levels and increased

acute respiratory conditions could be deduced from the reported results.

     FOR:  Stebbings, J. H., D.  C. Fogleman, K.  E. McClain, and M.  C.
          Townsend.   Effect of the Pittsburgh air pollution episode upon
          pulmonary function in schoolchildren.   J. Air Pollut. Control
          Assoc. 26:547-553, 1976.

          Stebbings, J. H., Jr., and D. G. Fogleman.  Identifying a
          Susceptible Subgroup:  Effects of the Pittsburgh Air Pollution
          Episode Upon Schoolchildren.  Am. J.  Epidemiol. 110:27-40,
          1979.

     Measurements of air pollution levels during the episode investigated in

these studies were made after highest levels of pollution had already past, as

were the health endpoints measured (mainly pulmonary function, e.g. FEV,

tests).  Method of subject selection and lack of clear association of health

results to specific particulate matter (TSP) or S0? levels precludes quantitative

conclusions regarding health effects/air pollution relationships.

NOTE:  Several published reports on EPA CHESS Program studies contain information

potentially bearing on acute exposure morbidity effects of sulfur oxides and

particulate matter.   Most CHESS studies, however, provide information mainly

on chronic exposure morbidity effects and are discussed below under Section D.
SOXGR3/G                                A-10                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx
C.    MORTALITY AND CHRONIC EXPOSURES
1.    British, European, and Japanese Studies

     Comments on several British studies earlier interpreted as ueilding

quantitative information on mortality relationships to particulate matter (BS)

and SO^ exposures are as follows for each.

     FOR: Buck, S. F., and A. D. Brown.  Mortality from Lung Cancer and
          Bronchitis in Relation to Smoke and Sulfur Dioxide Concentration,
          Population Density, and Social Index.  Research Paper No. 7.
          London, Tobacco Research Council.  1964.

     This study attempted to relate standardized mortality ratios from 214

areas in the United Kingdom (1955-59) to daily smoke (BS) and S0? levels for

March, 1962.  Several factors make it difficult to interpret or accept this

study's results, including:  (1) pollution levels for 1962 do not provide an

adequate basis for quantitatively estimating what were probably much higher BS

and S0? levels possibly contributing to mortality occurring in 1955-59; (2) it
                                                   3
is not clear what the reported 1962 BS data in ug/m  mean in terms of actual

mass indexed from the various U.K. areas, likely including many for which no

site-specific calibrations were carried out; (3) the 1962 BS levels calculated

were likely affected to an unknown extent by the computer error reported by

Warren Spring Laboratory for British National Survey BS data during 1961-64;

and (4) potential effects of differences in occupational exposure were not

taken into account.

     FOR: Stocks, P.  Air Pollution and Cancer Mortality in Liverpool
          Hospital Region and North Walls.  Inter.  J. Air Pollut. 1:1-13,
          1958.

          Stocks, P.  Cancer and bronchitis mortality in relation to
          atmospheric deposit and smoke.  Br. Med.  J. 1:74, 1959.

          Stocks, P.  On the relations between atmospheric pollution in
          urban and rural localities and mortality from cancer, bronchitis
          and pneumonia with particular reference to 3:4-benzopyrene,
          beryllium, molybdenum, vanadium, and arsenic.  Br. J. Cancer
          14:397-418, 1960.
SOXGR3/G                                A-ll                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx

     These studies on associations in the 1950s between standardized mortality

ratios for bronchitis, lung cancer,  and other cancers and particulate matter

(BS) levels in 101 urban and rural areas of Wales and England provide no way

to clearly determine quantitative relationships between BS and mortality

effects.   Interpretation of the BS aerometry data alone is clouded by ambiguities

regarding the actual mass of BS (in  ng/m ) indexed by measurements reported

for various areas of England and Wales (i.e.  were site-specific calibrations
                     o
used to make the jjg/m  estimates?).   Also, differences in smoking history were

not assessed as possibly accounting  for reported urban-rural differences.

     FOR: Wicken, A. J. , and S.  F. Buck.   Report on a study of environmental
          factors associated with lung cancer and bronchitis deaths in
          areas of northeast England.   Research Paper No.  8.  London,
          Tobacco Research Council.   1964.

     In this study of cancer and bronchitis in 12 areas of England, no actual

measurements of particulate matter (BS) or S0? were available except for 2

areas (North and South Eston) during 1963-1964 and an effort was made to

relate these levels to mortality during 1952-1962.   Similar objections to

retrospective linking of later aerometry data to earlier mortality information

apply here as were stated above for  the Buck and Brown (1964) study.   Also

mortality differences for the two Easton areas may have been due as easily to

differences in study population age  levels and smoking patterns as to any air

pollution gradient.

     FOR: Lave, L. B., and B. P. Seskin.   Air pollution and human health.
          The quantitative effect, with an estimate of the dollar benefit
          of pollution abatement is  considered.  Science 169:723-733,
          1970.

     Lave and Seskin (1970) attempted to demonstrate, by mathematical analyses

mainly involving regression analyses, relationships between BS measurements in

the United Kingdom and bronchitis mortality data once the effects of other

factors such as smoking and socioeconomic status (SES) are removed.  This Lave

and Seskin (1970) study has been extensively critiqued in detail by others



SOXGR3/G                                A-12                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SO
                                                                               X

(Holland et al., 1979; Ware et al., 1980), who have noted, for example, difficul-

ties in justifying inclusion of smoking, SES, and air pollution  levels in the

Lave and Seskin analyses as if they were completely independent variables and

the failure to make some direct allowance for smoking habits in the actual

analyses.  Nor is there any basis to determine specific quantitative levels of

pollutants associated with mortality from the reported results.

2.   American and Canadian Studies

     Among published American reports on mortality associations with chronic

particulate matter and sulfur oxides exposures are the following regarding

results from the Nashville air pollution study:

     Hagstrom, R. M., H. A. Sprague, and E. Landau.  The Nashville air
     pollution study.   VII.  Mortality from cancer in relation to air
     pollution.  Arch. Environ. Health 15:237-248, 1967.

     Zeidberg, L. D. , R. A. Prindle, and E. Landau.  The Nashville air
     pollution study.   I.  Sulfur dioxide and bronchial asthma.  A pre-
     liminary report.   Am. Rev. Res. Dis. 84:489, 1961.

     Zeidberg, L. D., R. J. M. Horton, E. Landau, and V. Raymond.  The
     Nashville air pollution study.  Mortality and diseases of the respiratory
     system in relation to air pollution.  Arch. Environ. Health 15:214-224,
     1967.

     One purpose of the Nashville study was to study relationships between air

pollution levels and mortality (total and respiratory disease specific) in

areas of the Nashville, TN, SMSA.  Particulate matter and sulfur oxides measure-

ment obtained during 1958-1959 were related to dealths occurring during 1949-1960,

opening this study to criticisms regarding retrospective use of  later aerometry

data in looking for links with earlier mortality.  Also, data regarding smoking

habits and occupational exposures were not taken into account.

     Two further publications by Lave and Seskin (1972, 1977) attempted to

extend their original U.K. analyses approach (Lave and Seskin, 1970) to metro-

politan statistical areas in the United States:

     Lave, L. B., and B. P. Seskin.  Air pollution, climate, and home
     heating:  Their effects on U.S. mortality rate?  Am. J. Public
     Health  62:909-916, 1972.


SOXGR3/G                                A-13                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOX

     Lave, L.  B.,  and B.  P.  Seskin.   Air Pollution and Human Health.
     Baltimore, The Johns Hopkins University Press.   1977.

Similar comments as indicated above for the earlier Lave and Seskin (1970)

publication apply here.   No clear information on quantitative relationships

between particulate matter or sulfur oxides levels and mortality can be derived

from these published analyses.

     Another set of widely cited American mortality studies was conducted in

Buffalo, NY, by Winkelstein and associates:

     Winkelstein,  W., S.  Kantor, E.  Davis, C.  Maneri,  and W.  Mosher.  The
     relationship of air pollution and economic status to total mortality
     and selected respiratory system mortality in men.  I.  Suspended
     particulates.   Arch. Environ.  Health 14:162-170,  1967.

     Winkelstein,  W., S.  Kantor, E.  Davis, C.  Maneri,  and W.  Mosher.  The
     relationship of air pollution and economic status to total mortality
     and selected respiratory system mortality in man.  II.  Oxides of
     Sulfur.  Arch. Environ.  Health.  15:401-405, 1968.

     Winkelstein,  W., and S.  Kantor.   Stomach cancer.   Arch.  Environ.
     Health  14:544-547,  1967.

     Winkelstein,  W. , and M.  Gay.  Suspended particulate air pollution.
     Relationship to mortality from cirrhosis of the liver.  Arch.  Environ.
     Health  22:174-177,  1971.

Numerous criticisms of these studies bave been discussed in detail  by Holland

et al. (1979)  and Ware et al. (1980).   Among the more  salient problems noted

were:  (1) the use of 1961-1963 particulate matter and sulfur oxides measurement

data in trying to relate air pollution to mortality among the elderly during

1959-1961; (2) inadequate controls for possible age differences between study

groups that may have covaried with the air pollution gradient used; (3) lack

of information on lifetime, including occupational,  exposures; and (4) failure

to correct for smoking habits.   In a later presentation, Winkelstein (1972)

comments on several of these points and later attempts to correct for some of

them:

     Winkelstein,  W.  Utility or futility of ordinary mortality statistics
     in the study of air pollution effects.   In:  Proceedings of the
     Sixth Berkeley Symposium on Mathematical Statistics and Probability.
     L. LeCam, J.  Newyman, and E. Scott, eds., University of California
     Press, Berkeley, CA, 1972.  pp.  539-554.

SOXGR3/G                                A-14                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SO
                                                                               y\

Still, this 1972 discussion does not lay to rest many of the different major

concerns regarding the Winkelstein Buffalo mortality findings.



D.    MORBIDITY AND CHRONIC EXPOSURES



!•    British, European and Japanese Studies

     Comments on several British studies often cited as demonstrating morbidity

effects to be associated with chronic exposures of particulate matter (BS) and

sulfur oxides are as follows for each.

     FOR: Burn, J. L., and J. Pemberton.  Air pollution bronchitis and
          lung cancer in Salford.  Int. J. Air Water Pollut. 7:5-16,
          1963.

     This study demonstrates increases  in sickness absences for bronchitis in

association with increases in BS levels, but failed to test for effects of

temperature decreases which covaried with the occurrence of pollution increases.

     FOR: Ministry of Pensions and National Insurance.  Report on an
          Enquiry into the Incidence of Incapacity for Work.  II.  Incidence
          of Incapacity for Work in Different Areas and Occupations.
          London, Her Majesty's Stationery Office, 1965.

     In this study,  rates of illness, absences for diseases such as bronchitis

were related to smoke (BS) and S02 measurements from six areas of England,

Scotland and Wales in 1961-1962, yielding apparent correlations between bronchitis

and pollutant  levels in some areas but  not others.  However, socioeconomic and

several other possible confounding factors were not taken into account.  Also,

BS aerometry measurements were likely impacted by the computer error affecting

1961-1964 British National Survey BS data and one cannot determine what the
                                                 3
reported BS levels actually mean in terms of ng/m  mass estimates in the

absence of information on site-specific mass calibrations.

     FOR: Fletcher,  C. M., R. Peto, C.  M. Tinker, and F. E. Speizer.  The
          Natural History of Chronic Bronchitis and Emphysema (an eight
          year study of early chronic obstructive lung disease in working
          men  in London). Oxford University Press, 1976.
SOXGR3/G                                A-15                               2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx

     This latter study above did concern relationships between smoke (BS)

levels and morbidity effects.   However, although certain apparent relationships

were detected, the authors (Fletcher et al, 1976) noted several factors which

complicate interpretation of their findings in such terms, and it is difficult

to link observed effects to quantitative levels of BS.

     FOR: Holland, W. W., T.  Halil, A.  E.  Bennett, and A.  Elliot.   Factors
          influencing the onset of chronic respiratory disease.  Br. Med.
          J.  2:205-208, 1969.

          Holland, W. W., T.  Halil, A.  E.  Bennett, and A.  Elliot.   Indications
          for measures to be taken in childhood to prevent chronic respiratory
          disease.  Milbank Mem. Fund Q. 47:215-227, 1969.

          Bennett, A. E., W.  W. Holland, T. Halil, and A.  Elliot.   Lung
          function and air pollution.  Chronic inflammation of the bronchi.
          Prog. Respir. Res.  6:78-89, 1971.

     These reports concern a study of pulmonary function in children living in

four areas of Kent, England.   Differences in Black Smoke concentrations were

small and S02 concentrations were not given.  Inconsistencies existed for

pulmonary function test results in relation to estimated air pollution gradients

across the different areas.

     FOR: Holland, W. W., H.  S. Kasap,  J.   R.  T.  Colley, and W. Cormack.
          Respiratory symptoms and ventilatory function:  A family study.
          Br. J. Prev. Soc. Med. 23:77-84, 1969.

     This study examined respiratory disease and pulmonary function in families

of Harrow, England (a suburb of London) during 1962-1965.   During this period,

mean winter  smoke levels declined in ug/m  from 108 (1962-1963) to 72 (1964-1965)  in

two "clean"  areas and from 175 (1962-1963) to 73 (1964-1965) in two "dirty"

areas, but SO^  levels for the same areas, respectively, were higher in 1963-1964

and 1964-1965 for the "dirty" areas than the "clean" ones.  The observed

differences  in  respiratory symptoms may have been related to earlier higher

pollutant levels.

     FOR: Irwig, L., D. G. Altman, R. J. W. Gibson, and C. Du V. Florey.
          Air Pollution:  Methods to study  its Relationship to Respiratory
          Disease in British Schoolchildren.  Proceedings of the Intermath
          Symp  on Recent Advances with Asses,  of the Health Effects of
          Environ. Pol., Luxembourg:  Commission of the European Communities
          Vol 1, 1975 pp. 289-300.
SOXGR3/G                                A-16                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx

          Melia,  R.  J.  W.,  C.  Florey and A.  V.  Swan.   The effect of
          atmospheric smoke and sulfur dioxide on respiratory illness
          among British schoolchildren:   A preliminary report.  Paper
          presented at VIII Int.  Scil. Meeting Int.  Epidemiol. Assoc.,
          Purerto Rico, 1977.

     These are preliminary reports from a study not yet completed of children

in many areas of the United Kingdom.   The results reported are not based on

final analyses of data and have not been subjected to peer review.   Also,

aerometry data for BS measurements employed appear to be based on mass estimates

derived from calibration of reflectance readings for the British National

Survey standard curve (for London air in 1963) not necessarily accurately

reflecting actual BS mass levels in ug/m  existing in non-London study areas.

     FOR: Sawicki, F.  Chronic non-specific respiratory disease in the
          city of Cracow.   X.   Statistical analysis of air pollution by
          suspended particulate matter and sulfur dioxide.  Epidemiol.
          Rev.  23:221, 1969.

          Sawicki, F.  Chronic non-specific respiratory disease in the
          city of Cracow.   XI.  The cross-section study.  Epidemiol. Rev.
          23:242, 1969.

          Sawicki, F.  Air pollution and prevalence of non-specific
          chronic respiratory disease.  _In:   Ecology of Chronic Non-Specific
          Respiratory Diseases.  Z. Brzezinski, J. Kopczynski, and F.
          Sawicki. ed., Warsaw, Panstwowy Zaklad Wydawnictw Lekarskich.
          1972.  p. 3-13.

          Sawicki, F. , and P.  S.  Lawrence, eds.  Chronic Non-specific
          Respiratory Disease in the City of Cracow--Report of a 5 year
          Follow-up Study Among Adult Inhabitants of the City of Cracow.
          National Institute of Hygiene, Warsaw, Poland, 1977.

     A series of studies from Poland by Sawicki (1969, 1972, 1977) reported

higher prevalence rates of chronic bronchitis in males (all smoking categories)

and  females (smokers and nonsmokers but not ex-smokers) in a high-pollution

community.  However, many of the reported differences by air pollution gradient

disappeared when rates were adjusted for age, sex, and smoking habits.  Also,

no consistent relationship was found between the chronic bronchitis prevalence

rate and length of residence in the high-pollution community.  Several reviewers

(e.g., Holland et al., 1979) have taken this as being evidence indicating that

Sawicki's findings do not show a relationship between air pollution and  bronchitis.

SOXGR3/G                                A-17                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOX

In a repetition of this study in 1973,  Sawicki  and Lawrence (1977) found some

evidence suggesting a further relationship between the prevalence of chronic

bronchitis and air pollution levels.   By 1973,  annual  smoke concentrations in

                                         3                             3
the high pollution area averaged 190 (jg/m  (OECD) compared with 86 ug/m

(OECD) for the low-pollution area.   Ambiguities exist  regarding whether site-

specific calibrations were employed in  generating the  OECD smoke estimates.

