Draft
Do Not Quote or Cite
                               External Review Draft No  1
                                              April 1980
             Air  Quality Criteria
          for Particulate Matter
             and Sulfur Oxides
                     Volume  IV
                   Health Effects
                          NOTICE

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

-------
Draft
Do Not Quote or Cite
                                 External Review Draft No. 1
                                                 April 1980
              Air Quality  Criteria
           for  Particulate  Matter
               and  Sulfur  Oxides
                       Volume IV
                     Health Effects
                            NOTICE

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

-------
                             Preface to Volume IV

     Volume IV of this Criteria Document addresses the effects of sulfur
oxides and particulate matter on health.  To understand these effects, however,
one must first appreciate the characteristics of these substances as they
occur in the environment.  This prerequisite information may be found in
Volume II, which covers chemical and physical properties, analytical and
measurement techniques, sources and emissions, environmental concentrations
and exposures, and atmospheric transmission.
     This volume begins its assessment  of health effects by examining
respiratory deposition and biological fate of inhaled aerosols and sulfur
dioxide (Chapter 11).   The respiratory system is the principal route of
exposure to airborne particles and gaseous sulfur oxides, viz. SCL.   Such
exposure is a function of physicochemical properties of the pollutants as well
as anatomical and physiological features of the exposed organism.  Moreover,
exposure consists not only of the inhalation and deposition of substances, but
their movement to other organs, biological transformation, or removal from the
body.
     Chapter 12 assesses jjn vitro and j_n vivo studies of toxic effects of
sulfur oxides and particulate matter.   In vitro studies focus on specific
mechanisms whereas j_n vivo studies examine morphological and physiological
responses of whole organisms after chronic or acute exposures.
     Although animal toxicological studies provide essential  information on
the basic mechanisms of the health effects of sulfur oxides and  particulate
matter, they are, of course, limited to subjects other than humans.   Controlled
                                 ill

-------
human studies, discussed in Chapter 13,  provide an important  perspective on



the health effects of these pollutants by exposing humans  under  controlled



laboratory conditions.   It has thus been possible to evaluate respiratory  and



other responses of humans to a number of specific forms of sulfur oxides  and



particulate matter.   Human studies are limited, however, to relatively short-



term exposure regimens.   For information on long-term exposures, epidemiological



studies must be used.



     Chapter 14 evaluates evidence relating certain health indices in selected



populations exposed to ambient conditions.   In contrast to controlled experiments



discussed in the two previous chapters,  epidemiological studies  do not examine



variables under the control of the investigator.   That is, they  must deal  with



variations in pollution as they occur in the real world.  Evaluation of such



studies is complicated by differences in study design and conduct, selection



of variables, assessment of pollution exposure, assessment of health status,



and suitability of statistical techniques.   Such studies necessarily include



possible confounding variables, but have the advantage of direct relevance to



other human exposures.



     The progression from i_n vitro and j_n vivo animal studies to human laboratory



studies to epidemiological studies reflects the trade-offs that must be made



in any analysis of the health effects of environmental pollutants.  The more



specific the conditions of exposure and experimental manipulation, the less



general are the results thus obtained; and the more general  the conditions of



study, the less precise are the findings that  result.  Taken as a whole,



however, these various types of studies provide a basis for  formulating



conclusions regarding the health effects of sulfur  oxides  and particulate



matter.





                                   iv

-------
                                   CONTENTS
11.   RESPIRATORY DEPOSITION AND BIOLOGICAL FATE OF INHALED  AEROSOLS
     AND S0?	              	      11-1
     11.1  INTRODUCTION	      11-1
            11.1.1  General Considerations 	      11~1
            11.1.2  Aerosol and S0? Characteristics	      11-4
            11.1.3  The Respirator^ Tract	      11-9
            11.1.4  Respiration	     11-15
     11.2   DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS	     11-18
            11.2.1  Insoluble and Hydrophobic Solid Particles	     11-18
            11.2.2  Soluble, Deliquescent, and Hygroscopic  Particles  .     11-42
            11.2.3  Surface Coated Particles 	     11-44
            11.2.4  Gas Deposition 	     11-45
     11.3   TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT  .     11-59
            11.3.1  Deposited Particulate Material 	     11-60
            11.3.2  Absorbed S0?	     11-74
            11.3.3  Particles ahd S09 Mixtures 	     11-79
     11.4   DISCUSSION AND SUMMARY /	     11-79
     11.5   REFERENCES	       11-83

-------
                                    LIST OF FIGURES

Number                                                                     Page

11-1   Features of the respiratory tract of man used in the description
       of the deposition of inhaled particles and gases with insert
       showing parts of a silicon rubber cast of a human lung showing some
       separated bronchioles to 3 mm diameter, some bronchioles from 3 mm
       diameter to terminal bronchioles, and some separated respiratory
       acinus bundles	11-10

11-2   Representation of five major mechanisms of deposition of inhaled
       airborne particles in the respiratory tract 	  11-19

11-3   Total and regional deposition fractions in the human respiratory
       tract for various sizes of inhaled3airborne spherical particles
       with physical density of one ug/cm  as calculated by the ICRP Task
       Group on Lung Dynamics for breathing rate of 15 breaths per minute
       (BPM) and a tidal volume (TV) of 750 ml	11-26

11-4   Total and regional deposition fractions in the human respiratory
       tract for various sizes of inhaled.,airborne spherical particles
       with physical density of one  g/cm  as calculated by the ICRP Task
       Group on Lung Dynamics for a breathing rate of 15 breaths per minute
       (BPM) and a tidal volume (TV) of 1450 ml	11-27

11-5   The range of regional deposition fractions for log-normally
       distributed spherical aerosols in human nose breathing at 15
       BPM and 1450 ml TV.   Geometric standard deviation ranges between
       1.2 and 4.5; particle physical density is one g/cm  so that MMD =
       MMAD	11-28

11-6   Selected data reported for the deposition in the entire respiratory
       tract of monodisperse aerosols inhaled through the nose by people
       are compared with predicted values calculated by the ICRP Task
       Group on Lung Dynamics	  11-31

11-7   Selected data reported for the deposition in the respiratory tract
       of monodisperse aerosols inhaled through the mouth by people are
       compared with predicted values calculated by the ICRP Task Group  on
       Lung Dynamics	11-32

11-8   Selected data reported for the deposition fraction of monodisperse
       aerosols in the human nasopharyngeal (NP) region of the respiratory
       tract are plotted against the characteristic term (D   Q, where Q
       is the average inspiratory flow in 1/min) that contrBfs inertial
       impaction;  for reference, the calculated value is shown for 15 BPM
       at 1450 ml  TV	  11-33

-------
11-9   Selected data reported for tracheobronchial  (TB)  deposition  of
       monodisperse aerosols inhaled through the mouth by  people  are
       compared with predicted values calculated by the  1CRP  Task Group
       on Lung Dynamics	   11-34

11-10  Selected data reported for pulmonary (P) deposition of monodisperse
       aerosols inhaled through the mouth by people are  compared  with
       predicted values calculated for tidal volumes (TV)  of  750  ml and
       1450 ml by the ICRP Task Group on Lung Dynamics	    11-35

11-11  Deposition of inhaled^polydisperse aerosols  of lanthanum oxide
       (radiolabeled with    La) in beagle dogs exposed  in a  nose-only
       exposure apparatus showing (a) the deposition fraction in  the total
       dog, (b) the deposition fraction in the tracheobronchial region,
       (c) the deposition fraction in the nasopharyngeal  region,  and (d)
       the deposition fraction in the pulmonary region	    11-39

11-12  Deposition of inhaled monodisperse aerosols  of fused alumino-
       silicate spheres in small rodents showing the deposition in  the
       nasopharyngeal (nasal) region, the tracheo-bronchial (T-B) region,
       the pulmonary region and in the total respiratory tract 	   11-41

11-13  Single exponential model, fit by weighted least-squares, of  the
       buildup (based on text Equation 10) and retention (based on  text
       Equation 12) of zinc in rat lungs	    11-69

11-14  Example of the use of the sum of exponential models for describing
       models for describing lung uptake during inhalation exposure
       (Equation 14) and retention (clearance phase) after exposure ends
       (Equation 16) for three lung compartments with half-lives  50 d,
       350 d, and 500 d, and twenty-day exposure rates  of 1.4 mg/d  (E,),
       1.7 mg/d (E9), and 2.1 mg/d (E-,), respectively	  .    11-71
                  c*                  *j
11-15  Example of the use of the power function model for describing  lung
       uptake during inhalation exposure (text Equation  18) and retention
       (clearance phase) after exposure ends (text Equation 19) for a
       twenty-day exposure at 8.5 mg/d (E)	    11-73

11-16  Model of the multicompartmental deposition,  clearance, retention,
       translocation, and excretion of inhaled particulate material in the
       respiratory tract and tissues of the body; the numbered circles
       represent the transfer rate constants	    11-75

11-17  Multicomponent model of the deposition, clearance,  retention,
       translocation and excretion of an example sparingly soluble
       metallic compound (   CeCl_ continued in CsCl particles)  inhaled
       by man or experimental animals; the  rate constants  are based upon
       first order kinetics as in text Equation 11	    11-76

11-18  Example of the organ retention of an inhaled sparingly soluble
       metallic compound assuming a single  acute exposure  demonstrating
       the translocation from lung and build-up and clearance from other
       organs	  11-77
                                      vii

-------
                                   LIST OF TABLES
Number
11-1   Summary of the respiratory deposition and clearance of inhaled
       aerosols.
                                                                            11-82