S0? average annual concentrations were  114 and  46 ug/m ,  respectively, for the

high and low pollution areas.   Both chronic bronchitis and asthma were more

prevalent in the high pollution area in males and females aged 31 to 50 and in

smokers.   Chronic bronchitis was also more prevalent in female non-smokers in

the high pollution area in both 1968 and 1973.   The investigators demonstrated

an interaction between air pollution and smoking.   However, the authors concluded

that air pollution, in comparison to other factors, such  as smoking, exerted a

relatively minor effect on the health of their  study populations.

     FOR: Petrilli, F.  L., G.  Agnese, and S.  Kanitz.   Epidemiologic
          studies of air pollution effects in Genoa,  Italy.  Arch.  Environ.
          Health 12:733-740, 1966.

     Petrilli et al. (1966) studied chronic respiratory illness, rhinitis,

influenza, and bronchopneumonia in several areas of Genoa, Italy,  in relation

to air pollution concentrations, between 1954 and 1964.   Respiratory illness

rates in non-smoking women over age 64  with a long residential  history and no

industrial exposure history was strongly correlated with  S0? concentrations

(Higgins and Ferris, 1978).  These investigators found that all illness rates

were higher in industrial  districts with higher annual mean pollution con-

centrations.  However, differences in socioeconomic status between study areas

were not adequately controlled for and  ambiguities exist  regarding methodology

and interpretation of reported aerometric measurements.
SOXGR3/G                                A-18                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx
2.    American and Canadian Studies
     Numerous American and Canadian studies are often cited as showing

associations between morbidity and chronic exposures to particulate matter or

sulfur oxides.  Comments on two Canadian studies as examples are as follows.

     FOR: Aubrey, F. , G. W. Gibbs, and M. R. Becklake.  Air Pollution and
          Health in three urban communities.  Arch. Environ. Health
          34:360-368, Sept/Oct 1979.

     This study of three communities in the Montreal area was marked by

relatively small air pollution differences between cities.  Cough and phlegm

were weakly associated with air pollution concentration, but lung function was

not.  Little meaningful quantitative information can be extracted from the

report.

     FOR: Neri, L. C., J. S. Mandel, D. Hewitt, and D. Jurkowski.  Chronic
          obstructive pulmonary disease in two cities of contrasting air
          quality.  Can. Med. Assoc. J. 113:1043-1046, 1975.

     This study compared the prevalence of symptomatic disease and the level

of pulmonary function in Sudbury, a mining community, and in Ottawa.  Although

chronic  bronchitis was more prevalent  in Sudbury men, 58 percent of Sudbury

men had  an occupational history suggesting high pollution exposure.  Lung

function levels were lower for both men and women  in Sudbury.  Very high

periodic peak SO^ exposure levels (exceeding 1000  ug/m ) more likely account

for any  pollutant effects than long-term chronic exposures to relatively low

annual average  levels of SOp or annual mean particulate levels (which didn't

vary by  much between Sudbury and Ottowa).

     Two examples of recently published American studies possibly relevant for

present  purposes are those by Bouhuys  et al. (1978) and Manfreda et al. (1978).

Comments on each are as follows.

     FOR: Bouhuys, A., G. J. Beck, and J. B. Schoenberg.  Do present
          levels of air pollution outdoors affect  respiratory health?
          Nature 276:466-471, 1978.
SOXGR3/G                                A-19                               2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOx

     Although the authors report that the two communities studied had very

different air pollution histories,  concentrations during the study period were

actually very similar.   Only a few associations were found with air pollution

concentration among several  illness measures and lung function measurements

studied, perhaps not unexpectedly in view of the limitations of this study

regarding and pollution concentrations.

     FOR: Manfreda, J., N.  Nelson,  and R.  M.  Cherniack.   Prevalence of
          respiratory abnormalities in a rural  and an urban community.
          Am. Rev.  Respir.  Dis.  117:215-226,  1978.

     This was a qualitative study of urban-rural  differences in two

communities with similar air pollution concentrations and provides no clean

quantitative information on the health effects  of S02 or particulate matter.

     Not included in the discussion in the main text of  Chapter 14 concerning

quantitative studies of morbidity associated with acute  or chronic exposures

to airborne sulfur oxides and particulate matter is a series of studies

conducted by the U. S.  Environmental Protection Agency under the Community

Health and Environmental Surveillance System (CHESS) program, an integrated

set of epidemiological  studies performed between 1969 and 1975.   In those

studies, the health status of volunteer participants was either ascertained

during single contacts or followed for time periods of up to nine months.

Attempts were made to coordinate these health measures with air pollution

observations from the residential neighborhoods of the study participants in

an effort to derive information on quantatitive relationships between

morbidity effects and both acute and chronic exposures to sulfur oxides,

particulate matter and other air pollutants.

     The results of approximately ten CHESS studies were published in summary

or review form in the early 1970's and were later presented in more detail in

a 1974 EPA monograph entitled "Health Consequences of Sulfur Oxides:  A Report

from CHESS 1970-1971," U.S.  EPA document No EPA-650/1-74-004 (May, 1974).  The

manner in which the CHESS results were reported and interpreted in the 1974

SOXGR3/G                                A-20                              2-14-81

-------
                                                           Appendix A - Chapter 14 PM/SO

         monograph  raised questions  regarding inconsistencies in data collection and

         analyses,  as  well  as possible mis-  or overinterpretation of results,  for CHESS

         data sets  discussed in the  early published reports or the 1974 monograph.*  Of

         particular concern with regard to many of the studies was the adequacy of

         aerometric data or other estimates  of air quality parameters, as well  as the

         collection and analysis of  health endpoint measurement data, upon which numerous

         key conclusions were based  regarding possible air pollution-health effects

         relationships.   Many questions regarding the validity of most CHESS study

         findings published in the early 1970s still  remain to be fully resolved.   In

         view of this, their potential usefulness in yielding information on quantitative

         relationships between health effects and well-defined air concentrations of

         sulfur oxides and particulate matter is extremely limited at this time; such

         CHESS Program study results are, therefore,  not included in the discussion in

         the main chapter text concerning morbidity effects.
*The matter of  misinterpretation  or overinterpretation of data or results of analyses of data
collected as part  of  the CHESS Program contributed to  considerable  controversy regarding the
validity and accuracy of results of early CHESS studies, as interpreted and reported in a 1974
EPA monograph entitled  "Health  Consequences  of Sulfur Oxides:  A  Report  from CHESS" 1970-71,
U.S. EPA Document No.  EPA-6550/1-74-004 (May 1974).   The controversy  eventually led to the 1974
"CHESS Monograph" becoming the subject of U.S.  Congressional  oversight hearings in 1976.   Subcommi
of  the  U.S. House  of  Representatives Committee on Science and Technology  produced a report on
the Monograph,  other  aspects  of the CHESS Program, and  EPA's air pollution research programs
generally—a report entitled "The Environmental Protection Agency's Research Program with Primary
Emphasis on the  Community  Health and Surveillance System  (CHESS):   An Investigative Report."
Of  primary  importance for the  present  discussion,  that report, widely referred  to  either as
the "Brown  Committee  Report"  or  the "Investigative Report"  (IR), contained  various comments
regarding sources  of  error in CHESS Program air  quality and health effects  data and quality
control problems  associated with such  data  collection and analysis. The  I.R.  also contained
various recommendations  to  be  implemented by the Administrator of EPA pursuant to Section 10
of the Environmental  Research, Development, and Demonstration Authorization Act of 1978 ("ERDDAA,"
P.L. 95-155, 91 Stat.  1275, November 8, 1977).   ERDDAA also requires  that  EPA and the Agency's
Science Advisory  Board  report  to  Congress on  the  implementation of  the IR recommendations.
     One recommendation  of the IR was that an  addendum to the 1974 sulfur oxides monograph be
published,  to be  used in part to qualify  the  usefulness of the CHESS studies, and to apprise
the public  of the controversy surrounding CHESS.  An addendum has  been published, and is available
from EPA, as announced  in  the Federal  Register of April 2, 1980,  45  F.R.  21702.  The addendum
is  incorporated  by reference in this  document in partial qualification  of  the CHESS studies
cited herein,  and is  part of the public file (or docket) established for revision of this criteria
document.  The addendum  contains  the full  text  of the  IR, reports to  Congress  by EPA, on its
implementation of  the  IR recommendations,  and  a  report  to Congress  by EPA's Science Advisory
Board on the same subject.
         SOXGR3/G                                A-21                              2-14-81

-------
                                                  Appendix A - Chapter 14 PM/SOX
     Perhaps most controversial  were studies discussed in a 1974 Monograph
reporting on certain of the CHESS studies,  entitled:   "Health Consequences of
Sulfur Oxides:   A Report from CHESS, 1970-1971."  Subcommittees of the House
Committee on Science and Technology of the  U.S.  Congress later produced a
report on the Monograph, the CHESS Program, and EPA's air pollution programs
in general—a report entitled:   "The Environmental  Protection Agency's Research
Program with Primary Emphasis on the Community Heal nth and Environmental
Surveillance System (CHESS):   An Investigative Report."  This report, cited in
the present criteria document as the Investigative Report or "IR (1976)," is a
comprehensive reference for qualifying the  use of the CHESS Monograph, and the
CHESS studies generally.  The full text of  the IR (1976) is contained in an
Addendum to the CHESS Monograph, EPA-600/1-80-021,  which is available from EPA
as noticed in the Federal Register on April 2, 1980,  45 FR 21702.
     A proper evaluation of any  CHESS study cited in  this document should
include careful reference to the entire IR  (1976).  To put the evaluation of
problems associated with CHESS studies into perspective, the passage on General
Problems of Epidemiologic Investigations of Pollution Effects in Section VI of
the IR (1976) should be read.  Based on considerations outlined in that passage,
critiques of specific CHESS studies in the  1974 monograph were presented by
the IR (1976).   Those critiques  which specifically address studies cited in
the present Chapter 14 or its appendices are reprinted verbatim on the following
pages.
SOXGR3/G                                A-22
                                                                          2-14-81

-------
      No.l,  "Prevalence of  chronic respiratory disease symptoms  in adults

1970  survey of  Salt  Lake Basin Communities."   Reported by Chapman et  al.
                                   APPENDIX A
                                  \f
            A  RECAPITULATION OF  THE AEROMETRIC  AND METEOROLOGICAL
              FINDINGS OF THE INVESTIGATION AS THEY  RELATE TO SPECIFIC
              SECTIONS OF THE CHESS MONOGRAPH AND THE HEALTH FINDINGS

                                   A. INTRODUCTION

              This section contains citations of errors and omissions found in a
            careful review of the CHESS Monograph which show that the use of
            aerometric and meteorological data in correlation with health effects
            end point measurements can easily mislead the reader of the CHESS
            document  into  inferences  which are not wholly or even partially
            supported  by the data in the report. Page, paragraph, and figure
            references are to the 1974 CHESS Monograph.
              Since an important application of the aerometric data is to deter-
            mine  correlations with health  effects, any errors or overusage of
            aerometric data based upon estimates or improper measurements will
            obviously reduce or negate the value of any health effects correlations
            which are attempted. This misusage or overusage of aerometric data
            will be particularly  damaging as the extension of the conclusions i»
            made in an attempt to discover possible threshold effects.

                                      B. CRITIQUE

            1. Prevalence of Chronic  Respiratory Disease  Symptoms  in  Adults:
                 1970 Survey of Salt Lake Basin Communities
              Observed  concentrations for  only  one year have  been used to
            crudely estimate concentrations of sulfur  dioxide and suspended
            sulfates relating to  a 4-7 year exposure. The 1971 observed annual
            average concentration of  sulfur dioxide  was used with the  1971
            emission rate from the smelter to obtain a ratio that was then mul-
            tiplied by emission  rates for other years to estimate concentrations
            for the other years. The. estimated sulfur dioxide concentrations
            were then used in a regression equation based on a 1971 relationship
            to estimate suspended sulfate  concentrations. Possible  changes in
            meteorological conditions  and  mode  of smelter operations  were
            neglected. Acknowledgment is not given in  the discussion and sum-
            mary that the critical concentrations relating to health effects  are
            nothing more than estimated concentrations.
              It is questionable whether or not long-term exposures should have
            been attempted for Magna, based on only one year's record of ob-
            servations that are abnormal because of the smelter strike. It would
            certainly have born approprintc to have mentioned  that only es-
            timated lonjj-terni data were available and indicated their degree of
            uncertainty m the discussion and summary.
                                          (85)
                                         A-23

-------
                               86

  Further, we find many errors on Page 2-37, Table 2.1.A. 14. It seems
tliat this table should have never been included in the report. Aside
from the misuse of the diffusion model (discussed in Chapter IV) this
table lists suspended sulfate values for Magna for the years 1940-1970,
that are not the same as listed in Table 2.1.A.16, on page 2-39. The
values are estimated by a simple ratio from the smelter emission rates,
but this is not explained. On page 2-39 a regression equation is used for
the same purpose. All of the sulfate concentrations under the heading
CHESS are estimated observations except  those for the year 1971.
This has not been properly indicated, e.g. by the use of parentheses.
  On pnges 2-37 emission rates are not sulfur dioxide rates as indicated
but emission rates in tons of sulfur per day. This means that the sulfur
dioxide emissions were twice the values listed. It also means that the
dispersion model estimates are incorrect. However, the listed estimated
concentrations in Magna and Kearns, which are  based  on a simple
ratio between observed concentrations in 1971 and  some emission rate
for  1971, whatever it might be, are not changed.
  Note that the  regression  equation for  suspended sulfates, Salt
Lake City, (pages 2-39) which is:

                      SS=0.101(TSP)-3.65

is quite different thaa that which can be obtained from Table 2.1.4,
i.e.:
                      SS=0.065(TSP) + 1.93

  S02  exposures  were  derived by multiplying the yearly smelter
emission  of S02 by the ratio of the 1971 measured annual average
SO2  concentration to  the 1971  SO, emission rate (193  tons/day).
  Estimates of suspended  sulfates were derived  from the estimates of
S02, using the following regression equation for 1971:

                       SS=0.09(S02)+6.66

  The annual TSP exposures were derived by multiplying  the yearly
smelter production of copper by the ratio of  the 1971 measured annual
arithmetic mean TSP concentration to  the 1971  copper production
late (260,000 tons/year).
  Smelter emissions of sulfur dioxide in the early 1940's  were roughly
three times greater than they were after 1956  although copper pro-
duction has remained more or less constant. The method for estimating
suspended sulfate, which is based on sulfur  dioxide estimates leads to
very high values in the 1940's whereas the total suspended particulate
are estimated lower in 1940 than in 1971. The procedure used produced
very high ratios between SS and TSP for the earlier years.  For example,
the 1940 ratio (34.6/63) is 0.55. This ratio is so large that it is obviously
questionable.
  The audacity of the estimates can be se^n in  Figure 2.1.17. The
lowest value, which occurecl in 1971, is extrapolated all the way back to
1940, reaching unusually high annual average concentrations of more
than one part per million. Considering the effects of  wind direction,
which would result in low concentrations much of the time because the
smelter stack plume would not be blowing  toward the town, such an
annual average would result in short-period concentrations many times
                             A-24

-------
                               87

the annual average. It is questionable that such high concentrations
ever occurred. If they did, they would be well-remembered, and living
conditions in Magna would be different than in 1971. Such unreasonably
high estimates should have been further investigated before being
presented.
  The grossness of the estimates made overrides other shortcomings
in this study pertaining to exposure that might be mentioned. How-
ever, more carefully made estimates would have required considerably
more work,  including obtaining meteorological records and details of
smelter operations affecting  plume behavior over the period  of years
studied. Such a large effort may not have been worthwhile considering
the inexactness of some of the other aspects of the study. Nevertheless,
a study of this nature seems to call for actual  observations, more ac-
curate estimates, or considerably less exactitude in its conclusions.
2. Frequency of Acute Lower Respiratory Disease in  Children: Retro-
     spective Survey of Salt Lake Basin Communities, 1967-1970
   The same comments apply to this study as for the  preceding study
on the prevalence of disease symptoms in adults. Inadequate recogni-
tion is given to the fact that  only estimated concentration data are
being used in the discussion and summary.
3. Aggravation of Asthma by  Air Pollutants:  1971 Salt Lake Basin
     Studies
   In this study, daily entries in a dairy were used to determine weekly
asthma attack rates. A statistical relationship was then determined
between the attack rates (weekly) and observed air pollution concen-
trations (averaged weekly).  Participants lived  within a 2-mile radius
of air monitoring stations.
   Daily exposure of asthmatics in a community such as Magna, which
is close to the smelter, are poorly characterized by a single monitoring
station. On a given day, one side of the community could be much more
affected by  the smelter stack plume than the other, and high concen-
trations from looping or fumigation might affect one  neighborhood
but not others. The study inadequately assesses the effects of peak ex-
posures and episodes.
   This report does not make clear that the minimum temperatures
used were from the Salt Lake City airport. The assumption seems to
have been made that temperature was uniform over  the entire study
area. This is not true because of the differences in elevation and the
effects of the mountains, and  the lake.  Perhaps the  differences were
not important, but they should have been  considered.  It is not clear
why days were stratified by minimum rather than mean temperature.
   Minimum temperatures occur during the early morning when peo-
ple  are generally indoors and perhaps in bed. When tempera-tures are
low, windows are generally closed. Also, lower minimum temperatures
are  correlated with other meteorological phenomena that could also
affect asthma attack rates, e.g., lower humidity and lower wind speed.
Further there may be a correlation with wind direction. A lower than
average minimum temperature probably  is also  associated with  a
strong  temperature  inversion which would be conducive to lofting
the smelter stack plume. Because of the many questions raised, the
findings pertaining to temperature merely  suggest further study and
have no general application.
                             A-25