-------
                                  CONTENTS
12.1  INTRODUCTION	                                      12-1
12. 2  EFFECTS OF SULFUR DIOXIDE	'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.    12-2
      12.2.1  Biochemistry of Sulfur Dioxide	    12-2
              12.2.1.1  Chemical Reactions of Bisulfite with
                        Biological Molecules	     12-3
              12.2.1.2  Potential Mutagenic Effects of Sulfite + S0?	    12-5
              12.2.1.3  Metabolism of Sulfur Dioxide	  	    12-6
                        12.2.1.3.1 Integrated metabolism	    12-6
                        12.2.1.3.2 Sulfite oxidase	   12-11
              12.2.1.4  Activation and Inhibitation of Enzymes by Bisul-
                        fite	   12-14
      12.2.2  Mortality	   12-15
      12.2.3  Tumorogenesis in Animals Exposed to S0? or S0? and
              Benzo(a)pyrene	   12-16
      12.2.4  Morphological Alterations	   12-19
      12.2.5  Alterations in Pulmonary Function	   12-30
      12. 2. 6  Effects on Host Defenses	   12-39
12. 3  EFFECTS ON PARTICULATE MATTER	   12-43
      12.3.1  Mortality	   12-45
      12.3.2  Morphological Alterations	   12-46
      12.3.3  Alterations in Pulmonary Function	   12-48
              12. 3. 3.1  Acute Exposure Effects	   12-48
              12.3.3.2  Chronic Exposure Effects	   12-66
      12.3.4  Alteration in Host Defense	   12-70
              12.3.4.1  Mucociliary Clearance	   12-70
              12.3.4.2  Alveolar Macrophages	   12-74
              12.3.4.3  Interaction with Infectious Agents	   12-80
              12.3.4.4  Immune Suppression	   12-83
12.4  INTERACTION OF SULFUR DIOXIDE AND OTHER POLLUTANTS	   12-88
      12.4.1  Sulfur Dioxide and Particulate Matter	   12-88
              12.4.1.1  Acute Exposure Effects	   12-88
              12.4.1.2  Chronic Exposure Effects	   12-91
      12.4.2  Interaction with Ozone	  12-100
12. 5  CARCINOGENESIS AND MUTAGENESIS	  12-104
      12.5.1  Airborne Particulate Matter	  12-106
              12.5.1.1  In vitro studies	  12-106
              12.5.1.2  In vivo studies	  12-109
      12.5.2  Sulfur Oxides	  12-114
      12. 5.3  Metals	  12-117
12. 6  CONCLUSIONS	  12-124
      12.6.1  Sulfur Dioxide	  12-124
      12.6.2  Particulate Matter	  12-128
      12.6.3  Interactions of Gases and Particles	  12-132
12.7  REFERENCES	  12-135

APPENDIX A	   12A-1
                                      1x

-------
                                  LIST OF TABLES

Table                                                                     Page

12-1.   Potential Mutagenic Effects of S02/Bisulfate	  12-7

12-2.   Lethal Effects of S02 on Animals	 12-17

12-3.   Tumorigenesis in animals  exposed to SC^ or SC^ and
        benzo(a)pyrene	 12-20

12-4.   Effects of  sulfur dioxide on lung morphology	 12-21

12-5.   Effects of  sulfur dioxide on pulmonary function	 12-40

12-6.   Effects of  sulfur dioxide on host defense	 12-44

12-7.   Effects of  particulate matter on lung morphology	 12-49

12-8.   Respiratory response of guinea pigs exposed  for 1 hour to
        particles in the Amdur et al. studies	 12-50

12-9.   Effects of  acute exposure to particulate matter on pulmonary
        function	 12-67

12-10.  Effects of  chronic exposure to particulate matter on pulmonary
        function	 12-69

12-11.  Effects of  sulfuric acid  on muociliary clearance	 12-73

12-12.  Effects of  metals and other particles on host defense mechanisms. 12-86

12-13.  Effects of  acute exposure to sulfur dioxide  in combination with
        particulate matter	 12-92

12-14.  Pollutant concentrations  for chronic exposure of dogs	 12-95

12-15.  Effects of  chronic exposure to sulfur oxides and particulate
        matter	 12-101

12-16.  Effects of  interaction of sulfur oxides and  ozone	 12-105

-------
                                 LIST OF FIGURES


FIGURE                                                                    Page

12-1.  An integrated scheme for metabolism of sulfur dioxide in
      mammals	   12-9

12-2.  Mitotic count after S02 exposure up to 6 weeks	  12-24

12-3.  Histogram areas covered by PAS sensitive material	  12-26

12-4.  Increase in goblet cells after exposure to S0?	  12-27

12-5.  Dose-response curves	  12-36

12-6.  Mean number and standard error of alveolar cells	  12-79

-------
                                   CONTENTS
13.   CONTROLLED HUMAN STUDIES 	     13-1
     13.1  INTRODUCTION 	     13-1
     13.2  SULFUR DIOXIDE 	     13-2
           13.2.1  Subjective Reports	     13-3
           13.2.2  Sensory Effects 	     13-4
                   13.2.2.1  Odor Perception Threshold 	     13-4
                   13.2.2.2  Sensitivity of the Dark-Adapted Eye 	     13-7
                   13.2.2.3  Interruption of Alpha Rhythm	     13-8
           13.2.3  Respiratory and Related Effects	     13-9
                   13.2.3.1  Water Solubility	     13-17
                   13.2.3.2  Nasal Versus Oral Exposure 	     13-17
                   13.2.3.3  Subject Activity Level 	     13-18
                   13.2.3.4  Temporal Parameters 	     13-20
                   13.2.3.5  Mucociliary Transport 	     13-22
                   13.2.3.6  Health Status 	     13-25
     13.3  PARTICULATE MATTER 	     13-26
     13.4  SULFUR DIOXIDE AND OZONE 	     13-30
     13.5  SULFURIC ACID AND SULFATES 	     13-33
           13.5.1  Sensory Effects 	     13-33
           13.5.2  Respiratory and Related Effects 	     13-37
     13.6  SUMMARY 	     13-42
     13. 7  REFERENCES	     13-47

-------
                                LIST OF TABLES

Table
 13-1  Sensory effects of S0?	      I3"5
 13-2  Pulmonary effects of SCL	     13-1Q
 13-3  Pulmonary effects of aerosols	     13-27
 13-4  Pulmonary effects of S0~ and other air pollutants	     13-34
 13-5  Sensory effects of sulfaric acid and sulfates	     13-35
 13-6  Pulmonary effects of sulfuric acid	     13-43
                                     XTM

-------
                                CONTENTS
14.  EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF ATMOSPHERIC
     CONCENTRATIONS OF SULFUR DIOXIDE AND PARTICULATE MATTER ON
     HUMAN HEALTH	    14-1

     14.1 INTRODUCTION	    14-1

     14. 2 AIR QUALITY MEASUREMENT CONSIDERATIONS	   14-15
          14.2.1 British Approaches	   14-15
                 14.2.1.1 British S02 Measurements	   14-15
                 14.2.1.2 Daily smoke measurements of the United
                          kingdom national survey	   14-22
          14. 2. 2 American Approaches	   14-26
                 14. 2. 2.1 American SO^ measurements	   14-26
                 14.2.2.2 American high volume TSP sampling measurements.  14-30
     14. 3 AIR POLLUTION AND MORTALITY	   14-34
          14. 3.1 Introduction	   14-34
          14.3.2 Acute episodes	   14-36
          14.3.3 Mortality associated with short-term variations
                 in pol lution	   14-49
          14.3.4 Cross-sectional studies of mortality	   14-69
          14. 3. 5 Lung cancer mortal ity	   14-87
          14.3.6 Summary for mortality studies	   14-89

     14.4 MORBIDITY ASSOCIATED WITH SHORT-TERM POLLUTION EXPOSURES	   14-92
          14.4.1 Introduction	   14-92
          14.4.2 Episodes	   14-98
          14.4.3 Panel studies of acute respiratory disease (ARD)	  14-106
          14.4.4 Aggravation of asthmatic symptoms	  14-114
          14.4.5 Hospital/clinical admission studies and absence
                 studies	  14-114
          14.4.6 Pulmonary function studies	  14-114
14.5 MORBIDITY ASSOCIATED WITH LONG-TERM POLLUTION EXPOSURES	       14-127
          14. 5.1 Introduction	  14-127
          14.5.2 Chronic respiratory disease prevalence studies	  14-130
          14.5.3 Other respiratory disease/symptom prevalence
                 studies	  14-158
          14.5.4 Pulmonary function studies	  14-177
          14.5.5 Studies combining respiratory disease symptoms
                 with pulmonary function	  14-189
     14. 6  SUMMARY AND CONCLUSIONS	  14-199
          14.6.1 American summary of chapter contents	  14-199
                 14.6.1.1 Health effects of acute exposure to S0~ and
                          Particulate Matter	  14-205
                 14.6.1.2 Health effects of chronic exposure to S0? and
                          particulate matter	  14-206
                 14.6.1.3 Health effects of atmospheric sulfates	  14-207
                 14.6.1.4 Respirable particulates effects	  14-207
                                 xiv

-------
          14.6.2 Methodological factors impacting interpretation of
                 results	   14-208
          14.6.3 Quantitative dose-response relationships defined by
                 community health studies	   14-214
                 14.6.3.1 Review articles and commentary (1974-1978)	   14-216
                 14.6.3.2 Major evaluative documents (1978)	   14-227
     14. 7 REFERENCES	   14-252
APPENDICES
     APPENDIX A	      A-l
     APPENDIX B (To be added later)	      B-l
     APPENDIX C	      C-l
                                    xv

-------
                                LIST OF TABLES


Number                                                                       Page

14-1   Summary of evaluation of sources, magnitudes, and directional
       biases of errors associated with British SCL measurements	     14-19
14-2   Summary of evaluation of sources, magnitudes, and directional
       biases of errors associated with British Smoke (particulate)
       measurements	     14-24
14-3   Summary of evaluation of sources, magnitudes, and directional
       biases of errors associated with American SCL measurements	     14-29
14-4   Summary of evaluation of sources, magnitudes, and directional
       biases of errors associated with total suspended particulate
       (TSP) measurements	     14-32
14-5   Excess deaths and pollutant concentrations during severe air
       pollution episodes in London (1948-75)	     14-40
14-6   Acute air pollution episodes in the United States	     14-43
14-7   Other acute air pollution episodes	     14-47
14-8   Mean deviation of daily mortality from 15 day moving average,
       by  level of smoke (London, November 1, 1958-January 31, 1959	     14-55
14-9   Mean deviation of daily mortality from 15 day moving average,
       by  level of SOp (London, November 1, 1958-January 31, 1959)	     14-55
14-10  Mean deviation of daily mortality from 15 day moving average,
       by  level of smoke (London, 1958 to 1960)	     14-57
14-11  Mean deviation of daily mortality from 15 day moving average,
       by  level of SOp (London, 1958-1959	     14-57
14-12  Minima temperature data for London (Croydon)	     14-61
14-13  Pollution and temperature data for London, December 1958	     14-63
14-14  Average deviation of daily mortality from normal, by level
       of  smoke shade (CoH), (New York, 1960 to 1964, October
       through March)	     14-67
14-15  Average deviation of daily mortality from normal, by level
       of  S02 (New York, 1960 to 1964, October through March)	     14-67
14-16  Qualitative association of geographic differences in mortality
       with residence in areas of heavy air pollution	     14-70
14-17  Average annual death rates per 1000 population from all causes
       according to economic and particulate levels, and age:  white
       males, 50-69 years of age, Buffalo and environs, 1959-1961	     14-74
14-18  Average annual death rates per 1000 population from all causes
       according to economic, particulate and SO  levels	     14-75
14-19  Comparison of arithmetic and geometric means of TSP data--
       Buffalo study, 1961-1963	     14-78
14-20  Comparison of arithmetic and geometric means of sulfur data--
       Buffalo study, 1961-1963	     14-79
14-21  Summary of evidence for mortality effects of acute exposure  to
       particulate matter and SOp (non-episodic)	     14-90
14-22  Summary of evidence for mortality effects of chronic exposure to
       particulate matter and S0?	     14-91
14-23  Qualitative studies of air pollution and acute respiratory
       disease	     14-93
                                  xvi

-------
14-24  Chicago mean annual levels of pollutants in areas,  12/69-11/70..      14-110
14-25  Acute respiratory illness among families living in  two metropolitan
       areas	     14-111
14-26  Smoking-adjusted, acute respiratory disease attack  rates	     14-112
14-27  Average deviation of respiratory and cardiac morbidity from
       15-day moving average, by S02 level (London, 1958-1960)	     14-118
14-28  Average deviation of respiratory and cardiac morbidity from
       15-day moving average, by smoke level (BS) (London,
       1958-1960)	     14-118
14-29  Summary of evidence for morbidity effects of acute  exposure
       to SOp and particulates	     14-125
14-30  Qualitative studies of air pollution and prevalence of
       chronic respiratory symptoms and pulmonary function declines	     14-131
14-31  Prevalence ratios for persistent cough and phlegm standardized
       for age and smoking, by air pollution indices	     14-137
14-32  The prevalence (%) of respiratory symptoms and diseases by low
       and high smoke pollution in boys and girls	     14-144
14-33  The prevalence (%) of respiratory symptoms and diseases by low
       and high SO- pollution in boys and girls	      14-145
14-34  Summary of associations (±) of pollution with health data	      14-146
14-35  Chronic prevalence rates and pollution levels in four Utah
       communities , 1970	      14-154
14-36  CRD prevalence rates for Chicago recruits	      14-157
14-37  Frequency of lower respiratory tract of children in Britain
       by pollution levels	      14-161
14-38  Four-year reported rates of one or more episodes of
       LRD among white and black children by community
       exposure Southeastern U. S. 1971	      14-169
14-39  Estimated pollutant exposure levels in Charlotte,
       North Carolina (intermediate exposure and Birmingham,
       Alabama (high exposure) 1960-1971	     14-171
14-40  Pollution levels, Berlin, New Hampshire, during three study
       periods	     14-192
14-40a Summary of long-term exposure studies of pulmonary  function
       deficits and chronic respiratory disease	     14-196
14-41  Summary table - acute exposure effects	     14-201
14-42  Summary table - chronic exposure effects	     14-203
14-43  Summary of dose-response relationships for effects  of particles
       and S0? and health	     14-217
14-44  Expected health effects of air pollution on selected population..     14-218
14-45  Particulate and sulfur dioxide levels and effects on health	     14-222
14-46  Summary of effects of sulfur dioxide and particulates on
       human health—long term effects	     14-225
14-47  NRC/National Academy of Sciences health effects and  dose/response
       relationships for particulates and sulfur dioxide	     14-228
14-48  Exposure-effect relationships of sulfur dioxide, smoke;
       and total suspended particulates:  Effects of short-term
       exposures	•	     14-233
14-49  Exposure-effect relationships of sulfur dioxide, smoke, and
       total suspended particulates:  Effects of long-term  exposures	     14-234
14-50  Expected effects of air pollutants on health in selected
       segments of the population:  Effects of short-term exposures	     14-235
                                     xvn

-------
14-51  Expected effects of air pollutants on health in selected segments
       of the population:   Effects of long-term exposures	     14-236
14-52  Guidelines for exposure limits consistent with the protection
       of publ ic health	     14-237
14-53  Summary of evidence for health effects of acute exposure to
       S02 and particulates	     14-240
14-54  Summary of evidence for health effects of chronic exposure
       to SOp and particulate matter	     14-241
14-55  Epidemiologic studies suggesting an effect of particulate air
       pollution at concentrations at or near the U.S. ambient air
       quality standard and comments by Shy on the reviews of them
       by Hoi 1 and et al	   14-247
                                   xvi ii

-------
                                LIST OF FIGURES

Number                                                                      Page

14-1   A comparison of  lead dioxide and hydrogen peroxide methods
       for sulfur dioxide showing wide variations between simultaneous
       measurements	     14-17
14-2   Daily air pollution and deaths, London, 1952	     14-38
14-3   Residual mortality as a function of S0? for the New York-
       New Jersey Metropolitan area, 1962 to 1966	     14-53
14-4   Effect on bronchitic patients of high pollution levels
       (January 1954)	     14-99
14-5   Locations of air monitoring stations in Birmingham, Alabama,
       from which air quality data employed in Hammer study were
       obtained	    14-174
14-5A  Acute dose-response relationships from selected studies	    14-231
14-5B  Chronic dose-response relationships from selected studies	    14-231
14-6   Locations of air monitoring stations in Charlotte, N.C. from
       which air quality data employed in Hammer study were obtained	    14-175
14-8   Comparison of interpretations of studies evaluated by Holland
       et al. (1979), WHO (1979), and other reviews such as those
       in the NRC/NAS documents and the present chapter	    14-245
                                    xix

-------
Terms and Symbols Used in Respiratory Physiology

A.  General
X
X
%x

X/Y%
t
anat
max

B.

1.

V

F

2.

I
E
A
T
D
B
STPO

BTPS

ATPO
ATPS
L
              Pressures in general
              Dash above any symbol  indicates a mean value
              Dot above any symbol  indicates a time derivative
              Two dots above any symbol  indicate the second time derivative
              Percent sign preceding a symbol indicates percentage of the
              predicted normal  value
              Percent sign after a  symbol  indicates a ratio function with
              the ratio function with the  ratio expressed as a  percentage.
              Both components of the ratio must be designated;  e.g.,
              FEV,/FEV% = 100 X FEV,/FVC
              Frequency of any event in time, e.g., respiratory frequency:   the
              number of breathing cycles per unit of time
              Time
              Anatomical
              Maximum
Gas Phase Symbols

Primary
Qualifying
              Gas volume in general.   Pressure, temperature, and percent
              saturation with water vapor must be stated
              Fractional concentration in dry gas phase
              Inspired
              Expired
              Alveolar
              Tidal
              Dead Space
              Barometric
              Standard temperature and pressure, dry.  These are the conditions
              of a volume of gas at 0°C, at 760 torr, without water vapor
              Body temperature (37°C), barometric pressure (at sea level = 760
              torr), and saturated with water vapor
              Ambient temperature, pressure, dry
              Ambient temperature and pressure, saturated with water vapor
              Lung
C.

1.

0
C
s
Blood Phase Symbols

Primary
              Volume flow of blood
              Concentration in blood phase
              Saturation in blood phase
                                      xx

-------
2.   Qualifying
b
a
v
v
c
                  Blood in general
                  Arterial.   Exact location to be specified in text when term  is  used
                  Venous.   Exact location to be specified in text when term is  used
                  Mixed venous
                  Capillary.   Exact location to be specified in text when term  is  used
                  Pulmonary end-capillary
D.  Pulmonary Function

1.  Lung volumes (expressed as BTPS)
RV

ERV

Vr

IRV

VL

1C

IVC

VC

FRC

TLC

RV/TLC%
Vc
                                                that can be inspired from the  end-tidal