-------
                               88

  Near the middle of the left hand column, page 2-89, the following
sentence appears. "The shut-down of operations by the strike was
aceompaniea by a pronounced improvement in air quality and a reduc-
tion in asthma attack rates that occurred sooner and were larger than
seasonal reductions  observed in the more distant study communities
some 2 weeks later." Here there is a lack of appreciation of the natural
climatic differences  that exit in the Salt Lake Basin. Some effects of
summer weather could easily be delayed two weeks before reaching
Ogden.  The average date for the last killing frost in Ogden  is  about
May 6, whereas the average date of the last killing frost at Saltair
(the climatic station nearest to Magna with  a long record)  is  about
April 12.
  On Page 2-76 (near middle of page, right hand column) the smelter
is not "5 miles north of Magna."
  On page 2-81 the first graph in Figure 2.4.1 is incorrectly  drafted.
After the 17th week the broken line should be solid and the solid line
broken. The temperature curve should appear  as  in  the graph for
the high exposure community.
  Figure 2.4.2, page 2-81, shows a weakness in the argument  that the
sulfur dioxide concentrations are responsible  for the asthma attack
rate. In the High Exposure Community the attack rate starts  up at
the 18th week as  the sulfur dioxide concentrations approach zero, or
near zero, and remain very low for about six  weeks. It is noted that
this same graph shows the highest S02 peak occurring at the 9th week,
which seems to begin about May 9. The  graph on page 2-16 seems to
show the peak in April.
  In Figure 2.4.4,  page 2-82, with  respect  to the High Exposure
Community, it may be noted that the sulfate concentrations are not
particularly well-correlated with the sulfur  dioxide  concentrations
plotted  in Figure 2.4.2, on the preceding page. The  highest sulfate
reading occurs in the 3rd week, whereas  the  sulfur dioxide levels
build up to a peak in the 9th week.
  On page 2-87, left hand column, it is stated that a threshold concen-
tration  of  1.4 /ig/m*  was calculated for suspended sulfates for the
higher temperature range. In Figure 2.4.4 all of the plotted concentra-
tions  are greater than  this value.  Considering the background of
suspended sulfates generally observed, this low threshold value seems
to nave no  practical  significance.
  The third paragraph that appears  in the right hand  column, page
2-89, probably applies to  Magna, however,  this is not made clear.
There  is  a  possibility that the paragraph  could be given broader
interpretation than  actually intended since the last three sentences
seem to refer to conditions in urban areas generally. The paragraph
probably should  have been divided into two  separate  paragraphs.
However, the main fault with the paragraph is that important con-
clusions are drawn that are not supported by information presented
elsewhere in the report. It snys "excess asthma  attributable  to sulfur
dioxide might be expected 5 to 10 percent of summer days", "total sus-
pended particulates could occur on up to  5 percent of summer  days and
30  percent of fall and winter days",  and "excesses due  to suspended
sulfates are likely to occur on 10 percent of fall and winter days and
90  percent  of summer days." Assuming that the stated relationships
                             A-26

-------
                               89

between  concentrations and temperature  are  true, the report does
not explain how the percentages of days  were obtained. Ihe study
covered only 26 weeks, but these conclusions apply to an entire year.
The percentages given seem to be rough estimates since they appear to
be given only  to the nearest 5 or 10 percent. The percentages might
have been obtained from daily values  for the minimum temperature,
pollutant concentrations and asthma attack rate; but it is not clear
now they were obtained.
  Presumably daily average concentration levels of specific pollutants
were used in the construction of the "hockey stick" curves shown on
pages 2-86 and 2-88.  The discussion implies  that "24-hour levels"
were used, but the precise nature of the air quality data used in the
threshold analyses is not made clear.
  There could be various reasons not  explored by the study  why the
thresholds for asthma attacks  were lower on warmer  days. One of
these is that there may be more plume looping on warmer days. This
might result  in  localized,  short-period, high  concentrations,  but
relatively low  average  concentrations.
  The validity of scientific work can be tested by the repeatability of
results. In this and the other CHESS  studies  there were factors
affecting asthma attack rates  that were not  considered and whose
effects are unknown. Such factors are:  time spent outdoors, percentage
of time windows are open, temperature change, relative humidity, etc.
The incompleteness 01 the study and the lack of understanding of the
causes of the  asthma attacks suggest  that it might be repeated with
significantly different results.
  Short-term  exposures to concentrations much higher than average
annual or weekly concentrations could have occurred in the commu-
nities  studied that were near large sources of air pollution such as
smelters. There exists the possibility that asthma attacks  could be
triggered by brief-duration nigh concentrations. Such exposures could
have been determined only inadequately by the procedures used in
the study. The report does not make clear why more  attention was
not devoted to peak concentrations.
4- Human Exposure to Air Pollutants in  Five Rocky Mountain Com-
     munities, 1940-1970
  On  pages 3-7 through 3-12 beginning with the second  column]
paragraph near middle of page, which begins  "By comparing .  . .".
There is not  a simple relationship between average daily pollutant
emissions and average annual pollutant  concentrations because  the
receptor area  is often now downwind.  Also, some consideration should
have been given to determining if the years for which data are  available
were representative meteorologically.
   (Page 3-11) Second paragraph, left hand  side of page. Information
obtained during this investigation indicates that the ratio 1.63 ±0.21
should be 1.42±0.21. (The value 1.63 is the upper limit of this ratio.)
   (Page 3-12) Emission ratios  of particulate and sulfur dioxide for
1971 are omitted from  this report. Therefore, it is not possible to
verify the ratios given here.
   (Page 3-12) According to information obtained during this investi-
gation, the two values for TSP listed as  99.5 for  the years  1971-70,
should be 98.1 for both years.
                            A-27

-------
      No.  7, "Prevalence of chronic  respiratory  disease symptoms  in military

recruits:   Chicago  induction center."   Report by Chapman et al.212
                                           92

             ties where  certain health effects  were observed,  the  source  of the
             suspended sulfate is inadequately determined. The study findings are
             much too incomplete to  call for the stringent control of suspended
             sulfates as has been done on page  3-51.
             7.  Prevalence of Chronic  Respiratory Disease  Symptoms  in Military
                 Recruits: Chicago Induction Center (Paragraph 4.2)
               Exposure estimates in this study are extremely crude.  In the sum-
             mary the following statement is made, "Available evidence indicates
             that exposures lasting 12 years or more to ambient air pollution
             characterized by elevated  annual average levels of sulfur dioxide
             (96 to 217 »jg/m3),  suspended particulates (103  to  155  p$[m')  and
             suspended  sulfates  (14 Mg/m') were accompanied by significant in-
             creases  in the frequency of chronic respiratory disease  symptoms."
               The 96 Mg/m3 value is the average  urban core value for 1969-70,
             which ranges from 54 to 138 (ig/m3, whereas the 217 Mg/ma is an average
             •value for five suburban communities for  thq year 1969.  Going back
             12 years concentrations were much higher. During  the  period 1960
             through 1965, the lowest value was 222, and there was a nigh of 344
             in 1964. For the five suburban communities there was data only for
             one other year. It averaged 183 jxg/m3. The 14 <*g/m3 concentration for
             eulfates is for a period of  7 years, not 12 as stated. It basically repre-
             sents data for the Chicago core area, with some scattered observations
             from East  Chicago  and Hammond, Ind. The average concentrations
             for the city should be somewhat less than  in the core area. Use of the
             core area value would generally result in an overestimate.
               It is difficult to characterize exposures lasting 12 years for the entire
             Chicago area. Either this  should have  been  done  in  very general
             terms, nonquantitatively, or a greater effort should  have been made
             to present more representative estimates.
               The assumption is being made that sulfate observations made at a
             central  urban location in Chicago, averaged with  a  few  observations
             from East Chicago and Hammond, Ind. are generally representative  of
             the entire Chicago area.
                (Page 4-8) Referring to the Chicago area the following statement is
             made:  "Each sampler  location,  identified  by a station  name  in
             Figure  4.1.2, represents  the -central business-commercial  district  of
             that particular area." This statement is  not true. Practically all, if
             not all the samplers are located on the roofs of school buildings in  an
             effort  to  obtain  representative community values: They were not
             located deliberately in  business  commercial  districts  and do not
             slightly overestimate area-wide concentrations as suggested.
                (Page 4-23) In reading this paper about th_ prevalence of chronic
             respiratory disease symptoms in military recruits, questions arise about
             the actual locations from which the men came and the local pollution
             levels to which they might have been exposed. Some  rural occupations
             result in high exposures to dusts,  plant allergens, etc.
                (Pn?e 4-35)  (Summary) The 12-year value for suspended sulfates
             should be 16 micrograms per cubic meter, not 14, as stated. Also, it
             appears that the concentrations of sulfur dioxide and suspended par-
             ticulate are for  only the period 1969-1970  and not for 12 years as
             is stated. (See Table 4.1.A.6)
                                   A-28

-------
      No.  8, "Prospective  Surveys of  Acute  Respiratory Disease in Volunteer

Families:   Chicago Nursery School Study, 1969-1970."   Report by  Finklea et  al.117
                                            93

              8. Prospective Surveys of Acute Respiratory Disease in Vflunteer Fam-
                  ilies: Chicago Nursery School Study, 1969-1970
                On page 4-41, in Table 4.3.1, it is riot clear where the sulfur dioxule
              data for the years 1959-63 come from. The Chicago network, which
              would have provided community data, was not operating effectively
              until 1964.
                On the same page the suspended sulfate data are probably repre-
              sentative for the core area but are high to be used as an average for the
              city as a whole.
                A serious weakness in this study is that the communities are ranked
              Intermediate,  High, and  Highest according to a ranking  that was
              determined by suspended particulate values, whereas the  most im-
              portant finding pertains to sulfur dioxide. Referring back  to Table
              4.I.A.I, it can be seen that a considerably different ranking would have
              resulted if  the communities had been ranked  according  to sulfur
              dioxide concentrations. In Table 4.3.1, it may be noted  that during
              the study that the "High" community had the lowest concentration
              of sulfur dioxide.
                Also note in Table 4.I.A.I that  the Highest communities include-
              GSA, which happens to be on  the south edge of the Chicago Loop
              area. This  station probably  contributed considerably  to  the  high
              concentration of sulfur dioxide attributed to the Highest community
              during 1969-1970, yet it is very nonrepresentative of a nursery school.
              Also, note that the Highest stations  include Carver, which for some
              reason ranks highest because of suspended particulate concentrations
              whereas the sulfur dioxide concentrations are relatively low.
                Sulfates are not considered in the  summary of this study, which
              seems to focus on sulfur dioxide without quantitative considerations of
              suspended sulfate levels.
                (rage 4-54) In the first paragraph of the Summary, the  following
              statement appears:  "It is also possible  that more  recent  lower air
              pollution levels contributed to increased respiratory  illness." On page
              4-51 the following statement is found. "Acute respiratory morbidity
              was significantly lower among families living in neighborhoods where
              sulfur dioxide levels had been substantially decreased." These  two
              statements are contradictory and  require clarification.  The first
              statement is remarkable. It can be interpreted to mean that some air
              pollution is good for you. Did the authors intend to say this? Such an
              important finding is inadequately supported by the contents of the
              report.
              9,  Human Exposure to Air  Pollution in Selected New  York Metro-
                  politan Communities, 19^-1911
                An overusage of estimated data can be found on page 5-19. The
              following two  statements appear: (Left  hand column, middle  para-
              graph) "Measured values for suspended  sulfates for 1956-1970 were
              available from the Manhattan 121st Street Station, and these values-
              were used  for citywide values." (Lust  paragraph  on page)   "The
              observed annual rutios of suspended sulfiite to dustfull for New  York
              City were used to estimate the suspended sulfate levels in Queens and
              Bronx."
                                         A-29

-------
      No  10  "Prevalence of  Chronic Respiratory Disease  Symptoms  in Adults
                                                                          212
1970  Survey of  New York Communities."   Report by  Chapman et  ai.
                                          94

            10.  Prevalence of Chronic Respiratory Disease  Symptoms  in Adults:
                  1970 Survey of New York Communities
              Three communities were compared: Riverhead, Long Island, a low
            exposure community, Queens, an intermediate  exposure community,
            and the Bronx, a high exposure community. Parents of all children
            attending certain elementary schools located within 1.5 miles of an
            air monitoring station in each community were asked to participate
            in the study. Each child was given  a questionnaire to be filled out by
            his parents and returned.
              Regarding exposure,  were the  concentrations measured  at the
            monitoring  stations  generally representative?  Assuming  a person
            remains reasonably near the station, in this case within lj| miles, and
            breathes the outside air, the station measurements would be generally
            representative  for  long-term average exposure. Maps  of  annual
            concentrations which are for sulfur dioxide and  suspended  participate
            matter, show reasonably uniform concentrations across  the study
            areas.  However, as has been mentioned in the report (5.1) Human
            Exposure to Air Pollution Selected New  York Metropolitan Com-
            munities, 1944-1971, by Thomas D. English, et al., the Queens Com-
            munity lies about 1 mile west of the Jonn F. Kennedy International
            Airport.  The effect of  this airport and  the various other possible
            :sources of  air  pollution that could have affected particular local
            Areas were not determined.
              The fact that the CHESS monitoring sites were the same as used
            in the city  air  pollution control  programs suggests that the sites
            were  picked and are  being used because they seem to be generally
            representative.
              More  important than  the representativeness of the  monitoring
            site locations in this study is the proper interpretation of the effects
            of the greatly reduced pollution levels during  the period  1969-1971.
            It is not meaningful to draw conclusions from sulfur dioxide exposures
            ranging  from 144 to  404 ng/m* and sulfate exposures ranging^ from
            9-24  Mg/m3, as was done in this study. The implication is  that nealth
            effects can be caused by the lowest concentrations mentioned, and this
            is not shown in the study. Also, it is stated that annual sulfur dioxide
            levels of 50  to CO Mg/m3 (accompanied by annual average suspended
            sulfate levels of about 14 >ig/m3 and annual  arithmetic  mean  total
            suspended participate levels of about 60 to 105 Mg/m3) could be assoc-
             ciated with such effects. These are levels.that were measured in 1971,
             whereas in the study there seems to have been no way to  have differ-
             entiated between the effects of pollution in 1971, or that  might have
             occurred during some earlier time. It is not reasonable to infer that
             lower pollution levels are responsible for the observed health effects.
                                         A-30

-------
      No.  11,  "Prospective  Surveys of Acute Respiratory Desease  in Volunteer