                                               maximum volume measured on inspiration
VD
VD
  anat
Residual volume:  volume of air remaining in the lungs  after
maximum exhalation
Expiratory reserve volume:   maximum volume of air that  can
be exhaled from the end-tidal volume
Tidal Volume:  volume of gas that  is inspired or expired
during one ventilatory cycle
Inspiratory reserve volume:  maximum volume that can be inspired
from an end-tidal inspiratory level
Volume of the lung, including the conducting airways.   Conditions
of measurement must be stated
Inspiratory capacity:   volume
expiratory volume
Inspiratory vital capacity:
after a full expiration
Vital capacity:  volume measured on complete expiration after the
deepest inspiration, but without respect to the effort  involved
Functional residual capacity:  volume of gas remaining  in  the lungs
and airways at the end of a resting tidal expiration
Total lung capacity:  volume of gas in the lung and  airways  after
as much gas as possible has been inhaled
Residual volume to total lung capacity ratio, expressed as  a  percent
Physiological dead space:  calculated volume (BPTS), which  accounts
for the difference between the presures of CO- in expired  gas and
arterial blood.  Physiological dead space reflects the  combination
of anatomical dead space and alveolar dead space, the volume  of the
latter increasing with the importance of the nonuniformity of the
ventilation/perfusion ratio in the lung
Volume of the anatomic dead space  (BTPS)
The alveolar dead-space volume (BTPS)
    Forced  respiratory  maneuvers  (expressed  as  BTPS)
                   Forced  vital  capacity:   The volume  of  gas  expired  after  full
                   inspiration,  and  with  expiration  performed as  rapidly and
                   completely  as possible
                   Forced  inspiratory  vital capacity:   maximal  volume of air  inspired
                   after a maximum expiration, and with inspiration performed as  rapidly
                   and completely  as possible
                   Denotes the volume  of  gas  that  is exhaled  in a given time  interval
                   during  the  execution of a  forced  vital  capacity
                   Ratio of timed  forced  expiratory  volume to forced  vital  capacity,
                   expressed as  a  percentage
2.
FVC
FIVC
FEV.
FEVt/FVC%
                                       xxi

-------
PEF
Vmax
    xx%
Vmax
    xx%TLC
FEF
Peak expiratory flow (liters/min or liters/sec)
Maximum expiratory flow (instantaneous) qualified by the volume
                   expressed as percent of the FVC that has been
                  :   VmaXyr^ is the maximum expiratory flow after
                   been exhaled and 25% remains  to be exhaled)
                   flow (instantaneous) qualified by the volume
                   expressed as percent of the TLC that remains
                         Vmax.no/T| - is the maximum expiratory
                        the TLtrrefrtains in the lung)
              at  which  measured,
              exhaled.   (Example
              75% of the FVC  has
              Maximum expiratory
              at  which  measured,
              in  the lung.   (Example:
              flow when 40  percent of
   x-y
 FEF,

 FEF
2-1-2L
    25%-75%
MVV
 FET
 MIF
Forced expiratory flow between two designated volume points in the
FVC.  These points may be designated as absolute volumes starting
from the full inspiratory point or by designating the percent of
FVC exhaled
Forced expiratory flow between 200 ml and 1,200 ml of the FVC;
formerly called maximum expiratory flow
Forced expiratory flow during the middle half of the FVC; formerly
called maximum midexpiratory flow
Maximum voluntary ventilation:  maximum volume of air that can be
breathed per min by a subject breathing quickly and as deeply as
possible.  The time of measurement of this tiring lung function
test is usually between 12 and 30 sec, but the test result is given
in  liters (BTPS)Xmin
Forced expiratory time required to exhale a specifed FVC, e.g.,
FETqry is the time required to deliver the first 95% of the
FVC, rET9t-
-------
                  Pleura! pressure:  the pressure between the visceral and parietal
                  pleura relative to atmospheric pressure, in cm H?0
Palv              Alveolar pressure
PL                Transpulmonary pressure:  transpulmonary pressure, PL = Palv - Ppl,
                  measurement conditions to be defined
PstL              Static recoil pressure of the lung; transpulmonary pressure measured
                  under static conditions
Pbs               Pressure at the body surface
Pes               Esophageal pressure used to estimate Ppl
PW                Transthoracic pressure:  pressure difference between parietal
                  pleural surface and body surface.  Transthoracic in the sense
                  used means "across the wall."  Pw + Ppl - Pbs
Ptm               Transmural pressure pertaining to an airway or blood vessel
Prs               Transrespiratory pressure:  pressure across the respiratory
                  system.  Prs + Palv - Pbs = PL + Pw

(b)  Flow-pressure relationships
R                 Flow resistance:  the ratio of the flow-resistive components of
                  pressure to simultaneous flow in cm H20/liter per sec
Raw               Airway resistance calculated from pressure difference between
                  airway opening (Pao) and alveoli (Palv) divided by the airflow,
                  cm H^O/liter/sec
RL                Total pulmonary resistance includes the frictional resistance of
                  the lungs and air passages.  It equals the sum of airway resistance
                  and lung tissue resistance.  It is measured by relating flow-dependent
                  transpulmcnary pressure to airflow at the mouth
Rrs               Total respiratory resistance includes the sum of airway resistance,
                  lung tissue resistance, and chest wall resistance.  It is measured
                  by relating flow dependent transrespiratory pressure to airflow at
                  the mouth.
Rus               Resistance of the airways on the upstream (alveolar) side of the
                  point in the airways where intraluminal pressure equals Ppl
                  (equal pressure point), measured during maximum expiratory flow
Rds               Resistance of the airways on the downstream (mouth) side of the
                  point in the airways where intraluminal pressure equals Ppl,
                  measured during maximum expiratory flow
Gaw               Airway conductance, reciprocal of Raw
Gaw/VL            Specific conductance expressed per liter of lung volume at which
                  Gaw is measured

(c) Volume-pressure relationships
C                 Compliance:  the slope of a static volume-pressure curve at a
                  point, or the linear approximation of a nearly straight portion
                  of such a curve expressed  in liter/cm H^O or ml/cm H^O
Cdyn              Dynamic compliance:  the  ratio of the tidal volume to the
                  tidal volume to the change in intrapleural pressure between
                  the points of zero flow at the extremes of tidal  volume  in
                  liter/cm H?0 or ml/cm  hLO
                  Static compliance, value  for compliance determined on the
                  basis of measurements  made during periods of cessation of
                  airflow
                                    xxm

-------
C/VL

E

Pst
W
Specific compliance:   compliance divided by the  lung  volume
at which it is determined, usually FRC
Elastance:   the reciprocal of compliance; expressed in cm
HpO/liter or cm H2/ml
Static components of pressure
Work of breathing:   the energy required for breathing movements
5.  Diffusing Capacity
DL
Diffusing capacity of the lung:   Amount of gas (02> CO, CCL)
commonly expressed as ml gas (STPD) diffusing between alveolar
gas and pulmonary capillary blood per torr mean gas pressure
difference per min.   Total resistance to diffusion for oxygen
  1    _...,,.„   1
                         and CO
                     includes resistance to diffusion of the
                                   ;o
 DM
 6

 Vc
 DL/VA
 p     OMU ^  p.

the gas across theualveolar-capillary membrane, through plasma
in the capillary, and across the red cell membrane (I/DM), and
the resistance to diffusion within the red cell arising from
the chemical reaction between the gas and hemoglobin, (1/6V ),

                              1   .  1   +   1
                             "DlT    DM     6Vc
The diffusing capacity of the pulmonary membrane
The rate of gas uptake by 1 ml of normal whole blood per min
for a partial pressure of 1 torr
Average volume of blood in the capillary bed in milliliters
Diffusion per unit of alveolar volume.  DL is expressed STPD,
and VA is expressed in liters (BTPS)
                  according to the formulation
 6.   Respiratory Gases
 Pa>
 PA'
 Sa
  02
PA-Pa
Ca-Cv
Arterial tension of gas x, torr (mm Hg)
Alveolar tension of gas x, torr (mm Hg)
Arterial oxygen saturation (percent)
Concentration:  for example, CaCQp is the concentration of
oxygen  in a blood sample, including both oxygen combined with
hemoglobin and physically dissolved oxygen, ordinarily expressed
at ml Op (STPD)/100 ml blood, or mmole Op/liter
Alveolar-arterial gas pressure difference:  the difference in
partial pressure of a gas (e.g., Op or Np)  in  the  alveolar
gas spaces and that in the systemic arterial blood,
measured in torr.  For oxygen, as an example,
PA   -  Pa
   Also symbolixed AaDnp
Arterial-venous concentration difference.   For oxygen, as an
                  example, CaQ2 - CV
                  '02
                                       XXIV

-------
7.  Pulmonary shunts
6s
Shunt:   vascular connection between circulatory pathways  so
that venous blood is diverted into vessels containing arterialized
blood (right-to-left shunt, venous admixture) or vice versa
(left-to-right shunt).   Right-to-left shunt within the lung,
heart,  or large vessels due to malformations are more important
in respiratory physiology.   Flow from left to right through a
shunt should be marked with a negative sign.
E.  Pulmonary Dysfunction
1.  Altered breathing
dysanea
hyperventilation
hypoventhetion
An unpleasant subjective feeling of difficult or labored breathing
An alveolar ventilation that is excessive relative to the
simultaneous metabolic rate.  As a result the alveolar
     is significantly reduced below the normal  for the altitude
    ilveolar ventilation that is small relative  to the
AfiC
simultaneous metabolic rate so
significantly above the normal
                                                 that alveolar Prn?
                                                 for the altitude^
                                                  rises
2.  Altered blood  gases
hypoxia


hypoxernia




hypocapnie

hyparcapnia
Any state in which the oxygen in the lung, blood,  and/or tissues
is abnormally low compared with that of normal  resting person
breathing air at sea level
A state in which the oxygen pressure and/or concentration in
arterial blood is lower than its normal value at sea level.
Normal oxygen pressures at seal level are 85-100 torr in
arterial blood.  In adult humans the normal oxygen concentra-
tion  is 17-23 ml 02/100 ml arterial blood
Any state in which the systemic arterial carbon dioxide
pressure is significantly below 40 torr, as in hyperventilation
Any state in which the
is significantly above
tion is inadequate for
                   or during  C09  inhalation
                       systemic arterial carbon dioxide pressure
                       40 torr.  May occur when alveolar ventila-
                       a given metabolic rate (hypoventilation)
 3.  Altered  acid-base  balance
acidemia
alkelemia
base  excess  (BE)
Any state of systemic arterial plasma in which the pH is
significantly  less than the normal value, 7.41 ± 0.02 in
adult man at rest
Any state of systemic arterial plasma in which the pH is
significantly  greater than the normal value, 7.41 ± 0.02
in adult man at  rest
Base excess:   A  measure of metabolic alkalosis or metabolic
acidosis (negative values of base excess) expressed as the
rnEq of strong acid or strong alkali required to titrate a
sample of 1 liter of blood to a pH of 7.40.  The titration
is made with the blood sample kept at 37°C, oxygenated, and
equilibrated to  PCQ2 of 40 torr
                                      xxv

-------
acidosis
alkelosis
The result of any process that by itself adds excess C0?
(respiratory acidosis) or nonvolatile acids (metabolic acidosis)
to arterial blood.  Acidemia does not necessarily result, because
compensating mechanisms (increase of HCO~ in respiratory acidosis,
increase of ventilation and consequently; decrease of arterial CO,
in metabolic acidosis) may intervene to restore plasma pH to norm*
The result of any process that, by itself, diminishes acids
(respiratory alkalosis) or increases bases (metabolic alkalosis)
in arterial blood.  Alkalemia does not necessarily result, because
compensating mechanisms may intervene to restore plasma pH to normal
 chronic  respira-
   tory failure
obstructive
  ventilatory
  defect
restrictive
  ventilatory
  defect
impairment
disability
                                                                                    n
4.  Other

pulmonary

   insufficiency
acute  respiratory
   failure
Altered function of the lung,
that usually include dyspnea
which produces clinical symptoms
Rapidly occurring hypoxemia, hypercabia, or both caused by a
disorder of the respiratory system.  The duration of the illness
and the values of arterial oxygen tension and arterial carbon
dioxide tension used as criteria for this term should be given.
The term acute ventilatory failure should be used only when the
arterial carbon dioxide tension is increased.  The term pulmonary
failure has been used to indicate respiratory failure specifically
caused by disorders of the lung
Chronic hypoxemia or hypercapnia caused by a disorder of the
respiratory system.  The duration of the condition and the
values of arterial oxygen tension and arterial carbon dioxide
tension used as criteria for this term should be given
Slowing of air flow during forced ventilatory maneuvers
Reduction of vital capacity not explainable by airflow obstruction
A measurable degree of anatomic or  functional  abnormality that
may or may not have clinical significance.   Permanent  impairment
is that which persists for  some period of  time,  e.g.,  one year
after maximum medical rehabilitation  has been  achieved
A legally or administratively determined state in which a patient's
ability to engage in a specific activity under certain circum-
stances is reduced or absent because  of physical or mental
impairment.  Other factors, such as age, education, and customary
way of making a livelihood, are^ considered in  evaluating disability.
Permanent disability exists when no substantial  improvement of
the patient's ability to engage in  the specific  activity can
be expected
                                    xxvi

-------
REFERENCES

1.   (Pappenheirner Committee) Standardization of definitions and symbols in
    respiratory physiology, Fed. Proc. 1950, 9, 602.
2.   Glossary on respiration and gas exchange, J. Appl. Physio!., 1973, 34, 549.
3.   Mead, J. and Milic-Emili, J.:   Theory and methodology in respiratory mumanics
    with glossary of symbols, in Handbook of Physiology-Respiration I.  pp.  363-364
4.   Hyatt, R. E.:  Dynamic lung volumes, in Handbook of Physiology-Respiration II.
    p. 1366.
5.   Clinical spirometry (ACCP Committee), Dis Chest, 1963, 43, 214.
6.   Gandevia, B. , and Hugh-Jones, P.:  Terminology  for measurements of ventilatory
    capacity:  A report to the Thoracic Society, Thorax, 1957, 12, 290.
7.   Pulmonary terms and symbols:  A report of the ACCP-ATS Joint Committee on
    Pulmonary Nomenclature, Chest, 1975, 67, 583.
                                    xxvn

-------
                        CONTRIBUTORS AND REVIEWERS
Mr. John Acquavella
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Roy E. Albert
Institute of Environmental Medicine
New York University Medical Center
New York, New York  10016

Dr. Martin Alexander
Department of Agronomy
Cornell University
Ithaca, New York  14850

Dr. A. P. Altshuller
Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. David S. Anthony
Department of Botany
University of Florida
Gainesville, Florida  32611

Mr. John D. Bachmann
Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Allen C. Basala
Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Neil Berg
Monitoring and Data Analysis Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Michael A. Berry
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711
                                     xxvm

-------
Mr. Francis M. Black
Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Joseph Blair
Environmental Division
U. S. Department of Energy
Washington, D.C.  20545

Dr. Edward Bobalek
Industrial Environmental Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Ms. F. Vandiver P. Bradow
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Ronald L. Bradow
Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Robert Bruce
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Angelo Capparella
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Robert Chapman
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Robert J. Charlson
Department of Environmental Medicine
University of Washington
Seattle, Washington  98195

Dr. Peter Coffey
New York State Department of Environmental Conservation
Division of Air Resources
Albany, New York 12233

Mr. Chatten Cowherd
Midwest Research Institute
425 Volker Boulevard
Kansas City, Missouri  64110
                                      xx ix

-------
 Dr.  Ellis  B.  Cowling
 School  of  Forest  Resources
 North  Carolina  State  University
 Raleigh, North  Carolina   27650

 Mr.  William  M.  Cox
 Monitoring and  Data Analysis  Division
 Office of  Air Quality Planning and  Standards
 U.S. Environmental  Protection Agency
 Research Triangle Park,  North Carolina  27711

 Dr.  T.  Timothy  Crocker
 Department of Community  and Environmental Medicine
 Irvine, California  92664

 Mr.  Stanley  T.  Cuffe
 Emission  Standards  and Engineering  Division
 Office of  Air Quality Planning and  Standards
 U.S. Environmental  Protection Agency
 Research  Triangle Park,  North Carolina  27711

 Dr.  Thomas C. Curran
 Monitoring and  Data Analysis  Division
 Office of  Air Quality Planning and  Standards
 U.S. Environmental  Protection Agency
 Research Triangle Park,  North Carolina  27711

 Dr.  Michael  Davis
 Environmental Criteria and Assessment Office
 U.S. Environmental  Protection Agency
 Research Triangle Park,  North Carolina  27711

 Dr.  Gerrold  A.  Demarrais
 National Oceanic  and  Atmospheri'c  Administration
 U. S.  Department  Of Commerce

 Dr.  Jerrold  L.  Dodd
 Natural Resources Ecology Laboratory
 Colorado State  University
 Fort Collins. Colorado  80523

 Dr.  Thomas G. Dzubay
 Environmental Sciences Research Laboratory
 U.S.  Environmental Protection Agency
 Research Triangle Park,  North Carolina  27711

Mr. Thomas G. Ellestad
Environmental Sciences Research Laboratory
U.S.  Environmental Protection Agency
Research Triangle Park,  North Carolina  27711

Dr. John Evans
School  of Public  Health
Harvard University
Boston, Massachusetts  02115

                                          xxx

-------
Dr. Lance Evans
Department of Energy and Environment
Brookhaven National Laboratory
Upton, New York  11973

Mr. Douglas Fennel]
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711

Dr. Benjamin G.  Ferris, Jr.
School of Public Health
Harvard University
Boston, Massachusetts  02115

Mr. Patrick Festa
New York Department of Environmental Conservation
Division of Fish and Wildlife
Albany. New York  12233

Mr. Terrence Fitz-Simmons
Environmental Monitoring Systems Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Christopher R. Fortune
Northrop Services, Inc.-Environmental Sciences
P. 0. Box 12313
Research Triangle Park, Nortn Carolina  27709

Dr. Robert Frank
Department of Environmental Health
University of Washington
Seattle, Washington  98195

Dr. Warren Galke
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Phil Galvin
New York Department of Environmental Conservation
Division of Air Resources
Albany. New York  12233

Dr. Donald Gardner
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. J.H.B.  Garner
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

                                       xxx i

-------
Dr. Donald Gillette
Health  Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Judy Graham
Health  Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Lester D. Grant
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Armin Gropp
Department of Chemistry
University of Miami
Miami,  Florida   33124

Dr. Jack Hackney
Rancho  Los Amigos Hospital
Downey, California   90242

Mr. Bertil Hagerhall
Ministry of  Agriculture
Pack
S-163 20 Stockholm
Sweden

Dr. Douglas  Hammer
2910 Wycliff Road
Raleigh, North Carolina  27607

Mr. R.  P. Hangebrauck
Industrial Environmental Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Thomas A. Hartlage
Environmental Monitoring Systems Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Victor Hasselblad
Health  Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Thomas R. Hauser
Environmental Monitoring Systems Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

                                   xxx ii

-------
Dr. Carl Hayes
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Fred H. Haynie
Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Walter Heck
Department of Botany
North Carolina State University
Raleigh, North Carolina  27650

Dr. Howard Heggestad
USDA-SAE
The Plant Stress Laboratory
Plant Physiology Institute
Beltsville, Maryland  20705

Dr. George R. Hendrey
Department of Energy and Environment
Brookhaven National Laboratory
Upton, New York  11973

Dr. Ian Higgins
Department of Epidemiology
School of Public Health
University of Michigan
Ann Arbor, Michigan  48109

Mrs. Patricia Hodgson
Editorial Associates
Chapel Hill, North Carolina  27514

Mr. George C. Holzworth
Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Robert Horton
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Steven M. Horvath
Institute of Environmental Stress
University of California
Santa Barbara, California  93106
                                     xxxm

-------
Dr.  F.  Gordon  Hueter
Health  Effects Research  Laboratory
U.S.  Environmental  Protection Agency
Research  Triangle  Park,  North Carolina  27711

Dr.  Janja Husar
CAPITA
Washington University
St.  Louis, Missouri  63130

Dr.  Rudolf Husar
Department of  Mechanical  Engineering
Washington University
St.  Louis, Missouri  63130

Dr.  William T. Ingram
Consulting Engineer
7 North Drive
Whitestone, New York 11357