Families:   1970-1971 New York  Studies."   Reports by  French et al,306
               214
Hammer et al,     and Chapman  et al.
           11. Prospective Surveys  of  Acute  Respiratory Disease in Volunteer
                 Families: 1970-1971 New York Studies
              In this study families were telephoned once every two weeks and
           questioned about possible health effects. The families resided within
           1 to 1.5 miles of the air monitoring stations. '•
              In the  discussion it is stated that acute lower respiratory disease
           morbidity can be attributed to exposures to 2 to 3 years involving
           annual average sulfur dioxide levels of 256 to 321 Mg/m  (accompanied
           by elevated  annual average levels of total suspended particulate of
            97  to  123 Mg/m8 and  annual average suspended  sulfate levels of
            10 to 15 Mg/m8). These values are average values for the period 1966-
            1970, a five year period, and not period of 2 to 3 years as indicated.
            Also, they are the averages for the Bronx and Queens, respectively,
            and therefore do not represent a range of concentrations  that would
            have occurred in any particular community, as implied. For example,
            the sulfur dioxide concentrations in  the  Bronx ranged from 184 to
            472 Mg/m3 and in the Queens from 131 to 420 Mg/m3, during the five
            year period. Three year averages are  174  to 247 jig/m8,  and two year
            averages, lower still.
              On page 5-16 the dustfall concentrations shown in  Figure 5.1.21
            seem to be greater than would be obtained from the data presented in
            Figure 5.1.16.
              On page 5-36 (Table 5.2.1) the  values in  this table seem to come
            from Table 5.1.A.8. The values  in the column headed 1949-58 are,
            except for dustfall, for shorter time periods.  For example, the values
            for Queens come from data for the years 1956-58.
              On page 5-45 (Summary) we find that since the concentration data
            base comes from Table 5.1.A.8, the long term exposure values repre-
            sent a period of less than  20 years.
              Further, it is stated that there is a distinct possibility that in-
            creased susceptibility to acute lower respiratory illness  is  maintained
            or  induced by exposures involving  annual average  sulfur dioxide
            levels of 51 to 63 /jg/m3  (accompanied by annual average total sus-
            pended particulate levels of 63 to 104 ^g/m3  and annual average sus-
            pended sulfate levels of 13 to 14 jig/ms). The 51 to 63 Mg/m3, is a range
            resulting from  two different analyses of samples  (see puge 5-53).
            It represents uncertainty in measurement techniques rather than  a
            range  of  exposure  as  would  be interpreted.  These concentrations
            and the suspended sulfate concentrations  of 13 to 14 Mg/m3 happen to
            have occurred in the  Intermediate I  and the  Intermediate II com-
            munities during 1971. This particular study as conducted could  not
            have differentiated  between the effects of these levels of pollution
            and the effects of higher levels that occurred earlier.
              Only average annual concentrations were  considered and  not peak
            or episode concentrations.
                                      A-31

-------
      No.  12, "Aggravation  of Asthma by Air  Pollutants:   1970-1971 New  York

Studies."   Reports by Finklea et al.
           12. Aggravation of Asthma by Air Pollutants: 1970-1971 New  York
                 Studies
             Panelists who lived within  a  1.5 mile radius of three monitoring
           stations in communities identified as Low, Intermediate I, and Inter-
           mediate II, because of  their average air pollution concentrations,
           recorded asthma attacks each day in a diary for  a period lasting 32
           weeks, October 1970-May 1971. From a statistical association between
           asthma  attack rates, 24-hour average concentrations from the moni-
           toring stations, and daily minimum temperatures from airpdrts near
           the study  communities, it was concluded  that  24-hour suspended
           sulfate levels of 12 yg/m3 on cooler days (T^i,, equal to 30  to 50°)
           and 7.3 Mg/ms on warmer days (Tmln greater than 50°F) were thresh-
           olds for the induction of excessive asthma attacks. No firm evidence
           could be found to associate elevations in sulfur dioxide  (100 to 180
           Mg/m* on 10 percent of days) with excessive asthma attack rates on
           either cold or warmer days.
                Regarding exposure levels, there is much less assurance that daily
             average levels throughout a community would  be more or less uni-
             form than would be the case with annual average levels. More moni-
             toring stations might have been operated, or mobile  stations  used,
             to determine how pollution exposure varied from location to location.
             The determination of such differences in air pollution concentrations
             might have been important,  but probably more important is that the
             other factors (in addition to  the observed air pollutants) that  could
             have caused or contributed to the asthma attacks were not examined.
             It would not be worthwhile to refine the information on the distri-
             bution of the air pollutants studied, unless a greater effort were  made
             to study all of the various possible causes of the  asthma attacks more
             thoroughly.
                The study focused on the effects  of minimum  temperature. The
             possible effects of other meteorological variables  could also have been
             explored. Of  particular interest would be  the effects of sudden, large
             temperature changes.
                It is not  made clear why minimum instead  of average, or even
             maximum,  temperatures were  picked   for  correlation.  Generally
             there would be less  actual exposure to minimum temperature, which
             usually occurs about sunrise, than to warmer  temperatures.  Asth-
             matics would generally be expected to protect themselves from colder
             temperatures, staying indoors and keeping windows closed, whereas
             on warmer days they might be more subject to exposure to outdoor
             air with its assortment of possible allergens. There are diverse reasons
             why temperature might be an important factor determining asthma
             attack rates.  No attempt was made in  the study  to provide an
             explanation.
                                       A-32

-------
   It is expected that there would be noticeable temperature differences
 between  Riverhead (the Low community)  and Queens (the Inter-
 mediate I, community). Although it is stated that the temperatures
 come  from nearby airports, the temperature curves plotted in Figure
 5.4.1  seem  to  be identical  for both communities.  It  may be noted
 that a different curve is plotted for the low community Figure 5.5.2.
   (Figure 5.4.4) Although at a glance it appears that for the Inter-
 mediate community  that the "Attack  Rate"  and the "Suspended
 Sulfate"  curves are similar, close inspection shows that more often
 than not, they are out of phase. Between the 2nd  and 3rd week the
 attack rate (AR) curve continues down as the suspended sulfate (SS)
 curve starts up, between  the  10th and  llth  week  the AR-curve
 continues down after the SS-curve starts up, between the 14th  and
 16th week the AR-curve goes up while the SS-curve continues down,
 between  the 19th and 20th week the AR-curve starts up while the SS-
 curve continues down,  and again on the 27th  week the AR-curve
 rises a week before an increase in the suspended sulfate concentrations.
 In all, three of the five increases in attack rate precede, rather than
 follow, increases in suspended sulfate concentrations.


 IS.  Frequency  and Severity of Cardiopulmonary Symptoms in Adult
       Panels. 1970-1971 New York Studies (Paragraph 5.5).
   Symptom diaries were maintained daily  for  the 32-week period
 October  8,  1970 through May 22,  1971, by four panels, depending
 on state of health. The panelists were distributed in three communities


and  lived within 1.5  miles  of air pollution monitoring stations. It,
was concluded that elderly panelists in the low exposure community
reported higher symptom rates on days when sulfate levels exceeded
10 pg.ms. There seemed to  be good evidence of a threshold effect
between 6 and  10 Mg'm8, with a greater morbidity excess on warmer
days.
  Since suspended  sulfates  seem  to be more uniformly distributed
than a pollutant such as sulfur dioxide, the concentrations determined
by monitoring should be generally representative of outdoor exposure
ard  in most  cases  indoor and outdoor  average  exposures would  be
expected to  be  similar. The question not answered  by this study is
whether or not the panelists are also being exposed to some other
causative  agent, or stress factor, that might nappen  to correlate with
the sulfftte concentrations. It,  and not  the suspended sulfate con-
centrations, might be the cause of the observed health effects.
  (Page 5-91)  (Figure 5.5.3) The low value of sulfur dioxide that
began  at the 19th week and continued until  the 24th  week are sus-
pected of  not being true values. Near the end of the last paragraph
on the preceding page it is  suggested that meteorological conditions
may have been responsible. A careful  study of the meteorological
conditions and  fuel usage would  be necessary to determine if these
might  have caused the  persistent  low concentrations. However, a
scanning of the  daily local  climatological data shows no  obvious
reason for the reported low values.
  Furthermore,  the minimum temperature curve for the Low com-
munity in Figure 5.5.2 is not the same as given in Figure 5.4.1.
  The New  York Department of Air Resources also reported  a large
drop in concentrations following the mid-winter peakjat the  Queens
(Intermediate I) monitoring station, but reported values were never
as loiv, mid ft period of low values was not followed by a rise as shown
in tlio  Figure.  Further, the low values shown,  which  are about 25
n
-------
      No.  14,  "Ventilatory Function  in School Children:   1970-1971 New York

Studies."   Report by May  et al.215



             14. Ventilatory  Function  in  School  Children:  1970-1971 New  York
                   Studies (Paragraph 5.6).
               Pulmonary tests were  made in three elementary schools in  com-
             munities with different air pollution levels, and there were four rounds
             of testing, November-December 1970, January 1971, February-March
             1971, and April  1971. The children lived within 1.5 miles of a particular
             air monitoring station. The Queens monitoring station is on top of a
             school where the testing was done. However, the Bronx station  is on
             top of a "court  house in  the center of a busy commercial area" (page
             5-6) and may not be close  to the school. For the Riverhead  com-
             munity it is not made clear whether or not the school and the monitor-
             ing station are at  the same location or near each other. It is assumed
             that the schools in Riverhead and the Bronx were within 1% miles of
             the monitoring stations, but this is not actually stated.
               It was concluded that 9 or more  years exposure to annual sulfur
             dioxide  levels  of  an estimated concentration of 131 to 435 itg/tn3
             (accompanied  by suspended  particulate  levels  of  about 75 to 200
             Mg/m8) and suspended sulfate levels of about 5 to  25 Mg/m3 can be
             associated with  a  small  but significant impairment in Ventilatory
             function. These values are from Table 5.6.2, and are the extreme high
             and low values listed. There is an. implication here that the low con-
             centrations,  131  Mg/m8 for sulfur dioxide and 5 ng/m* for suspended
             sulfates represent threshold values. Actually they are only annual
             average concentrations for the years 1969 and  1970.  The observed
             health effects may have been the result of exposure to much higher
             concentrations in other years, or to some other cause.
                                       A-34

-------
No.  15,  "Ventilatory Function in School  Children:  1967-68.
           Testing  in Cincinnati  Neighborhoods.   Reported  by Shy et  al.
                 15. Ventilatory Function in School Children: 1967-68 Testing in Cin-
                       cinnati Neighborhoods (Paragraph 6.1),
                   This study included a pair of public elementary schools in each of
                 six neighborhoods differing in socioeconomic level, race, or pollution
                 exposure. All children in one or two classrooms of the second grade of
                 the elementary schools were asked to participate in the study to achieve
                 sample sizes of 60  to 75  children  in  each-of  the six study sectors.
                 Ventilatory performance as measured by a spirometer was obtained 12
                 times from each child: once weekly in the  months of November 1967
                 and February and May 1968. The tests were administered on Tuesday
                 and Wednesday mornings.
                    Air monitoring stations were placed  in locations within three blocks
                 of each school to provide samples representative of the air quality in
                 the neighborhood served by the school. No information is reported
                 on the distances of the homes of the children from the school. Ap-
                 parently it was assumed that the home environment and the school
                 environment were  the same. Indoor soiling index and sulfur dioxide
                 observations were taken in the schools, but results  are not reported.
                 It is reported that it  was  determined  that indoor and outdoor sulfur
                 dioxide,  soiling index, and  suspended particulate  levels measured
                 over  the  24-hour  or  4-hour period  directly  preceding pulmonary
                 function  tests did not consistently correlate with the test values.
                    Details of this lack of correlation are not given, but it was concluded
                 that "ventilatory performance of children thus did not appear to be
                 acutely affected by variations in pollutant levels on the day of the
                 test." Possible exposures over intermediate periods, say three days or
                 one week, prior to testing were not considered. Conclusions seem to be
                 based on possible long-period exposures, probably over a lifetime.
                    Concentrations of sulfur dioxide were low (less than 52 ng/m?) in all
                 areas,  so health  effects were  attributed to  particulate pollutants
                 independent of atmospheric levels of gaseous sulfur dioxide.
                    Average sulfate levels during the period of the study were observed
                 to be between 8.9 and 10.1 itg/m*, in the polluted lower middle white
                 community, but previous  average exposure was estimated to be 10.7
                 to 12.1 pg/m3, based on the National Air Surveillance Network station.
                 The average suspended sulfate level in the clean white sectors was 8.3
                 Mg/m3, a relative difference  of 13 percent. (The largest differences in
                 area exposure were in the concentrations of suspended particulates.
                 Levels of total suspended  particulates were J31 Mg/m* in polluted sec-
                 tors and 61 to  92  MgM3 io clean sectors.
                    In reading this paper one wonders about the psychological inter-
                 action between the children and the team members administering the
                 tests, who could anticipate the outcome of the experiment. The curves
                 for the black children in Figure 6.1.3, are particularly interesting.
                                            A-35

-------
                                                                 Appendix B - Chapter 14 PM/SO
                                          APPENDIX B
                     Qualitative Community Health Epidemiology Studies of
                Particulate Matter and Sulfur Oxides (PM/SO )  Morbidity Effects
                                           Contents

                    Table B-l.   Qualitative Studies of Morbidity Effects
                                Associated with Acute PM/SO  Exposures
                                                           X

                    Table B-2.   Qualitative Studies of Air Pollution and
                                Prevalence of Chronic Respiratory Symptoms and
                                Pulmonary Function Declines

                    Table B-3.   Qualitative Association of Geographic Differences
                                in Mortality with Residence in Areas of Heavy Air
                                Pollution
SOXGR3/A                                          B-l                               2-14-81

-------
                                                                 Appendix  B  -  Chapter 14 PM/SO>


   TABLE B-l.   QUALITATIVE STUDIES OF  MORBIDITY  EFFECTS  ASSOCIATED WITH  ACUTE  EXPOSURES
                          TO PARTICULATE  MATTER  AND  SULFUR  OXIDES
       Study
         Characteristics
      Findings
   Levy et al.  (1977)
   Zeidberg et al.
    (1961)
   Cowan et al.
    (1963)
   Greenberg et al.
    (1964)
   Wei 11 et al. (1964)
    Carroll (1968)
   Phelps (1965)
    and Meyer (1976)
   Glasser et al.
    (1967)
   Chiaramonte
    et al. (1970)
Hospital  admissions for respira-
 tory disease in Hamilton,
 Ontario, correlated with
 sulfur oxide/particulate air
 pollution index.

Study during 1 year of 49 adults
 and 34 children with asthma in
 Nashville, Tenn.
History of asthma, and skin tests
 of University of Minnesota
 students, in relation to dust
 from nearby grain elevator.

New York City hospital emergency
 room visits for asthma in  -
 month of September.
Retrospective study of emergency
 room visits to New Orleans
 Charity Hospital.
"Tokyo-Yokohama asthma" in
 American servicemen stationed
 in Japan after World War II.
Emergency room visits in seven
 New York city hospitals during
 the November 1966 air pollution
 episode.

Emergency room visits at a
 Brooklyn hospital during a
 November 1966 air pollution
 episode.
Increased hospital  admissions on
 heavy pollution days, except at
 one hospital  far removed from
 major pollution sources.
Doubling of asthma attack rates
 in persons living in more S02
 polluted neighborhoods.   No
 adjustment for demographic or
 social  factors.

Significant association between
 grain-dust particulate matter
 exposure and asthma attacks.
Emergency room visits strongly
 associated with onset of cold
 weather but not with degrees of
 air pollution during the one
 month of study-

Periodic "epidemics" of asthma
 in New Orleans could not be
 traced to any common pollutant
 exposure.

Disease primarily in smokers
 attributed to allergic response
 to atmospheric substances that
 could not be characterized.
 Patients improved after leaving
 the area and were immediately
 affected on return.  Some had
 long-term effects afterwards.

Increased emergency room visits
 for asthma in three of seven
 hospitals studied.
Statistically significant
 increase in emergency room
 visits for asthma and for
 all respiratory diseases, con-
 tinuing to 3 days after the
 peak air pollution concen-
 trations.
SOXGR3/A
                          B-2
                        2-14-81

-------
                                  TABLE B-l (continued).
                                                                 Appendix B - Chapter 14 PM/SO
       Study
                              Characteristics
      Findings
   Derrick (1970)
   Rao (1973)
                     Nighttime emergency room visits
                      for asthma in Brisbane,
                      Australia.

                     Pediatric emergency room visits
                      for asthma at Kings County
                      Hospital, Brooklyn, October
                      1970-March 1971.
                        Emergency room visits for
                         asthma at a hospital in
                         Harlem and in Brooklyn,
                         September-December 1970 and
                         September-December 1971.
   Sulz et al.  (1970)   Hospitalizations for asthma
                         (1956-61) and for eczema (1951-61)
                         in Erie County NY.   Attack rates
                         of patients stratified into air
                         pollution/social  class categories.
Goldstein and
 Black (1974)
   Dohan and Taylor
    (I960),
   Dohan (1961)
   and Ipsen et al.
    (1969)

   McCarroll et al.
    (1967)
   Mountain et al.
    (1968)
   Thompson et al.
    (1970)
   Cassell et al.
    (1969, 1972)
   Lebowitz et al.
    (1972, 1977)

   Ministry of Pen-
    sions and National
    Insurance (1965)
                     Weekly industrial absenteeism
                      rates in women RCA workers in
                      several locals, 1957-63.
                     Frequency of cough and eye
                      irritation in a New York
                      population living close to an
                      air monitoring station.
Negative correlation between
 asthma visits with degrees
 of smoke shade.

Negative correlation of asthma
 visits with degrees of smoke
 shade.  Lack of temperature
 adjustments.   Considerable
 distance of hospital district
 from air monitoring stations.