Dr.  Patricia M. Irving
Argonne National  Laboratory
9700 South Cass Avenue
Argonne,  Illinois   60439

Dr.  Jay Jacobson
Boyce Thompson Institute
Cornell University
Ithaca, New York   14850

Mr.  James Kawecki
Biospherics, Inc.
4928 Wyaconda  Road
Rockville, Maryland  20852

Dr.  Sagar V. Krupa
Department of  Plant Pathology
University of  Minnesota
St.  Paul,  Minnesota  55108

Dr.  Edmund J.  LaVoie
Section of Metabolic Biochemistry
American  Health Foundation
Dana  Road
Valhalla,  New  York  10592

Dr. Michael  D.   Lebowitz
Arizona Health Sciences  Center
1501 North  Campbell
Tucson,  Arizona  85724
                                xxxiv

-------
Dr.  Robert E.  Lee
Health  Effects Research  Laboratory
U.S.  Environmental  Protection Agency
Research  Triangle Park,  North Carolina  27711

Dr.  Allan H.  Legge
Environmental  Science  Center
University of  Calgary
Calgary,  Alberta,  Canada T2N 1N4

Ms.  Peggy Le  Sueur
Atmospheric Environment  Service
Downsview,  Ontario,  Canada  M3H5T4

Dr.  Morton Lippmann
Institute of  Environmental Medicine
New  York  University
New  York,  New  York   10016

Dr.  James P.  Lodge
385  Broadway
Boulder,  Colorado 80903

Dr.  Gory  J. Love
Institute of  Environmental Studies
University of  North  Carolina
Chapel  Hill, North Carolina  27514

Dr.  David T. Mage
Environmental  Monitoring Systems Laboratory
U.S.  Environmental Protection Agency
Research  Triangle Park,  North Carolina  27711

Dr.  Delbert McCune
Boyce Thompson Institute
Cornell University
Ithaca, New York   14850

Mr.  Frank F. McElroy
Environmental  Monitoring Systems Laboratory
U.S.  Environmental Protection Agency
Research  Triangle Park,  North Carolina  27711

Dr.  David  J. McKee
Environmental  Criteria and Assessment Office
U.S.  Environmental Protection Agency
Research  Triangle Park,  North Carolina  27711

Mr. Thomas  McMullen
Environmental  Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park,  North Carolina  27711
                                    xxxv

-------
Dr. Daniel B. Menzel
Department of Pharmacology
Duke University Medical Center
Durham, North Carolina  27710

Dr. Edwin L. Meyer
Monitoring and Data Analysis Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr  Fred Miller
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. John 0.  Milliken
Industrial Environmental Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Jarvis Moyers
Department of Chemistry
University of Arizona
Tucson, Arizona 85721

Dr. Thaddeus J. Murawski
New York State Department of Health
Empire State Plaza
Albany New York  12337

Dr. David S. Natusch
Department of Chemistry
Colorado State University
Fort Collins, Colorado  80523

Dr. Stephen  A. Nielsen
Environmental Affairs
Joyce Environmental Consultants
414 Live Oak Boulevard
Casselberry. Florida  32707

Dr. Kenneth Noll
Department of Environmental Engineering
Illinois Institute of Technology
Chicago,  Illinois 60616

Mr. John R.  O'Connor
Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental  Protection Agency
Research Triangle Park, North Carolina  27711
                                xxxvi

-------
Mr. Thompson G. Pace
Monitoring and Data Analysis Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Jean Parker
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Nancy Pate
Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. Thomas W. Peterson
Department of Chemical Engineering
University of Arizona
Tucson, Arizona  85721

Mr. Martin Pfeiffer
New York State Department of Environmental  Conservation
Bureau of Fisheries
Raybrook, New York  12977

Dr. Marlene Phillips
Atmospheric Chemistry Division
Environment Canada
Downsview, Ontario, Canada  M3H5T4

Dr. Charles Powers
Environmental Research Laboratory
U.S. Environmental Protection Agency
Corvallis, Oregon 97330

Mr. Larry J. Purdue
Environmental Monitoring Systems Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. John C. Puzak
Environmental Monitoring Systems Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711
                                xxxvn

-------
Dr. Otto  Raabe
Radiobiology  Laboratory
University  of California
Davis,  California   95616

Mr. Danny Rambo
Environmental Research Laboratory
U.S.  Environmental  Protection Agency
Corvallis,  Oregon   97330

Mr. Kenneth A.  Rehme
Environmental Monitoring  Systems Laboratory
U.S.  Environmental  Protection Agency
Research  Triangle  Park, North Carolina  27711

Dr. Elmer Robinson
Department  of Chemical Engineering
Washington  State University
Pullman,  Washington  99163

Mr. Charles E.  Rodes
Environmental Monitoring  Systems Laboratory
U.S.  Environmental  Protection Agency
Research  Triangle  Park, North Carolina  27711

Mr. Douglas R.  Roeck
GCA Corporation
Technology  Division
Burlington  Road
Bedford,  Massachusetts  01730

Mr. J.  C. Romanovsky
Environmental Sciences Research Laboratory
U.S.  Environmental  Protection Agency
Research  Triangle  Park, North Carolina  27711

Dr. August  Rossano
University  of Washington
Seattle,  Washington  98195

Mr. Joseph  D.  Sableski
Control Programs Development Division
Office of Air Quality Planning and Standards
U.S.  Environmental  Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Dallas  Safriet
Monitoring  and Data Analysis Division
Office of Air Quality Planning and Standards
U.S.  Environmental  Protection Agency
Research Triangle Park, North Carolina  27711
                                  xxxvm

-------
Dr. Victor  S.  Salvin
University  of  North Carolina at Greensboro
Greensboro,  North Carolina 27408

Or. Shahbeg  Sandhu
Health  Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. Joseph P.  Santodonato
Life and Material Sciences Division
Syracuse Research Corporation
Merrill Lane
Syracuse, New  York  13210

Dr. Herbert  Schimmel
Neurology Department
Albert  Einstein Medical College
26 Usonia Road
Pleasantville, New York 10570

Dr. Carl L.  Schofield
Department of  Natural Resources
Cornell University
Ithaca, New  York  14850

Dr. David Shriner
Environmental  Sciences Division
Oak Ridge National Laboratory

Ms. Donna Sivulka
Environmental  Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. John M.  Skelly
Department of  Plant Pathology and Physiology
Virginia Polytechnic Institute
Blacksburg, Virginia  24061

Mr. Scott Smith
Biospherics, Inc.
4928 Wyaconda Road
Rockviell, Maryland  20852

Ms. Elaine Smolko
Department of Pharmacology
Duke University Medical Center
Durham, North Carolina

                                    xxxix

-------
 Dr.  Frank  Speizer
 School  of  Public Health
 Harvard University
 Boston,  Massachusetts  02115

 Dr.  John D.  Spengler
 School  of  Public Health
 Harvard University
 Boston,  Massachusetts  02115

 Mr.  Robert K.  Stevens
 Environmental  Sciences Research  Laboratory
 U.S.  Environmental  Protection  Agency
 Research Triangle  Park,  North  Carolina  27711

 Dr.  George E.  Taylor, Jr.
 Environmental  Sciences Division
 Oak Ridge  National  Laboratory
 Oak Ridge, Tennessee  37830

 Dr.  Larry  Thibodeau
 School  of  Public Health
 Harvard University
 Boston, Massachusetts  02115

 Dr.  W.  Gene Tucker
 Industrial Environmental  Research  Laboratory
 U.S.  Environmental  Protection  Agency
 Research Triangle  Park,  North  Carolina  27711

 Mr.  D.  Bruce Turner
 Environmental  Sciences Research  Laboratory
 U.S.  Environmental  Protection  Agency
 Research Triangle Park,  North  Carolina  27711

 Mr.  James  B. Upham
 Environmental  Sciences Research  Laboratory
 U.S.  Environmental  Protection  Agency
 Research Triangle Park,  North  Carolina  27711

 Dr.  Robert Waller
 Toxicology Unit
 St. Bartholomew's Hospital
 London,  England

Mr. Stanley Wall in
Warren Spring  Laboratory
Department of  Industry
Stevenage,  Hertfordshire SGI 2BX
England

                                       xl

-------
Dr. Joseph F. Walling
Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. James Ware
School of Public Health
Harvard University
Boston, Massachusetts  02115

Dr. David Weber
Office of Air, Land, and Water Use
U.S. Environmental Protection Agency
Washington, D. C. 20460

Dr. Jean Weister
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Mr. R.  Murray Wells
Radian Corporation
8500 Shaol Creek Boulevard
Austin, Texas  78766

Dr. Kenneth T. Whitby
Mechanical Engineering Department
University of Minnesota
Minneapolis, Minnesota  55455

Dr. Warren White
CAPITA
Washington, University
St. Louis, Missouri  63130

Dr. Raymond Wilhour
Environmental Research Laboratory
U.S. Environmental Protection Agency
Corvallis, Oregon  97330

Dr. William E. Wilson
Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. John W. Winchester
Department of Oceanography
Florida State University
Tallahassee, Florida  32306
                                   xli

-------
Mr. Larry Zaragoza
Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina  27711

Dr. William H. Zoller
Chemistry Department
University of Maryland
College Park, Maryland  20742
We wish to thank everyone who contributed their efforts to the preparation of
this document,  including the following staff members of the Environmental
Criteria and Assessment Office, U.S. Environmental Protection Agency, Research
Triangle Park,  North Carolina:
Mrs.  Dela Bates
Ms. Hope Brown
Ms. Diane Chappell
Ms. Deborah Doerr
Ms. Mary El ing
Ms. Bettie Haley
Mr. Allen Hoyt
Ms. Susan Nobs
Ms. Evelynne Rash
Ms. Connie van Oosten
Ms. Donna Wicker
The final draft of this document will cite the many persons outside of the
Environmental Criteria and Assessment Office who have assisted in its pre-
paration.
                                       xlii

-------
                 11.   RESPIRATORY DEPOSITION AND BIOLOGICAL FATE

                          OF  INHALED AEROSOLS AND S02*
11.1 INTRODUCTION

11.1.1  General Considerations

     The respiratory airways system  is the major route for exposure of people

to airborne particles (aerosols) and S02 gas. During inhalation (and exhalation)

a portion of the inhaled aerosol and gas may be deposited by contact with

airway surfaces or be transferred to unexhaled air. The remainder is exhaled.

The portion transferred to unexhaled air may be either deposited by contact

with airway surfaces or later exhaled.  These phenomena are complicated by

interactions that may occur between the particles, the S0? gas, other gases

such as biologically endogenous ammonia, and the water vapor present in the

airways.

     In inhalation toxicology, specific terminology is applied to these pro-

cesses.  The term deposition refers specifically to the removal of inhaled

particles or gas by the respiratory tract and to the initial regional pattern of

these deposited materials.  The term clearance refers to the subsequent trans-

location (movement of material in the lung to other organs), transformation, and

removal of deposited particles from the respiratory tract or from the body.  It can

also refer to the removal of reaction products formed from SO--  The temporal

distribution of uncleared deposited particulate materials or gas and reaction

products is called retention.  At the end of a brief aerosol or gas exposure,
*Report prepared with support of the Office of Health and Environmental Research
of the U.S. Department of Energy (DOE) under contract with the University of
California, Davis.
                                     11-1

-------
these three concepts may be described by the relationship:
     RETENTION (t) = DEPOSITION - CLEARANCE (t)                  (1)
where (t) refers to a function of time after deposition occurs (Raabe, 1979).
     The mechanisms involved in the deposition of inhaled aerosols and gases
are affected by physical and chemical properties, including aerosol particle
size distribution, density, shape, surface area, electrostatic charge, hygro-
scopicity or deliquescence, chemical composition, gas diffusivity, and related
reactions.  The geometry of the respiratory airways from nose and mouth to the
lung parenchyma also influences aerosol deposition; the important morphometric
parameters  include the  diameters, lengths, and branching angles of airway
segments.   Physiological factors that affect deposition include breathing
patterns, air  flow dynamics in the respiratory tract, and variations of rela-
tive humidity  and temperature within the airways.  With this  information,
theoretical models of regional deposition have been developed to predict the
fate of  inhaled aerosols of various types.  Carefully collected data  from
experiments with human  volunteers provide a basis for testing these theo-
retical  predictions.
     The current state  of  knowledge concerning the quantification  of  the
deposition  of  inhaled aerosols for both man and  experimental  animals  is  fairly
well established.   Important questions to be resolved concern the  deposition
of inhaled S02, especially with respect to gas-particle interaction and  the
extent of synergism between SO- and particulate  materials with  respect to
deposition and toxicological effects.  However,  the fundamental factors
associated with these processes have been recognized for over 20 years in that
the deposition in the deep lung during inhalation and, concomitantly. the
potential for biological response to S0? may be  enhanced by  the presence in
                                     11-2

-------
the atmosphere of certain aerosols emitted from both natural and man-made
sources.  Therefore one should consider the deposition, clearance, trans-
location, and biological response of inhaled SO- in conjunction with the
aerosols that are present in some in the environment.
     Clearance from the respiratory tract depends on many factors, including
site of deposition, chemical composition and properties of the deposited
particles, S02 reaction products, mucociliary transport in the tracheobronchial
tree, macrophage phagocytosis in the deep lung, and pulmonary lymph and blood
flow.
     Translocation of sulfur compounds or other materials from the lung to
other organs is important, since the lung can be the portal  of entry for toxic
agents that have effects on other organs of the body.  Hence, multicompartment
models of clearance from the respiratory tract to other organs can provide
predictive information about the potential for injury of those other organs.
Mathematical representations of lung retention and translocation require data
on the various factors that affect deposition and clearance.
     Since many conclusions concerning the deposition, clearance,  and health
impact of inhaled aerosols and SO- are based upon data obtained from animal
experiments, care must be taken to identify differences in physiological and
anatomical factors between human beings and animals that may influence these
phenomena.  In particular, air pollution experiments that use small rodents
must be interpreted with respect to important differences between human and
rodent airways, breathing patterns, flow dynamics, regional  deposition, and
subsequent clearance.  Emphasis in the following discussion will be on the
deposition and clearance that occur in the human airways, but selected com-
parisons are made with other mammalian species to clarify differences that may
affect health impact analyses of experimental data.
                                     11-3

-------
11.1.2  Aerosol and SO- Characteristics
     An aerosol may be defined as a relatively stable suspension of small
liquid or solid particles in a gaseous medium.  Airborne particulate materials
in the environment are aerosols.   Aerosols containing potentially toxic com-
ponents consist of particles with a variety of physical and chemical properties.
In particular, a given aerosol may include particles with a wide spectrum of
physical sizes, even if all the particles have similar chemical composition.
Another important property, physical density, may vary with particle size and
particle type  (Raabe et al., 1975).  Also, the concentration of of toxic
components  in  particles may be different for different sized particles
(Natusch et al., 1974).  Morphologically identical particles may have totally
different chemical compositions (Pawley and Fisher, 1977).  Common assumptions
that  particles in a given aerosol have a relatively homogeneous chemical
composition, toxic potential, and physical density should not be expected to
describe adequately general aerosol behavior in the atmosphere and may be
seriously misleading concerning specific aerosol toxicity, especially when
particles are  found in combination with S0? gas.
      It is  essential for evaluation of the possible health effects  associated
with  their  inhalation that the physical and chemical properties of  aerosols
and gases be appropriately characterized.  These properties then can provide
predictive  information concerning deposition and other  important dosimetric
factors that need to be considered if biological responses are  to  be fully
understood.
     If particles in an aerosol are s^r-oth and  spherical  or nearly spherical,
their physical  sizes can be conveniently described  in  terms of  their respective
geometric diameters.  Aerosols of solids rarely  contain  smooth,  spherical
                                     11-4

-------
particles, however; various conventions for describing physical diameters have
been based upon available methods of observing and measuring particle size.
For example, the size of a particle may be described in terms of its projected
area diameter (D ), defined as the diameter of a circle with an area equal  to
the apparent cross-sectional area of the particle when lying on a collection
surface and viewed with an optical or electron microscope.  Other conventions
for describing physical size are based on measurements of scattered light,
surface area, electrical mobility, diffusional mobility, or other physical  or
chemical phenomena (see Mercer, 1973; Stockham and Fochtman, 1979).
     Aerodynamic properties of aerosol particles depend upon a variety of
physical properties, including the size and shape of the particles and their
physical densities.  Two important aerodynamic properties of aerosol  particles
are the inertial properties, which are most important for particles larger
than 0.5 urn in diameter (related to the settling speed in air under the influence
of the earth's gravity) and the diffusional properties, which are most important
for particles smaller than 0.5 urn in diameter (related to the diffusion coef-
ficient) (Fuchs, 1964)  (see Section 11.2.1).  When particles are inhaled,
their aerodynamic properties, combined with various aspects of respiratory
mechanics, determine their fractional deposition and the deposition location
in the respiratory tract (Phalen and Raabe, 1974; Morrow, 1964a, 1974; Lippmann
et a!., 1971; Hamilton  and Walton, 1961).
     In order to avoid  the complications associated with the effects of parti-
cle shape, size, and physical density upon  the  inertial properties of  inhaled
airborne particles, "aerodynamic diameters" have been defined  and  used to
describe particles with common  inertial properties with the  same  "aerodynamic
diameter."  The aerodynamic diameter most  generally used  is  the  aerodynamic
                                      11-5

-------
equivalent diameter (Dae). defined by Hatch and Gross  (1964)  as  "the diameter



of a unit density sphere having the same ..ettling speed (under gravity)  as  the



particle in question of whatever shape and density."   Raabe  (1976)  has  recom-



mended the use of an aerodynamic resist nee diameter  (D  ),  defined more
                                                       dr


directly with terms used in physics to describe the inertial  properties of  a



particle. The relationship between these two aerodynamic diameters  is  given



by:
                       DV[pC(D)]
                 D   = 	——— = D  C(D  )                    (2)
                  ar      /	      ae   ae
with D   the aerodynamic (equivalent unit density sphere) diameter and C(D  ),



the (Cunningham) slip correction associated with a unit density (p*=l g/cm )



sphere of diameter D. .   The slip correction, C(D), a function of physical
                    QC


size D,  is a semi empirical factor that corrects the Stokes1  Law of viscous



resistance for the effect of "slip" between the air molecules when the aerosol



particles are almost as small as or smaller than the mean free path of air



molecules.  Both of these aerodynamic diameters have been widely used in the



inhalation toxicology literature.  It is probably not crucial to the general



properties of inhaled particles to differentiate between or be unduly concerned



with these two definitions, since their difference is only 0.08 urn or less



over all sizes under normal conditions at sea level.  Hence, the term aero-



dynamic diameter can be used to refer to either or both of these two defi-



nitions.   Particle characteristics described in terms of physical diameter  can



also be described in terms of aerodynamic diameter.