Temperature adjusted asthma
 rates positively correlated with
 S02 values in Brooklyn but not
 not in Harlem.   In 1971 period,
 50-90% increase in asthma
 visits on 12 days of heaviest
 pollution.

Area gradients in asthma and
 eczema hospitalization rates,
 adjusted for social class dif-
 ferences, corresponded to the
 air pollution gradient.  Metero-
 logical differences between areas
 not analyzed.

Correlations with sulfation
 explained by temperature
 and season.
Maximal effect on cough fre-
 quency occurred 1 or 2 days
 after peak air pollution
 concentrations, and cold
 incidence and prevalence
 correlates with S02 and Cons
 levels independent of weather.
                     Incidence survey of worker in-      Incapacity due to bronchitis
                      capacity from bronchitis and other correlated with winter concen-
                      illness in representative samples  trations of smoke and S02 in
                      throughout Britain, 1961/1962.       each of four 10-year age groups.
                                                          Socioeconomic and other
                                                          characteristics of the areas
                                                          may have contributed to the
                                                          associations.
SOXGR3/A
                                               B-3
                         2-14-81

-------
                                  TABLE B-l (continued).
                                                                 Appendix B -  Chapter 14 PM/SO>
       Study
         Characteristics
      Findings
   Lebowitz et al.
    (1974)
   Emerson (1973)
   Carnow et al.
    (1969)
   Burrows et al.
    (1968)
   Kalpazanov et al
    (1976)

   Kevany et al.
    (1975)
   Sterling et al.
    (1966, 1967)
Acute pulmonary function changes
 in normal children in a copper
 smelter town.
Weekly spirometry on bronchitis
 patients in London, 1969-71.

Daily symptoms in chronic bron-
 chitis patients in Chicago,
 1960s.
Daily symptoms in chronic bron-
 chitis patients in Chicago,  1960s.
Daily incidence of influenza in
 Sofia, Bulgaria, 1972, 1974/75.

Cardio-respiratory hospital
 admissions in Dublin, 1972-73.
Hospital admissions by disease
 in Los Angeles with measures
 of various pollutants.
   Verma et al. (1969)  NYC insurance workers'
                         absenteeism.
   Burn and Pemberton   Absenteeism among workers due to
    (1963)               bronchitis in Salford, England.
   Heimann (1970)
   Gregory (1970)
Acute morbidity and mortality in
 Boston episodes, 1955-66.
Sickness abseenteeism for
 Sheffield steelworkers in
 1950s.
Pulmonary function decreased
 with increasing air pollution
 especially after exercise.
 Temperature was controlled.

No correlation with air pollution
 levels.

Patients  over 55 with moderate-
 severe bronchitis had increased
 symptoms correlated with in-
 creased  S02 levels.

No relation of symptoms with
 S02 when data were adjusted
 for temperature and season.

Incidence was significantly
 correlated with S02 and dust.

Low but significant correlations
 between  cardiovascular admissions
 and S02/BS in winters.

Significant decrease of respira-
 tory admissions with decreasing
 S02, though S02 was low.  Other
 pollutants and weather may have
 been more important.

Respiratory disease absenteeism
 correlated with S02, controlled
 for temperature and season.

Significantly correlated with S02.
Respiratory patient visits
 higher, but mortality wasn't
 during episodes.

Correlation of weekly absences
 with SOx/TSP.
   Gervois et al.
    (1977)
Daily sickness absence of
 French workers in 2 areas of
 Northern France in winter
 period.
Association found in
 one town after adjusting
 for temperature.
 Monitoring method unknown.
SOXGR3/A
                          B-4
                         2-14-81

-------
                                                                 Appendix'B - Chapter 14 PM/SO
                                  TABLE B-l (continued).
       Study
         Characteristics
      Findings
   Lawther et al.
   (1973,  1974a,b)
   Ramsey (1976)
   Stebbings et al.
    (1976,  1979)
Day-to-day changes in ventilatory
 function of a small group of
 normal adult subjects and 2
 bronchitics in London.
Pulmonary function in 7 male non-
 smoking asthmatics (ages 19-21)
 daily over 3 months.
Acute pulmonary function in
 children after a pollution
 episode in Pittsburgh.
After multiple regression
 analysis to remove effects of
 time trend, S02 concentrations
 explained the largest
 proportion of variance in peak
 flow rates.  Clearest
 associations were shown after
 exercise in periods of heavy pol-
 lution.  In some subjects it
 was difficult to detect any
 consistent effects of pollution.

Multiple regressions showed
 significant correlation of some
 tests in 5 subjects but weather
 variables, but not with TSP or S02.

Continued decline seen during very
 very short periods of study.
 "Sensitive" subgroup defined by
 improvement during period.
SOXGR3/A
                          B-5
                         2-14-81

-------
                                                                 Appendix  B  -  Chapter 14 PM/SOX
        TABLE B-2.   QUALITATIVE STUDIES OF  AIR POLLUTION  AND  PREVALENCE  OF  CHRONIC
                   RESPIRATORY SYMPTOMS AND PULMONARY  FUNCTION  DECLINES
       Study
         Characteristics
      Findings
   Fairbairn and
    Reid (1958)
   Mork (1962)
   Deane et al.
    (1965)
   Hoi land and Reid
    (1965)
   Cederlof (1966)
    Hrubec et al.
    (1973)
   Bates et al.
    (1962, 1966)
   Bates (1967)
Comparison of respiratory illness
 among British postmen living
 in areas of heavy and light
 pollution.
Questionnaire and ventilatory
 function tests of male trans-
 port workers 40-59 years of age
 in Bergen, Norway and London,
 England.
Questionnaire and ventilatory
 function survey of outdoor
 telephone workers 40-59 years
 of age on the west coast of U.S.
Chronic respiratory symptom
 prevalence in large panels of
 twins in Sweden and in the
 U.S. Index of air pollution
 based on estimated residential
 and occupational exposures
 to S02, particulates, and CO.
Comparison of symptom prevalence,
 work absences, and ventilatory
 function in Canadian veterans
 residing in 4 Canadian cities.
Sick leave, premature
 retirement, and death
 due to bronchitis or
 pneumonia were closely
 related to pollution
 index based on visibility.

Greater frequency of
 symptoms and lower
 average peak flow rates
 in London.  Differences
 were not explained by
 smoking habits or socio-
 economic factors.

No differences in symptom
 prevalence between
 San Francisco and
 Los Angeles workers,
 although particulate con-
 centrations were approxi-
 mately twice as high in
 Los Angeles.

Increased prevalence of
 respiratory symptoms,
 adjusted for smoking and
 age, a larger volume of
 morning sputum and a lower
 average ventilatory function
 in London workers, and in
 the English compared with
 American workers.

Increased prevalence of
 respiratory symptoms in
 twins related to smoking,
 alcohol consumption,
 socioeconomic character-
 istics, and urban residence,
 but not to  indices of air
 pollution.

Lower prevalence  of symptoms
 and work absences and better
 ventilatory function in
 veterans  living  in the  least
 polluted city.
SOXGR3/A
                                                  B-6
                                                            2-14-81

-------
                                  TABLE B-2 (Continued).
                                                                 Appendix B - Chapter 14 PM/SO
       Study
         Characteristics
      Findings
   Bates (1973)
   Yashizo
    (1968)
   Winkelstein and
    Kantor (1969)
   Ishikawa et al.
    (1969)
   Fujita et al.
    (1969)
   Reichel, (1970)
   Ulmer et al.  (1970)
10-year follow-up study of
 Canadian veterans initially
 evaluated in I960, and
 followed at yearly intervals
 with pulmonary function tests
 and clinical evaluations.

Bronchitis survey of 7 areas of
 Osaka, Japan, 1966, among
 adults 40 years of age and over.
Survey of respiratory symptoms
 in a random sample of white
 women in Buffalo, New York.
Comparison of lungs obtained at
 autopsy from residents of
 St. Louis and Winnipeg.
Prevalence survey (Medical
 Research Council questionnaire)
 of post office employees in
 Tokyo and adjacent areas, 1962
 and re-surveyed in 1967.
Respiratory morbidity prevalence
 surveys of random samples of
 population in 3 areas of West
 Germany with different degrees
 of air pollution.
Least decline in pulmonary
 function with age in veterans
 from least polluted city.
Bronchitis rates, standardized
 for sex, age, and smoking
 were greater among men and
 women in the more polluted
 areas.   Bronchitis rates
 followed the air pollution
 gradient.

In nonsmokers 45 years of age
 and over, and among smokers
 who did not change residence,
 respiratory symptoms were
 correlated with particulate
 concentrations obtained in
 the neighborhood of residence.
 No association of symptom pre-
 valence with S02 concentrations.

Autopsy sets, matched for age,
 sex and race, showed more
 emphysema in the more polluted
 city.  Autopsied groups may
 not reflect prevalence of
 disease in general population.

Two-fold increase over time in
 prevalence of cough and sputum
 production in same persons,
 irrespective of smoking habits.
 Change was attributed to
 increasing degrees of air
 pollution.

No differences in respiratory
 morbidity, standardized for
 age, sex, smoking habits,
 and social conditions,
 between populations  living
 in the different areas.
SOXGR3/A
                          B-7
                        2-14-81

-------
                                  TABLE B-2 (Continued).
                                                                 Appendix B - Chapter 14 PM/SO>
       Study
         Characteristics
      Findings
   Nobuhiro et al.
    (1970)
   Comstock et al.
    (1973)
   Speizer and
    Ferris
    (1973a,b)
   Linn et al.
    (1976)
   Prindle et al.
    (1963)
   Watanabe (1965)
   Anderson and
    Larsen
    (1966)
Chronic respiratory symptom
 survey of high and low exposure
 areas of Osaka and Ako City,
 Japan.

Repeat survey in 1968/1969 of  east
 coast telephone workers and of
 telephone workers in Tokyo.
Comparison of respiratory
 symptoms and ventilatory
 function in central  city and
 suburban Boston traffic police-
 men.
Respiratory symptoms and function
 in office working population
 in Los Angeles and San Francisco,
 1973.
Comparison of respiratory
 disease and lung function
 in residents of Seward and
 New Florence, PA.
Peak flow rates in Japanese
 school children residing in
 Osaka.
Peak flow rates and school
 absence rates in children  6-7
 years of age from 3 towns  in
 British Columbia.
Higher prevalence of chronic
 respiratory symptoms in more
 polluted areas.
After adjustment for age and
 smoking, no significant
 association of respiratory
 symptom prevalence with
 place of residence.

Slight but insignificant
 increase in symptoms pre-
 valence among non-smokers
 and smokers, but not
 ex-smokers, from the central
 city group.  No group
 differences in ventilatory
 function.

No significant difference in
 chronic respiratory symptom
 prevalence between cities;
 women in the more polluted
 community more often reported
 nonpersistent (<2 years)
 production of cough and sputum.

Increased airway resistance in
 inhabitants of more polluted
 community.   Differences in
 occupation, smoking, and
 socioeconomic level  could
 account for these differences.

Lower peak flow rates in
 children from more polluted
 communities.  Improved peak
 flow rates when air pollution
 levels decreased.

Significant decrease in peak
 flow rates in 2 towns
 affected by Kraft pulp
 mill emissions.  No effect
 on school absences.
 Ethnic differences were
 not studied.
SOXGR3/A
                          B-8
                        2-14-81

-------
                                  TABLE  B-2  (Continued).
                                                                 Appendix B -  Chapter 14 PM/SO
       Study
         Characteristics
      Findings
   Collins  et  al.
    (1971)
   Toyama et al.
    (1966)
   Tsunetoshi  et al.
    (1971)
   Suzuki et al.
    (1978)
   Yoshida et al.
    (1976)
   Kagawa and Toyama
    (1975)
   Kagawa et al.
   (1975)

   Zaplatel et al.
    (1973)
   Holland et al.
    (1969)
   Col ley and
    Holland (1967)
Death rates in children 0-14
 years of age, 1958-1964,
 in relation to social and air
 pollution indices in 83 county
 boroughs of England and Wales.
Respiratory symptoms and
 spirometry in an agricultural
 area of Japan, 1965, 678 subjects
 ages 40-65, by smoking and sex.

Prevalence survey of chronic bron-
 chitis in 9 areas of Osaka and
 Hyogo Pref., Japan, in residents
 ages 40 or more.
Prevalence survey of respiratory
 symptoms in housewives ages 30
 or over in Japan.

Prevalence of asthma in school-
 children in areas of Japan.
Respiratory function of Tokyo
 schoolchildren.
Pulmonary function in school-
 children in Czechoslovakia.
Chronic bronchitis prevalence
 in 2365 families in 2 London
 suburbs, 1965.
Partial correlation analysis
 suggested that indices of
 domestic and industrial
 pollution account for a
 greater part of the area
 differences in mortality
 from bronchopneumonia and
 all respiratory diseases
 among children 0-1 year
 of age.

Much lower prevalence rates and
 and higher lung function than
 elsewhere.  S02<0.01 ppm,
 mean TSP of 90
Multiple regression analysis
 indicated increasing pre-
 valence, adjusted for age, sex
 and smoking, corresponding
 to the area gradient of air
 pollution.

Prevalence rates correlated
 with various pollutants,
 especially in older smokers.

Increased prevalence rates
 in areas with higher sulfa-
 tion rates.

Correlation seen with various
 pollutants after controlling
 for temperature.
Some children living in areas
 of high air pollution had
 functional abnormalities.

More symptoms in previously
 polluted area in mothers and
 in children, controlling
 for smoking, social class, a
 area of residence, place of
 work, overcrowding, family
 size and genetic factors.
SOXGR3/A
                          B-9
                         2-14-81

-------
                                  TABLE B-2 (Continued).
                                                                 Appendix B -  Chapter 14 PM/SO>
       Study
         Characteristics
       Findings
   Holland et al.
    (1969a,b)
   Bennet et al.
    (1973)
   Col ley and Reid
    (1970)
   Ramaciotti et al.
    (1977)
   Bouhuys et al.
    (1978)
   Biersteker and
    van Leeuwen
    (1970a,b)
Prevalence of respiratory symptoms,
 degrees of ventilatory function,
 and past histories of respiratory
 illness in more than 10,000 school
 children 5-16 years of age re-
 siding in 4 different areas of
 northwest London,  1964/1965.
 Greatest differences among areas
 were found in degrees of air
 pollution.
Respiratory disease prevalence
 in more than 10,000 children
 6-10 years old, England and
 Wales, 1966.
   Yoshii et al.
    (1969)
Bronchitis symptoms and peak flow
 in 1182 men in Geneva in relation
 to S02, smoke and N0? at resi-
 dence, smoking, and age, 1972-76.
Respiratory symptoms in an urban
 and a rural Connecticut com-
 munity, adjusting for sex, race,
 age, smoking, occupation and
 previous residence.
Peak flow rates in 935 school-
 children living in 2 districts
 of Rotterdam, one relatively
 affluent and having good air
 quality (40 ug of smoke per m3
 and 120 ug of S02 per m3) and
 the other less affluent, and
 having 50% higher concentrations
 of smoke and S02.

Chronic pharyngitis and histo-
 pathological changes in 6th
 grade children in 3 areas of
 Yokkaichi, Japan.
 Childhood smoking habits and
  degree of air pollution were
  found to have the greatest
- influence on respiratory
  symptom prevalence and venti-
  latory function.   Social class,
  family size, and past history
  of respiratory disease also
  contributed.  All factors operated
  independently and exerted their
  effects additively.

 Definite gradient of past
  bronchitis and current cough
  from lowest rates in rural
  areas to highest rates in
  the most heavily polluted areas.
  Differences were more clear
  in children of semi-skilled
  and unskilled workers.   No
  effect on upper respiratory
  ilIness rates.

 Regression analysis showed
  independent effect of S02,
  smoke and N02 after con-
  trolling for smoking and
  age.

 Communities had low concen-
  trations of TSP and S02,
  (<64 and 14 ug/m3, resp.)
  No differences were found
  among smokers.   More asthma
  in rural area.

 No significant area differences
  in peak flow, adjusted for
  height and weight.  Signifi-
  cantly more childhood bronchitis
  in more polluted district, but
  differences were judged to be
  due to poor living conditions,
  because low pollution area of
  of higher class residences.

 Correlation  of both with sulfation
  rates seen.
SOXGR3/A
                          B-10
                         2-14-81

-------
                                  TABLE  B-2  (Continued).
                                                                 Appendix B -  Chapter 14 PM/SO
       Study
         Characteristics
      Findings
  Wailer  et  al.
    (1974)
   Hammer et al.
    (1976)
Ventilatory function and respira-
 tory symptom prevalence among
 18-year-olds born in London
 just before and after the smog
 episode of 1952.
Retrospective survey of lower
 respiratory illness in children
 0-12 years of age living in 4
 New York City area communities,
 1969-1972.
   Chapman et al.
    (1973)
Retrospective survey of chronic
 respiratory disease (CRD) rates
 in elementary and high school
 children living in four Utah
 communities, 1970.
No differences were found between
 the 2 groups.   Both were exposed
 to high degree of pollution during
 the 1950s.   History of lower
 respiratory illness in childhood
 had major influence on current
 symptoms and ventilatory function.

Rates of total  respiratory illness
 croup, bronchitis, and other
 chest infections were significantly
 higher among black and white
 children residing in communities
 with heavier air pollution.

 Differences in family size,
 crowding, parental smoking,
 and social  class could not
 explain the findings.

CRD prevalence rates reflected
 community pollutant level
 differences, with statistically
 significant differences in CRD
 rates between high and low
 areas within sex and smoking
 status groups.  Communities
 differed mainly in S02 levels,
 in the presence of similar TSP
 levels, suggesting qualitative
 relationship between CRD effects
 and elevated S02 levels.

Errors in aerometry measurements
 around period of CRD rate
 measurement and limitations
 of retrospective estimation
 of earlier exposure  levels
 preclude determination of
 quantitative health effects/air
 pollution relationships.
SOXGR3/A
                          B-ll
                        2-14-81

-------
                                                                 Appendix B - Chapter  14  PM/SC^
                     Qualitative Community Health Epidemiology Studies of
                Particulate Matter and Sulfur Oxides (PM/SO ) Mortality Effects
                                                           )\
                                           Contents

               Table B~3.  Qualitative Association of Geographic Differences
                           in Mortality with Residence in Areas of Heavy Air
                           Pollution
SOXGR3/A                                          B-12                               2-14-81

-------
                                                                Appendix  B  -  Chapter  14  PM/SO
       TABLE B-3.  QUALITATIVE ASSOCIATION OF GEOGRAPHIC  DIFFERENCES  IN MORTALITY
                     WITH RESIDENCE  IN AREAS OF HEAVY AIR POLLUTION
      Study
         Characteristics
      Findings
  Pemberton and
   Goldberg (1954)
1950-1952 bronchitis mortality
 rates in men 45 years of age
 and older in county boroughs
 of England and Wales.
   Stocks  (1958,  1959,   Bronchitis  mortality,  1950-1953,
    1960a,b)
   Gorham  (1958,  1959)
   Gore  and Shaddick
    (1958)  and
    Hewitt  (1956)
   Hagstrom et al.
    (1967)  Zeidberg
    et al.  (1967)
    Sprague and
    Hagstrom (1969)
   Lepper et al.
    (1969)
   Jacobs and
    Landoc (1972)
   Morris et al.
    (1976)
 in urban and rural areas of
 Britian, with adjustments for
 population density and social
 index.

1950-1954 deaths, 53 counties
 of England, Scotland, and
 Wales.

Mortality in London, 1954-1958
 and in 1950-1952, respectively.
1949-1960 deaths for each cause
 in Nashville, Tenn., categor-
 ized by census tract into 3
 degrees of air pollution and
 3 economic classes (levels
 not accurately determined).
1964/1965 mortality rates in
 Chicago census tracts strati-
 fied by socioeconomic class and
 S02 concentration.
1968/1970 mortality rates
 in Charleston, S.C.,
 industrial vs. non-indus-
 trial areas.

1960-72 mortality rates
 compared to  1959-60 air
 pollution  levels.
Sulfur oxide concentrations
 (sulfation rates) were con-
 sistently correlated with
 bronchitis death rates in the
 35 county boroughs analyzed.

Significant correlation of mor-
 tality from bronchitis and
 pneumonia among men, and from
 bronchitis among females, with
 smoke density.

Bronchitis mortality was strongly
 correlated with acidity of
 winter precipitation.

Duration of residence in London
 significantly correlated with
 bronchitis mortality, after
 adjusting for social class.

Within the middle social class,
 total respiratory disease
 mortality, but not bronchitis
 and emphysema mortality, were
 significantly assoicated with
 sulfation rates and social index.
 White infant mortality rates
 were significantly related to
 sulfation rates.

Increased respiratory disease
death rates in areas of inter-
 mediate and high S02 concen-
 tration, within a socioeconomic
 status, without a consistent
 mortality gradient between the
 areas of intermediate and  high
 S02 concentration.

Higher total and heart disease
 mortality rates in  industrial
 area.
Mortality  higher  in  smokers
 with  lower  air pollution
 exposures.
SOXGR3/A
                           B-13
                         2-14-81

-------
                                  TABLE B-3  (Continued).
                                                                 Appendix  B  -  Chapter 14 PM/SO>
       Study
         Characteristics
      Findings
   Collins et al.
    (1971)
   Toyama (1964)
Death rates in children 0-14
 years of age, 1958-1964,
 in relation to social  and air
 pollution indices in 83 county
 boroughs of England and Wales.
Mortality in districts
 of Tokyo.
   Lindeberg (1968)     Deaths in Oslo winters.
   US/Canada
   Internat. Joint
    Commission (1960)
   Buck and Brown
    (1964)
   Winkelstein et al,
    (1967),
   Winkelstein and
    Kantor (1967),
   Winkelstein and
    Gray (1971)
   Zeidberg et al.
    (1967)
Mortality, episodic and non-
 episodic in Detroit and Windsor
 (Canada in 3 areas, 1953.
Partial correlation analysis
 suggested that indices of
 domestic and industrial
 pollution account for a
 differences in mortality
 from bronchopneumonia and
 all respiratory diseases among
 children 0-1 year of age.

Bronchitis mortatliy associated
 with dustfall (but not cardio-
 vascular, pneumonia or cancer
 mortality).

Average deaths per week, 1958-65
 winter, correlated with pollution.

Respiratory cancer and infant
 mortality correlated with
 episodic and non-episodic
 levels of TSP and SO  (as
 did morbidity).
Bronchitis mortality in 214 areas   Social  index and S02 accounted
 of Britain, 1955-1959, evaluated
 with respect to S02, particulates,
 social index, and population
 density.
120 census tracts in Buffalo
 stratified into 4 degrees of
 particulate pollution and cross-
 stratified into 5 economic
 classes.
1949-1960 deaths for each cause
 in Nashville, Tenn., categorized
 by census tract into 3 degrees of
 pollution and 3 economic classes.
 for 36 percent of the variation
 in bronchitis mortality within
 county and noncounty boroughs
 and in urban districts.  Within
 London boroughs, social index
 was the most important factor.

Within an economic class,
 death rates of white male 50-69
 years of age, for all causes
 and for chronic respiratory
 disease corresponded to the
 gradient of particulate, but
 not S02 pollution.

Within the middle social class,
 total respiratory disease
 mortality, but not bronchitis
 and emphysema mortality, were
 significantly associated with
 sulfation rates and social index.
 White infant mortality rates
 were significantly related to
 sulfation rates.
SOXGR3/A
                          B-14
                                                            2-14-81

-------
                                                                 Appendix  B  -  Chapter 14  PM/SO
                                  TABLE  B-3  (Continued).
      Study
         Characteristics
      Findings
   Burn  and  Pemberton
    (1963)
   Wicken  and  Buck
    (1964)
   Kevany et al.
    (1975)
   Watanabe and Kaneko
    (1971)
1950/59 deaths from all causes,
 bronchitis and lung cancer in 3
 polluted areas of Sal ford, U.K.
1952-62 deaths from bronchitis
 and lung cancer in areas of
 northeast England.
1970-73 deaths from various
 causes in Dublin, Ireland.
1965-66 mortality by cause in 3
 areas of Osaka, Japan.
The gradient of mortality from
 all causes and from bronchitis
 and lung cancer followed the
 pollution gradient.

Differences in death rates
 between areas were correlated
 with their differences in air
 pollution.

Partial correlation analysis
 was significant for air
 pollutants and some specific
 causes of death.

A stepwise increase in circu-
 latory mortality was related
 to air pollution independent
 of temperature.
SOXGR3/A
                          B-15
                         2-14-81

-------
                                                  Appendix C - Chapter 14 PM/SO
                                   APPENDIX C








                  OCCUPATIONAL HEALTH STUDIES ON PARTICULATE



                           MATTER AND SULFUR OXIDES
SOXGR3/J                               C-l                                2-16-81

-------
                                                Appendix C - Chapter 14 PM/SO>


 Adamson, L.  F. ,  and  R. M.  Bruce.   Suspended Particulate Matter:  A Report to
     Congress.   EPA-600/9-79-006,  U.S.  Environmental  Protection   Agency,
     Research Triangle Park, NC, June 1979.

 jjuselsson, K. R., C. G. Desaedeleer,  T. B.  Johansson,  and J. W.
      Winchester.  Particle Size Distribution and  Human Respi-
      ratory Deposition of Trace Metals  in Indoor  Work Environ-
      ments.  Ann. of Occup. Byg.  19:225-238, 1976.

 Andersen, I., P. Camner, P. L. Jensen, K. Philipson, and D. F.
      Proctor.   A Comparison of Nasal and  Tracheobronchial
      Clearance.  Arch. Envr. Health. 29:290-293,  1974.

 Anderson, I. B., G. R. Lundgvist, D.  F. Proctor, and D. L.
      Swift.  Human Response to Controlled Levels  of Inert Dust.
      Am. Rev.  Resp. Dis. 119:619-627, 1979.

 Archer, V. E., C. D. Fullmer,  and C.  H. Castle.  Chronic Sulfur
      Dioxide Exposure in a Smelter*.  III. Acute Effects and
      Sputum Cytology.  J.O.M. 21:359-364, 1979.

 Archer, V. E. and J. D. Gillam.  Chronic  Sulfur Dioxide Exposure
      in a  Smelter.   II. Indices of Chest  Disease.  J.O.M.
      20:88-95, 1978.

 Armstrong, B. K., J. C. McNulty, L. J.  Levitt, K.  A. Williams,
      and M. S. T. Hoffs.   Mortality in  Gold and Coal Miners  in
      Western Australia with  Special Reference to Lung Cancer.
      Brit.  J.  Ind. Med. 36:199-205, 1979.

 Ashley, D. J. B.  Environmental Factors  in  the Aetiology of  Lung
      Cancer and Bronchitis.   Brit.  J. Prev.  Soc.  Med. 23:258-
      262,  1969.

 Austin, E.,  J. Brock,  and E. Wissler.  A  Model for Deposition  of
      Stable and Unstable Aerosols in the  Human Respiratory
      Tract.  AIHAJ 40:1055-1066,  1979.

 Avol, E.  L.,  R.  M.  Bailey,  and K.  A.  Bell.   Sulfate Aerosol
      Generation  and  Characterization for Controlled Human
      Exposures.   AIHAJ 40:619-625,  1979.

Axelson,  0.,  E.  Dahlgren, C. D.  Jansson,  and  S. 0.  Rehnlund.
      Arsenic Exposure and Mortality:  A Case-Referent  Study
      from  a Swedish  Copper Smelter.  Brit.  J. Ind. Med.
      35:8-15,  1978.


 Babich, H., and G. Stotzky.  Atmospheric  Sulfur Compounds  and
        Microbes.  Environ. Res.  15:513-531,  1978.

 Baetjer, A. M.  Chronic Exposure  to Air Pollutants and Acute
         Infectious Respiratory Diseases.  Ind. Hyg. Occup.  Med.
         2:400-406, 1950.
                               C-2                           2-14-81

-------
                                                  Appendix C - Chapter 14 PM/SO


   Balchum, 0. J.  Environment in Relation to Respiratory Disease.
          Arch. Envr. Health.  4:9-22,  1962.

   BarZiv, J. and G. M.  Goldberg.  Simple Siliceous Pneumoconiosis
          Negev Bedouins.   Arch.  Environ. Health 29:121-126,  1974.

   Battigelli, J. C., and  J.  F. Gamble.   From Sulfur to Sulfate:
          Ancient and Recent Considerations.   J.O.M. 18:334-337,
          1976.

   Battigelli, M. C.  Sulfur Dioxide and Acute Effects of Air Pol-
          lution.  J.O.M.  10:500-515,  1968.

   Bell,  K. A., W. S. Linn, M. Hazucha,  J. D. Hackney, and D. V.
          Bates.  Respiratory Effects of Exposure to Ozone Plus Sul-
          fur Dioxide in Southern Californians and Eastern
          Canadians.  AIHAJ 38:696-705,  1977.

   Bennett, J. G., J. A. Dick, Y. S. Kaplan,  P. A. Shand, D.  H.
          Sherman, D. J. Thomas,  and J.  S. Washington.  The rela-
          tionship between coal rank and the prevalence of pneumo-
          coniosis.  Brit. J. Ind. Med.  36:206-210, 1979.

   Bernard, T. E., E. Kamon, and R. L. Stein.  Respiratory Responses
          of  Coal Miners for Use with Mechanical Simulators.   AIHAJ
          39:425-429,  1978.

   Binder,  R. E.,  C. A. Mitchell, H. R.  Hosein, and A. Bouhuys.
           Importance of Indoor Environment in Air Pollution Expo-
           sures.  Arch. Envr. Health. 31:277-279, 1976.

   Blair, A., and T.  J. Mason.  Cancer mortality  in United States counties with
       metal electroplating industries.  Arch Environ. Health 35:92-94, 1980.

   Blot, W.  J.,,  and J.  F.  Fraumeni.   Studies  of Respiratory  Cancer
          in High Risk Communities.  J.O.M. 21:276-278,  1979.

   Bonnevie, A.  Silicosis  and  Individual Susceptibility—Fact or
          Myth?  Ann. of Occup. Hyg. 20:101-108,  1977.

   Brain, J. D.,  D.  E.  Knudson, S.  P.  Sorokin,  M.  A. Davis.   Pulmo-
          nary Distribution of  Particles  Given by Intratracheal
          Instillation or by Aerosol Inhalation.   Environ. Res.
          11:13-33,  1976.

   Brambilla,  C.,  J.  Abraham, E.  Brambilla, K.  Benirschke, and C.
          Bloor.   Comparative Pathology of Silicate Pneurooconiosis.
          Aroer. J.  Path. 96:149-163, 1979.

Buckley,  R.  D., C. Posin, K. Clark, J. D.  Hackney,  M.  P.  Jones,
       and J.  V. Patterson.  Arch.  Envr.  Health.  33:318-324,
       1978.                                , «

Burke,  W.  A.,  and N.  Esmen.  The  Inertial Behavior of  Fibers.
       AIHAJ 39:400-405, 1978. .


                                c_3                           2-14-81

-------
                                                Appendix C - Chapter 14 PM/SOX

Camner,  P.,  P. Hellstrom, M. Lundborg, and X. Philipson.  Lung
       Clearance of 4-um Particles Coated with Silver, Carbon, or
       Beryllium.  Arch. Envr. Health.  32:58-62, 1977.

Carlson, M.  L., and G. R. Peterson.  Mortality of California
       Agricultural Workers.  J.O.M. 20:30-32, 1978.

Carnow,  B.  W., and S. A. Conibear.  The Impact of Exposure  to
       Hydrogen Fluoride and Other Pulmonary Irritants on the
       Lungs of Alluminum Smelter Workers (Abstract).  Amer. Rev.
       Resp. Disease.  117:223, 1978 (Supplement).

Chan,  T. L.  and M. Lippmann.  Experimental Measurements  and
       Empirical Modelling of the Regional Deposition of Inhaled
       Particles in Humans.  AIHAJ 41:399-408, 1980.

Chan-Yeung,  M., M. Schulzer, L. Maclean, E. Dorken, F. Tan,
       D. Enarson, and S. Grzybowski.  A Follow-Up Study of the
       Grain Elevator Workers in the Port of Vancouver.   Amer.
       Rev.  Resp. Dis. 121:228, 1980. (Supplement).

Chan-Yeung,  M., M. Schulzer, L. MacLean, E. Dorken, and  S.
       Grzybowski.  Epidemiologic Health Survey  of Grain Elevator
       Workers in British Columbia.  Amer. Review Resp.  Disease
       121:329-338, 1980.

Coffir, D.  L., and J. H. Knelson.  Effects of Sulfur Dioxide  and
        Sulfate Aerosol Particles on Human Health.  Ambio,
        5:239-242, 1976.

Cordasco, E.  M.  and H.  S. Van Ordstrand.  Air Pollution  and COPD.
        Postgrad.  Med. 62:124-127,  1977.

Corey,  P.,  I.  Broder, and M. Rutcheon.  Relationship Between  Dust
        Exposure  of Grain Elevator  Workers and Both Baseline
        Pulmonary Function and Acute  Work-Related Changes in
        Status. Amer.  Rev. Resp. Dis. 121:228, 1980  (Supplement).

Corn, M., Y.  Hammad,  D.  Whittier,  and N. Kotski. Employee
        Exposure  to Airborne Fiber  and Total  Particulate  Matter in
        Two  Mineral Wool Facilities.  Environ. Res.  12:59-74,
        1976.

Corn, M., F.  Stein,  Y.  Hammad,  S.  Manekshaw, R.  Freedman, and
        A. M.  Hartstein.  Physical  and Chemical  Properties of Re-
        spirable  Coal  Dust  from  Two United States Mines.   AIHAJ
        34:279-285, 1973.
   Costa, D. L.,  and  M.  O. Aradur.   Effect of Oil Mists  on the  Irri-
          tancy of Sulfur Dioxide.   I.   Mineral  Oils  and Light
          Lubricating Oil.   AIHAJ  680-685, 1979.

   Costa, D. L.,  and  M.  0.  Amdur.   Effect of Oil Mists  on the  Irri-
          tancy of Sulfur Dioxide.   II.  Motor Oil.   AIHAJ 40:
          809-815, 1979.

   Craighead,  J. E., and  N. V. Vallyathan.  Cryptic pulmonary lesions in workers
       occupationally exposed to dust containing silica.   JAMA 244:1939-1941,
       1980.

                                0-4                          2-14-81

-------
                                                Appendix C - Chapter 14 PM/SOX
Crosbie, W. A.,  R.  A.  P. Cox, J. V. Lcblanc,  and D.  Cooper.
       Survey of Respiratory Disease  in  Carbon Black Workers in
       the U.K.  and U.S.A.  Amer. Rev. Resp.  Die. 119, 1979
       (Supplement).

Decoufle, P.,  and D. J. Wood.  Mortality Patterns Among Workers
       in a Gray Iron Foundry.  Amer. J.  Epidemiol.  109:667,
       1979.

Decoufle, P.,  J. W. Lloyd, and L. G.  Salvin.   Causes of Death
       Among  Construction Machinery Operators.  J.O.M. 19:
       123-128,  1977.

Dolovich, M.  B., J. Sanchis, C. Rossman,  and M. T. Newhouse.
       Aerosol penetrance:  a sensitive  index of peripheral air-
       ways  obstruction.  J. Appl. Phy.  40:3, 468-471, 1976.

Desman,  J. A., D. J. Cotton, B. L. Graham,  K. Y. Robert, F.
       Froh,  and G. D. Barnett.  Chronic Bronchitis and Decreased
       Forced Expiratory Flow Rates in Lifetime Nonsmoking Grain
       Workers.  Amer. Review Resp. Disease 121:11-16, 1980.

Durham,  W. H.  Air Pollution and Student Health.  Arch. Envr.
       Health. 28:241-254, 1974.

Dutkiewicz,  J.  Exposure to Dust-Borne Bacteria in Agriculture.
        I.  Environmental Studies.  Arch.  Envr. Health. 33:250-259,
        1978.

Dutkiewicz,  J.  Exposure to Dust-Borne Bacteria in Agriculture.
        II.  Immunological Survey.  Arch.  Envr. Health. 33:260-270,
        1978.

  Environmental Criteria and Assessment Office.  Air Quality Criteria for Oxides
      of  Nitrogen  (External  Review Draft).   U.S.  Environmental  Protection
      Agency, Research Triangle Park,  NC, June 1980.

  Environmental Criteria and Assessment Office.   Health Assessment Document for
      Cadmium   (Revised  Preprint).   EPA-600/8-79-003.  U.S.  Environmental
      Protection Agency, Research Triangle Park,  NC, December 1979.

Farant,  J.,  and C. F.  Moore.  Dust Exposures in the Canadian
       Grain Industry.  AIHAJ 39:177-194, 1978.

Federspiel,  C. F., J.  T. Layne, C. Auer, and J. Bruce.  Lung
       Function Among  Employees of a  Copper Mine  Smelter:   Lack
       of Effect of Chronic Sulfur Dioxide Exposure.  J.O.M.
       22:438-444, 1980.

Ferin, J., J. R. Coleman, S. Davis,  and  B. Morehouse.  Electron
       Microprobe Analysis of Particle Deposited  in Lungs.  Arch.
       Envr.  Health.   31:113-115, 1976.

                                                              2-14-81
                                C-5

-------
                                               Appendix C - Chapter 14 PM/SO>
Ferris, B. G., Jr., F. E. Speizcr, J. D. Spengler, D. Dockery,
       Y. M. M. Bishop, M. Wolfson, and C. Humble.  Effects of
       Sulfur Oxides and Respirable Particler on Hunan Health.
       Amer. Review Resp. Disease 120:767-779,  1979.

Ferris, Jr., B. G., F. E. Speizer, Y. M. M. Bishop, and J. D.
       Spengler.  Effects of Indoor Environment on Pulmonary
       Function of Children 6-9 Years Old.  Amer. Rev. Resp.
       Disease 119, 1979 (Supplement).

Ferris, B. G., S. Puleo, and H. Y. Chen.  Mortality and Morbid-
       ity in a Pulp and a Paper Mill in the United States:  A
       Ten-Year Follow-Up-  Brit. Journ. of Ind. Med. 36:127-134,
       1979.

Ferris, Jr., B. G., W. A. Burgess, and J. Worchester.  Prevalence of
       Respiratory Disease in a Pulp Mill and a Paper Mill in the
       United States.  British Journal of Industrial Medicine,
       24:26-37, 1967.

Funahashi, A., K. A. Siegesmund, R. F. Dragen,  and K. Pintar.
       Energy Dispersive X-ray Analysis in the Study of Pneumo-
       coniosis.  Brit. J. Ind. Med. 34:95-101, 1977.

Gerrity, T. R., P. S. Lee, and R. V. Lourenco,  A Model for
       Mucociliary Clearance of Inhaled Particles.  Amer. Rev.
       Resp. Disease 119, 1979 (Supplement).

Gibson, E. S., R. H. Martin, and J. N. Lockington.  Lung Cancer
       Mortality in a Steel Foundry.  J.O.M., 19:807-12, 1977.

Glover, J. R., C. Bevan, J. E. Cotes, P. C. Elwood, N. G.
       Hodges, R. L. Kell, C. R. Lowe, M. McDermott, and
       P. D. Oldham.  Effects of Exposure to Slate Dust in
       North Wales, Brit. J. Ind. Med. 37:152-162, 1980.

Gold,  A., W. A. Burgess, and E. V. Clougherty.  Exposure of  Fire-
       fighters to Toxic Air Contaminants.  AIHAJ 39:534-539,
       1978.

Gross, P.  The Biologic Classification of  Insoluble Respirable
       Dusts.  J.O.M. 21:371-372,  1979.

Guest, L.  The Recovery of Dust  from Formalin-Fixed Pneumoconiotic
       Lungs:  A Comparison of the Methods Used  at SMRE.  Am.
       Occup. Hyg. 19:37-47, 1976.

Hackney,  J. D., W. S.  Linn, R. D.  Buckley, E. E.  Pedersen,  S. K.
       Karnza, D. C.  Law, and D.  A.  Fischer.  Experimental
       Studies on Human Health Effects  of  Air Pollutants, Design
       Considerations.  Arch. Envr.  Health.  30:373-378,  1975.
                                C-6                           2-14-81

-------
                                                 Appendix C - Chapter 14 PM/SOx
Hackney, J. D. , W. S. Linn, J. C. Mohlcr, E. E. Pedersen, P.
       Breisacher, and A. RUSBO.  Experimental Studies on Human
       Health Effects of Air Pollutants, 4-hour Exposure to Pol-
       lutant Cases.  Arch. Envr. Health. 30:379-384, 1975.

Hackney, J. D., W. S. Linn, D. C. Law, S. K. Karuza, H. Greenberg,
       R. D. Buckley, and E. E. Pedersen.  Experimental Studies
       on Human Health Effects of Air Pollutants, 2-Hour Exposure
       to Pollutant Gases.  Arch. Envr. Health. 30:385, 1975.

Hammer, D.  I., F. J. Miller, D. E. House, K. E. McClain, and
       C. G. Hayes.  Air Pollution and Childhood Lower Respira-
       tory Disease.  II.  Particulate Exposure for Nonasthmatic
       Children.  Araer. Rev. Resp. Dis. 121:238, 1980 (Supple-
       ment ) .

Hammer, D.  I., V. Hasselblad, B. Portnoy, and P. F. Wehrle.  Los
       Angeles Student Nurse Study.  Arch. Envr. Health, 28:
       255-260, 1974.

Harbison, M., and J. D. Brain.  Effect of Exercise on Patterns
       of Retention of Inhaled Particles.  Amer. Rev. Resp. Dis.
       121:238, 1980  (Supplement).

Herman, S.,  F. E. Speizer, B. G. Ferris, Jr., J. Ware, D.
       Dockery, and J. D. Spengler.  Acute Change in Pulmonary
       Function in Children Naturally Exposed to an Air Pollution
       "Alert."  Amer. Rev. Resp. Dis. 121:239, 1980 (Supple-
       ment).

Hickey, R.  J., R. C. Clelland, E. J. Bowers, and D. E. Boyce.
       Health Effects of Atmospheric Sulfur Dioxide and Dietary
       Sulfites.  Arch. Envr. Health 31:108-110, 1976.

Hosein, H.  R., C. A. Mitchell, and A. Bouhuys.  Daily Variation
       in Air Quality.  Arch. Envr. Health. 32:14-21, 1977.

Hosein, H.  R. , C. A. Mitchell, and A. Bouhuys.  Evaluation of
       Outdoor Air Quality in Rural and Urban Communities.
       Arch. Envr. Health. 32:4-13, 1977.

Hunter, W.  G., and J. J. Crawley.  Hazardous Substances,  The
       Environment and Public Health:  A  Statistical Overview.
       Environ. Health Perspect.  32:241-254, 1979.

Jedrychowski, W.  A Consideration of Risk Factors  and  Develop-
       ment of Chronic Bronchitis in  a  Five-Year Follow-up Study
       of  an Industrial Population.  J.  Epidemic,  and  Comm.
       Health 33:210-214,  1979.

Karol, M. H., H. H.  loset,  and Y. C. Alarie.   Effect of Coal Dust
        Inhalation on  Pulmonary  Immunologic Responses.   AIHAJ 40:
        284-290, 1979.
                                 C-7

-------
                                              Appendix C - Chapter 14 PM/SOX
Kleinerman, J., and M. P. C. Ip.  Effects of Nitrogen Dioxide on
       Elastin and Collagen Contents of Lung.  Arch. Envr.
       Health.  34:228-232, 1979.           "

Klosterkotter, W.  New Aspects on Dust and Pneumoconiosis
       Research.  AIHAJ 36:659-668, 1975.

Rung, V.A.  Morphological Investigations of Fibrogenic Action of
       Estonian Oil Shale Dust.  Environ. Health Perspect. 30:
       153-156, 1979.

Lammers, B., R. S. F. Schilling, and J. Walford, with S. Meadows,
       S. A. Roach, D. Van Geuderen, Y. C. van der Veen, and
       C. H. Wood.  A Study of Byssinosis, Chronic Respiratory
       Symptoms, and Ventilatory Capacity in English and Dutch
       Cotton Workers, with Special Reference to Atmospheric Pol-
       lution.  Br. J. Ind. Med. 21:124-134, 1964.

Lawther, P. J., P. W. Lord, A. G. F. Brooks, and R. E. Waller.
       Air Pollution and Pulmonary Airways Resistance:  A 6-Year
       Study with Three Individuals.  Environ. Res. 13:478-492,
       1977.

Lebowitz, M. D., A. Burton, and W- Kaltenborn.  Pulmonary Function
       in Smelter Workers.  J.O.M. 21:255-259, 1979.

Lebowitz, M. D., and B. Burrows.  The Relationship of Acute
       Respiratory Illness History to the Prevalence and In-
       cidence of Obstructive Lung Disorders.  Am. J. of
       Epidemiol. 105:544, 1977.

Lebowitz, M. D., and B. Burrows.  Tucson Epidemiologic Study of
       Obstructive Lung Diseases.  II:  Effects of In-Migration
       of the Prevalence of Obstructive Lung Diseases.  Amer. J.
       Epidemiol.  102:153-163,  1975.

Lebowitz, M. D.  Occupational Exposures in Relation to Symptoma-
       tology and Lung Function  in a Community Population.  Env.
       Res. 14:59-67, 1977.

Lebowitz, M. D., R. J. Knudson,  and B. Burrows.   Tucson Epidemio-
       logic Study of Obstructive Lung Diseases.   I:  Methodology
       and  Prevalence of Disease.  Amer. J.  Epidemiol.  102:
       137-152,  1975.

Lefcoe,  N.  M.,  and I. I. Inculet.  Particulates in Domestic
       Premises.   II. Ambient Levels and  Indoor-Outdoor Rela-
       tionships.  Arch. Envr.  Health. 30:565-570,  1975.

Leikauf, G. D.,  D. B. Yeates, D. M. Spektor,  and  M.  Lippmann.
       Effect  of Sulfuric  Acid  Aerosol on Bronchial  Mucociliary
       Clearnace.  Amer. Rev. Resp. Dis.  121:245, 1980  (Supple-
       ment).


                                C-8                         2-14-81

-------
                                                Appendix C - Chapter 14 PM/SOX
Leikauf, G., D. B. Yeates,  K.  Wales,  and M. Lippmann.  Effect of
       Inhaled Sulfuric  Acid Mist on Tracheobronchial Mucociliary
       Clearance and  Respiratory Mechanics in Health Nonsmokers.
       Amer. Rev. Resp.  Dis. 119, 1979 (Supplement).

Liddell, F. D. K.  Radiological Assessment of Small Pneumo-
       coniotic Opacities.   Brit. J.  Ind. Med. 34:85-94, 1977.

Lin, M. S., and D. A. Goodwin.  Pulmonary Distribution of an
       Inhaled Radioaerosol in Obstructive Pulmonary Disease.
       Radiology 118:645-651,  1976.

Love, R. G., and D. C. F.  Muir.  Aerosol Deposition and Airway
       Obstruction.   Amer.  Review Resp. Disease 114:891-897,
       1976.

Lowe, C. R., H. Campbell,  and  T. Kosha.  Bronchitis in Two Inte-
       grated Steel Works.   III.  Respiratory Symptoms and Venti-
       latory Capacity Related to Atmospheric Pollution.  Br. J.
       Industr. Med.  27:121-29, 1970.

Lowe, C. R., P. L. Pelmear, B. Campbell, R. A. N. Hitchens,
       T.  Khosla,  and T. C. King.  Bronchitis in Two Integrated
       Steel Works.   I.  Ventilatory Capacity, Age, and Physique
       of  Non-Bronchitic Men.   Br. J. Prev. Soc. Med., 22:1-11,
       1968.

McEuen, D. D.,  and J. L. Abraham.  Particulate Concentrations in
       Pulmonary Alveolar Proteinosis.  Environ. Res. 17:334-339,
       1978.

Milham,  S.  Mortality in Aluminum Reduction Plant Workers.   J.
       Occup. Med.,  21:475-480, 1979-

Mitchell,  C.  A.,  R.  S. F. Schilling, and A. Bouhuys.  Community
        Studies  of Lung Disease in Connecticut: Organization  and
       Methods.   Am.  Jour, of Epid. 103:212-225, 1976.

Morgan,  W. K.  C.   Industrial Bronchitis.   Brit. J.  Ind. Med.
        35:285-291, 1978.

Morgan,  W. K.  C.   Magnetite Pneumoconiosis.   J.O.M.  20:762-763,
        1978.

Mushak, P.,  W.  Galke, V. Hasselblad, and  L.  D.  Grant.   Health Assessment
    Document  for  Arsenic  (External  Review  Draft).  U.S. Environmental
    Protection Agency, Research Trianlge  Park,  NC, April  1980.
       A  W    J  M.  Peters,  D.  H.  Wegman, and L. J. Fine.  Pulmo-
      , A  Wy'  J'c«:on .n G^anite Dust Exposure:  A Four-Year
        Follow-up.   Amer. Review Resp. Disease 115:769-776, 1977.
                                C-9

-------
                                                        Appendix C - Chapter 14 PM/SO,
National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:   Occupational  Exposure to  Beryllium.  DHHS (NIOSH)
     72-10268,  U.S.  Department of Health and Human  Services, Washington,  DC,
     1972.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:    Occupational   Exposure  to  Coke Oven  Emissions.
     DHHS  (NIOSH) 73-11016,  U.S. Department  of  Health and Human  Services,
     Washington, DC, 1973.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:   Occupational  Exposure  to Inorganic  Mercury.   DHHS
     (NIOSH)   73-11024,   U.S.  Department  of  Health   and   Human   Services,
     Washington, DC, 1973.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:    Occupational  Exposure  to  Sulfur  Dioxide.   DHHS
     (NIOSH) 74-111, U.S. Department of Health and Human Services, Washington,
     DC, 1974.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:    Occupational   Exposure  to  Sulfuric Acid.   DHHS
     (NIOSH) 74-128, U.S. Department of Health and Human Services, Washington,
     DC, 1974.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:   Occupational Exposure to Ammonia.    DHHS (NIOSH)
     74-136,  U.S. Department of Health  and  Human  Services, Washington,  DC,
     1974.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:    Occupational  Exposure  to  Cotton  Dust.    DHHS
     (NIOSH) 75-118, U.S. Department of Health and Human Services, Washington,
     DC, 1975.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:    Occupational   Exposure  to  Inorganic  Arsenic.
     (Revised).   DHHS  (NIOSH)  75-149,  U.S.  Department  of  Health  and  Human
     Services, Washington, DC, 1975.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:   Occupational Exposure  to Inorganic Fluoride.   DHHS
     (NIOSH) 76-103, U.S. Department of Health and Human Services, Washington
     DC, 1973.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:   Occupational Exposure  to Zinc Oxide.  DHHS (NIOSH)
     76-104,  U.S. Department of Health  and  Human  Services, Washington   DC
     1974.

National  Institute  for  Occupational  Safety  and  Health.   Criteria  for   a
     recommended  standard:    Occupational  Exposure  to  Chromium  VI.   DHHS
     (NIOSH) 76-129, U.S. Department of Health and Human Services  Washinaton
     DC, 1976.                                                           M    '
                                  0-10                                2-14-81

-------
                                                    Appendix C -  Chapter 14  PM/SO^


National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:   Occupational  Exposure  to  Nitric  Acid.    DHHS
     (NIOSH) 76-141, U.S. Department of Health and Human Services, Washington,
     DC, 1976.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended standard:  Occupational Exposure to Oxides of Nitrogen.  DHHS
     (NIOSH) 76-149, U.S. Department of Health and Human Services, Washington,
     DC, 1976.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:   Occupational  Exposure  to Cadmium.   DHHS  (NIOSH)
     76-192,  U.S.  Department  of Health  and  Human Services,  Washington,  DC,
     1976.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:   Occupational   Exposure  to  Hydrogen Cyanide  and
     Cyanide  Salts.   DHHS (NIOSH) 77-108, U.S. Department of Health and Human
     Services, Washington, DC, 1977.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:   Occupational  Exposure to  Organotin  Compounds.
     DHHS  (NIOSH)  77-115,  U.S.  Department  of  Health  and  Human  Services,
     Washington, DC, 1977.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:   Occupational  Exposure  to  Inorganic  Nickel.  DHHS
     (NIOSH) 77-164, U.S. Department of Health and Human Services, Washington,
     DC, 1977.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:   Occupational  Exposure  to  Asbestos.   DHHS  (NIOSH)
     77-169,  U.S.  Department  of Health  and  Human Services,  Washington,  DC,
     1977.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended   standard:    Occupational   Exposure   to  Refined  Petroleum
     Solvents.   DHHS  (NIOSH)  77-192,  U.S.  Department  of  Health  and Human
     Services, Washington, DC, 1977.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:   Occupational  Exposure  to  Vanadium.   DHHS  (NIOSH)
     77-222,  U.S.  Department  of Health  and  Human  Services,  Washington,  DC,
     1977.

National  Institute  for  Occupational  Safety  and  Health.    Criteria  for  a
     recommended  standard:  Occupational  Exposure  to Tungsten  and Cemented
     Tungsten  Carbide.    DHHS  (NIOSH) 77-227,  U.S.  Department  of  Health and
     Human Services, Washington,  DC, 1977.

National  Institute  for  Occupational  Safety  and  Health.    Criteria   for   a
     recommended  standard:   Occupational  Exposure  to  Asphalt  Fumes.  DHHS
     (NIOSH) 78-106, U.S. Department of Health and  Human  Services, Washington,
     DC, 1978.


                                       C-ll                           2-14-81

-------
                                               Appendix C - Chapter 14 PM/SOX


National  Institute  for Occupational  Safety  and  Health.   Criteria  fora
     recommended  standard:  Occupational Exposure to Coal Tar Products.   DHHS
     (NIOSH) 78-107, U.S. Department of Health and Human Services, Washington,
     DC, 1978.

National  Institute  for Occupational  Safety  and  Health.   Criteria  for  a
     recommended  standard:   Occupational  Exposure  to  Inorganic  Lead.   DHHS
     (NIOSH) 78-158, U.S. Department of Health and Human Services, Washington,
     DC, 1978.

National  Institute  for Occupational  Safety  and  Health.   Criteria  for  a
     recommended   standard:   Occupational   Exposures   in  Coal  Gasification
     Plants.   DHHS  (NIOSH)  78-191,  U.S.  Department  of  Health  and  Human
     Services,  Washington, DC, 1978.

National  Institute  for Occupational  Safety  and  Health.   Criteria  for  a
     recommended   standard:   Occupational  Exposure to  Carbon  Black.   DHHS
     (NIOSH) 78-204, U.S. Department of Health and Human Services, Washington,
     DC, 1978.

°ffiCcDA°cfnn/RoeS-,e-Jarch  and  Deve1°Pment.   Air  Quality  Criteria   for  Lead.
     hPA-600/8-77-017,  U.S.  Environmental  Protection Agency,  Washington,  DC,
     December 1977.


Ogden, T.  L.  and J.  L. Burkett.   An  Inhalable Dust Sample for
       Measuring the Hazard from  Total Airborne Particulate.
       Ann.  Occup. Hyg. 21:41-50, 1978.

Ogden, T. L. and J. L'. BurXett.  The Human  Head as a Dust Samp-
        ler.  In:   Inhaled  Particles IV.  W- H. Walton, ed.
        Pergamon Press, Oxford.  1977.   p. 93'.''

Ohman, K. H. G.  Prevention of Silica Exposure and Elimination
        of Silicosis.  AIHAJ 39^847-859,  1978.

Farobeck, P. S.,  and R.  A. Jankowski.   Assessment of the Respi-
        rable Dust Levels in the Nation's Underground and Surface
        Coal  Mining  Operations.  AIHAJ 40:910-915, 1979.

Favia, D.,  and M. L. Thomson.  The Fractional Deposition of  In-
        haled 2 and  5 pro  Particles in  the Alveolar and  Tracheo-
        bronchial Regions of the  Healthy Human Lung.  Ann. Occup.
        Hyg.  19:109-114,  1976.

Pham, Q.  T., R. Beigbeder, R. Deniau, P. Sadoul,  and J. M. Mur.
        Methodology  of an Epidemiological Survey in  the  Iron-Ore
        Mines of Lorraine.   Research into the Long-term  Effect of
        Potentially  Irritant Gases on the Pulmonary System.   Amer.
        Occup.  Hyg.  19:33-35,  1976.

 Plumlee,  L., S. Coerr, H.  L. Needleraan, and R. Albert.   Panel
        Discussion:  Role of High Risk Groups  in  the Derivation of
        Environmental Health Standards.  Environ.  Health Perspect.
        29:155-159,  1979.

 Reid, L.  M.   Introductory Remarks:   Session on Disease  Conditions
        Predisposing Afflicted Individuals  to  the Toxic  Effects of
        Pollutants.  Environ.  Health Perspect.  29:127-129,  1979.

                                   C-12                           2-14-81

-------
                                               Appendix C - Chapter 14 PM/SO>


 Rencher, A.  c.,  M.  W. Carter, and D. W. McKee.  A Retrospective
      Epidemiological Study of Mortality at  a  Large Western
      Copper Smelter.  J.O.M. 19:754-58, 1977.
     35:181-186.                         o   4-  Arch- Environ. Health

Rockette, H.E.   Cause Specific Mortality of Coal Miners.  J.O.M.
       19:795—801,  1977.

Roger, J., and K. A.  Paton.  Reading Chest Radiographs for Pneumo-
       coniosis by  Computer.  Brit. J. Ind. Med. 32:267-272,
       X 7 / W •

Rynbrandt, D., and  J.  Kleinerman.  Nitrogen Dioxide and Pulmonary
       Proteolytic  Enzymes:  Effect on Lung Tissue and Macro-
       phages.  Arch.  Envr. Health.  32:165-73, 1977.

Sackner, M. A., M.  Broudy,  A. Friden, G. Villavicencio, and
       M. A. Cohn.  Effects of Breathing Nitrate and Sulfate Mi-
       croaerosols  for Four Hours on Pulmonary Function of Normal
       Adults.  Amer.  Rev.  Resp. Dis. 121:225, 1980 (Supplement).


  Sackner,  M.  A.,  and D. Ford.   Effects of  Breathing NaCl and
         Sulfate Aerosols in  High Concentrations  for 10 Minutes on
         Pulmonary Function of Normal ,and Asthmatic  Adults.   Amer.
         Rev.  Resp.  Dis. 121:255, 1980  (Supplement).

  Sackner, M. A., B.  Marchette,  S.  Birch,  R. McDonald, and C. S.
         Kim.  Effects of Sodium Chloride and Sulfate Aerosols in
         High Concentrations on Nasal Airflow Resistance and Nasal
         Mucous Velocity  of Normal  Subjects and Patients with
         Allergic Rhinitis.  Amer.  Rev. Resp. Dis. 121:254, 1980
          (Supplement).

  Santodonato,  J. , P.  Howard, D. Basu, S.  Lande, J. K. Selkirk,  and P. Sheehe.
      Health Assessment  Document for Polycyclic  Organic Matter  (Preprint).
      EPA-600/9- 79-008, U.S.  Environmental  Protection Agency, Research Triangle
      Park, NC, December 1979.


   Saric, M., I.  Kalacic,  and A. Holetic.   Follow-up of Ventilatory
          Lung Function in a Group  of Cement Workers.  Brit. J. Ind.
          Med. 33:18-24,  1976.

   Saric, M., S.  Lucic-Palaic,  and  R. J. M. Horton.  Chronic Non-
          specific  Lung Disease and Alcohol Consumption.  Environ.
          Res. 14:14-21,  1977.

   Schilling, R.  S. F., A. D. Letal, S. L. Hui, G.  J.  Beck,  J.  B.
          Schoenberg,  and A. Bouhuys.  Lung Function,  Respiratory
          Disease,  and Smoking  in Families.  Am. Jour. Epid.
          106:274-283, 1977.


                                    C-13                      2-14'81

-------
                                             Appendix C - Chapter 14 PM/SOX
 Seeker-Walker,  R.,  P. Miller, R.  Slavin, «. Paine,  and M.
        McCrate.  The Effects of Air Pollution  and Meteroiogic
        Conditions on Daily Lung Function of Health  Non-Smoking
        Outdoor Workers.   Amer.  Rev. Resp. Dis.  121:258,  1980
        (Supplement).

 Severs, R.  K.   Air Pollution and  Health.  Texas Rep.  Biol.  Med.
        33:45-83,  1975.

 Sharratt, M. T. and F. J.  Cerny.  Pulmonary Function  and Health
        Status  of Children in Two  Cities of Diffemet  Air Quality.
        Arch. Envr.  Health 34:114-119,  1979.

 Shaw,  D. T., N. Rajendran,  and  N. S. Liao.  Theoretical  Modeling
        of Fine-Particle  Deposition in  3-Dimensional Bronchial
        Bifurcations. AIHAJ 39:195-201, 1978.

 Sherwin, R. P., M.  L. Barman, and J. L. Abraham.  Silicate
        Pneumoconiosis of Farm Workers. Lab. Invest.  40:576-582,
        1979.

 Smith, R. M.,  and V. D.  Dinh.   Changes in Forced Expiratory Flow
        due to  Air Pollution from  Fireworks.  Env. Res.  9:321-331,
        1975.
Smith, J. T., J. M. Peters,  J.  C.  Reading,  and C.  B.  Castle.
       Pulmonary Impairment from Chronic Exposure  to  Sulfur
       Dioxide in a Smelter.  Am.  Rev.  Resp.  Dis.  116:31-39,
       1977.

Smith, T. J., W. L. Wagner,  and D. E. Moore.   Chronic Sulfur
       Dioxide Exposure in a Smelter.   I. Exposure to S02 and
       Dust:  1940-1974.  J.O.M.,  20:83-87, 1978.

Spengler, J. D., B. G. Ferris,  D.  W. Dockery, and F.  E. Speizer.
       Sulfur Dioxide and Nitrogen Dioxide Levels Inside and Out-
       side Homes and the Implications  on Health Effects Re-
       search.  Environ. Sci. Technol.  13:1276, 1979.

Stahlhofen, W., J. Gebhart,  and J. Heyder.  Experimental Determi-
       nation of the Regional Deposition of Aerosol Particles in
       the Human Respiratory Tract.  AIHAJ 41:385-398a, 1980.

Stebbings, J.H.  Panel Studies of Acute Health Effects of Air
       Pollution.  II.  A Methodologic Study of Linear Regression
       Analysis of Asthma Panel Data.  Environ. Res. 17:10-32,
       1978.

Sterling, T. D., S. V. Pollack, and J.  Weinkam.  Measuring the
       Effect of Air Pollution on Urban Morbidity.  Arch.  En-
       viron.  Health 18:485-494,  1969.


                                C-14                     2-14-81

-------
                                              Appendix C - Chapter 14 PM/SOX
Strahilevitz,  M.,  A. Strahilevitz, and J. E. Miller.  Air Pollu-
       tants and the Admission Rate of Psychiatric Patients.
       Amer. J. Psychia. 136:2, 1979.

Stuart, B. O.   Deposition and Clearance of Inhaled Particles.
       Environ. Health Perspect. 16:41-53, 1976.

Sweet, D. V.,  W. E. Crouse, and J. V. Crable.  Chemical and
       Statistical Studies of Contaminants in Urban Lungs.
       SIJAJ 39:515-26, 1978.

Sweet, D. V.,  W. E. Crouse, J. V. Crable, J. R. Carlberg, and
       W. S. Lainhart.  The Relationship of Total Dust, Free
       Silica, and Trace Metal Concentrations to the Occupational
       Respiratory Disease of Bituminous Coal Miners.  AIHAJ
       35:479-488, 1974.

Tabershaw, I. R.  Oxides of Sulfur.  J.O.M. 18:360-361, 1977.

Toca, F. M., C. L. Cheever, and C. M. Berry.  Lead and Cadmium
       Distribution in the Particulate Effluent from a Coal-
       Fired Boiler.  AIHAJ 34:396-403, 1973.

Utidjian, M. D., M. Corn, B. Dinman, P. F. Infante, P. Seminario.
       Panel Discussion:  Role of High Rish Groups in Standard
       Deviation.  Environ. Health Perspect.  29:161-173, 1979.


Valic, F., D.  Beritic-Stahuljak, and B. Mark.  A Pollow-Up Study
       of Functional  and Radiological Lung Changes in Carbon-
       Black Exposure.  Int. Arch. Occup., 34:51-63, 1975.

Vitek, J.   Respirable Dust Sampling in Czechoslovak Coal Mines,
       AIHAJ 38:247-252, 1977.

Walkonsky,  P.  M.   Pulmonary Effects of Air Pollution.  Current
       Research.   Arch. Envr. Health. 19:586-592, 1969.


 Warner,  C. G., G. M. Davies, J. G. Jones, and C. R. Lowe.
        Bronchitis In Two Integrated Steel Works.  II.  Sulphur
        Dioxide and Particulate Atmospheric Pollution In and
        Around the Two Works.

 Warren,  C. P. W.  Lung Disease in Farmers.  Cand. Med. Assn. J.
        116:391-394, 1977.

 Whiting, W. B.  Occupational Illnesses and Injuries of California
        Agricultural Workers.  J.O.M. 17:177-181, 1975.

 Wolf, A. F.  Occupational Diseases of the Lung.  III.  Pulmonary
        Disease Due to Inhalation of Noxious Gases, Aerosols or
        Fumes.  Ann. Allergy. 35:165-171, 1975.

 Yoshida, K., H. Oshima, and M. Imai.  Air Pollution and Asthma in
        Yokkaichi.  Arch. Environ. Health 13:763-768,  1966.
                                                             2-14-81
                                  C-15

-------
                                              Appendix C - Chapter 14 PM/SO
Yu, C. P., P. Nicolaides, and T. T.  Soong.   Effect of Random

       ,i^ay Slzcs on Aerosol Deposition.   AIHAJ 40:999-1005,
       1979.


Zaidi, S. H.  Some Aspects of Experimental  Infective Pneumo-
       coniosis.  AIHAJ 38:239-245,  1977.
                            C-16                           2-14-81

-------