     Since not all particles in an aerosol are of the same physical  or aero-



dynamic size,  the distribution of sizes must be described.   If either the
                                     11-6

-------
physical diameter  (D) or the projected aerodynamic diameter is used to charac-
terize particles,  the distribution of particle sizes in a mixed aerosol is
most conveniently  described as a probability density function f(D) [f(D   or
                                                                       d r
f(Dae)L with

               /   f(D)dD = 1                      (3)
                o
One such generally useful function, the  log-normal function, involves two
parameters, the geometric mean size (or  median) and the geometric standard
deviation (o ).  Environmental aerosols  have size distributions that are more
complicated, reflecting the production of particles in atmospheric processes,
emission sources or other anthropogenic  activities, and the particle dynamics.
They may have  several modes (Whitby. 1978).  Photochemically generated aerosols
create small nucleated particles that are generally smaller than 0.1 urn (the
nuclei mode) while combustion and other  particle generation processes usually
yield relatively coarse particles larger than 2 urn.  Another mode usually
exists between 0.1 urn and 2 urn  because  of the great stability of particles  in
this range  (see Chapters 3 and 5).
     Since  aerosols rarely consist of particles of a single size, they must  be
described in terms of parameters of size distribution functions.  It has
become customary in the absence of detailed data and for the sake of general-
ization to  describe aerosols in terms of their geometric mean or median
diameter and the geometric standard deviation (a ) of the size distribution.
Hence, if the  particle number is being considered, the particle size may be
reported as the count median (physical)  diameter (CMD) and og, or the count
median aerodynamic diameter (CMAD) and og  if aerodynamic sizes have been
measured.   Numerically, half the particles in an aerosol have physical  sizes
                                     11-7

-------
less than the CMD and half are larger.  Likewise, half the particles  have
aerodynamic diameters smaller than the CMAD and half have larger aerodynamic
diameters.  Since the mass of a material is usually more relevant to  Its
potential toxicity, the mass median (physical) diameter (HMD) or »ass median
aerodynamic diameter (MMAD) and o  is usually preferred in describing aerosols
1n inhalation toxicology research.  Half the mass of particles in an aerosol
is associated with particles smaller than the HMD and half with larger particles,
Likewise, half the mass of particles is associated with particles whose aero-
dynamic  diameters are smaller than the MMAD and half with particles having
larger aerodynamic diameters.  If an aerosol is radioactive or radiolabeled,
mass measurements may be replaced by activity measurements yielding the activity
median diameter  (AMD) or activity median aerodynamic diameter (AMAD).  Inter-
relationships among these various ways to express the diameter of the aerosol
have been examined for the log normal distribution by Raabe (1971).
     In  addition to particle characteristics, conditions of the gas medium
influence the properties of aerosol dispersions.  Such environmental conditions
as relative humidity, temperature, barometric pressure, and fluid flow con-
ditions  (e.g., wind velocity or state of turbulence) affect the aerodynamics
of aerosol particles.  Another property that affects particle behavior  is
electrostatic charge.  Environmental aerosols normally have some electrostatic
charge distribution.
     The concentration of environmental aerosols or gases affects  inhalation
deposition and particle dynamics.   The number of particles per  unit  volume  of
gas (#/cm ) provides information  indicative of  the coagulation  rate  for  an
aerosol.   The mass concentration  (mg/m  or ug/m ) or concentration of  a  spe-
cific potentially toxic species (mg of constituent/m  ) provides  information
                                     11-8

-------
needed to calculate inhalation exposure levels.   For SO-, the concentration
may be expressed in parts per million (ppm) or in mass concentrations  (mg/m3);
each 1 ppm of S02 equals 2.62 mg/m3 (2620 ug/m3).
     Sulfur dioxide gas is a rapidly diffusing reactive gas that 1s readily
soluble in water and body fluids (Aharonson, 1976).   Through normal and catalyst
nediated oxidation processes in air S02 gas is slowly oxidized to form H2$04,
leading to sulfate salts.  Since NH3 is formed in natural biological processes
including endogenously in the airways, (NH4)2$04 and NH4HS04 are important
products of S02 oxidation (Charlson et al., 1978).   Specific instrumental  and
chemical techniques are available for SCL and other sulfur containing  compound:
in aerosol-gas mixtures.
11.1.3  The Respiratory Tract
     To evaluate the regional deposition of inhaled aerosols and sulfur dioxide,
the normal dimensions of each anatomical section of the respiratory tract  from
nasal cavity to the parenchyma of the lung are needed (Figure 11-1).  With
these measurements, predictive models of the deposition of inhaled particles
and gases have been devised.  Although differences exist among individuals,
and variability occurs during the breathing cycle of any given individual
(Marshall and Holden, 1963), general descriptions of the anatomical features
of the respiratory tract and airflow characteristics are quite satisfactory
for general predictive models of deposition.
     Morphometric measurements of the airways have been made by (a) preparation
of corrosive casts of the airspaces (Tompsett, 1970; Frank and Yaeder, 1966;
Phalen et al., 1973; Raabe et al., H76-); (b) direct measurements ui vivo,
such as by endoscopy, radiography, (Nadel , et al., 1967; Adams r-^t-a+rT '1942;
Yeh, et al., 1975), or at autopsy (Berg,  et al., 1949); or  (c) two-dimensional
                                     11-9

-------
FIGURE 11-1.   Features of the respiratory tract of man used in the description
of the deposition of inhaled particles  and gases with insert showing
parts of a silicon rubber cast of a human lung showing some separated
bronchioles to 3 mm diameter, some bronchioles from 3 mm diameter to
terminal bronchioles,  and some separated respiratory acinus bundles
(adapted from Raabe, 1970).
                                     11-10

-------
measurements of cross-sectional cuts of tissue either by direct observation or

with the aid of light and electron microscopy (Weibel and Elias, 1967; Nagashi,
             $1td^ L^ilL^A^g1—-
1972; Hansen .*W4, ( 1074; Hansen et al , 1975; Hansen and Ampaya, 1975).

     The respiratory tract includes the passages of the nose, mouth, nasal

pharynx, oral pharynx, epiglottis, larynx, trachea, bronchi, bronchioles,  and

small ducts  and alveoli of the pulmonary acini.  For consideration of the

mechanisms associated with deposition  and clearance of inhaled aerosols, the

respiratory  tract  can be divided  into  three functional regions:  (1) naso-

pharynx (NP), the  airways extending from the nares down to the epiglottis  and

larynx at the entrance to the trachea  (the mouth is included in this region

during mouth breathing); (2) tracheobronchial region (TB), the primary conduct-

ing airways  of the  lung from the  trachea to the terminal bronchioles (i.e.,

that portion of the lung respiratory tract having a ciliated epithelium);  and

(3) pulmonary region (P), the parenchymal airspaces of the lung, including the

respiratory  bronchioles, alveolar ducts, alveolar sacs, atria, and alveoli

(i.e., the gas-exchange region).  Although the anatomical and physiological

divisions between  these regions are gradual and difficult to distinguish, the

formal separation  of the ciliated from the unciliated regions  has useful

applications, particularly when considering particle clearance.

     The NP  consists primarily of hollow portions of the nose  and throat.  The

nose is a complex  structure of cartilage and muscle  supported  by  bone and

lined with mucosa  (Holmes, et al., 1950).  The vestibule of  the nares is

unciliated but contains a low-resistance filter consisting of  small  hairs.

The nasal volume is separated into two cavities by a 2- to 7-mm thick septum.

The inner nasal fossae and turbinates  are ciliated,  with mucus flow in  the

direction of the pharynx.  The turbinates are  shelf-like projections of bone
                                      11-11

-------
covered by ciliated mucous membranes with a high surface-to-volume  ratio  that



facilitate humidification of the incoming air.



     The larynx consists of two pairs of elevated mucosal  folds  that partially



obstruct the airway.   The distance from the epiglottis to  below  the larynx is



5 to 7 cm, with a vertical diameter of 3.6 to 4.4 cm (Snyder,  1975).  Females



have smaller laryngeal regions than do males.



     The trachea, an elastic tube supported by 16 to 20 cartilagenous rings



that circle about 3/4 of its circumference, is the first and largest of a



series of conductive airway ducts (Tenney and Bartlett, 1967).   The trachea



divides into two major bronchi.  The caliber of the trachea and  major bronchi



and their cross-sectional geometry is about 15 percent larger  during inspiration



than during expiration (Marshall and Holden, 1963; Fraser  and  Pare, 1971;



Raabe et al., 1976b).



     The lungs consist of two major parts, the left and right  lungs, connected



to the two major bronchi of the trachea (Figure 11-1).  The left lung consists



of two clearly separated lobes, the upper and lower lobes; and the  right  lung



consists of three lobes, the upper, middle, and lower lobes.  Each  lobe  is



served by a bronchus from one of the two major bronchi.  The conductive  airways



in each lobe of the  lung consist of up to 18 to 20 dichotomous branches  from



the bronchi to the terminal bronchiole (Pump, 1964; Raabe et al.,  1976b).



Bronchial caliber correlates with body size (Thurlbeck and Haines,  1975).  The



caliber of the smaller conductive bronchioles may be  up to 40 percent greater



during inspiration than during expiration (Marshall and Holden, 1963; Hughes



et al., 1972).



     The pulmonary,  gas-exchange region of the  lung begins with the partially



alveolated respiratory bronchioles.  Pulmonary branching proceeds  through  a
                                     11-12

-------
few levels of respiratory bronchioles to completely alveolated ducts  (Smith
and Boyden, 1949; Whimster et al., 1970; Krahl,  1963) and alveolar sacs
(Tenney and Remmers, 1963; Rattle, 1961b; Machlin, 1950; Frasier and  Pare,
1971).  Alveoli are thin-walled polyhedron air pouches which cluster  about  the
acinus through connections with respiratory bronchioles, alveolar ducts,  or
alveolar sacs.  The airway spaces in the respiratory zone are coated  with a
complex aqueous liquid containing several biochemically specialized substances,
including pulmonary surfactants (Green, 1974).
     Several  researchers have measured the conductive airways of the  lung.
Weibel (1963) used a corrosion cast of the human lung prepared by Liebow  and
co-workers (1947) to make detailed measurements of unbroken segments  to the
tenth branching; he could not measure further.  He used these measurements  in
conjunction with histological data (Weibel and Elias, 1967) on the human
alveolar acinus to develop a consistent model of airway number and dimensions.
Horsfield (1972), Horsfield and Gumming (1968), Horsfield and Gumming (1967),
Horsfield et  al. (1971), and Parker et al. (1971) also measured casts of  the
human conductive airways.  Raabe et al. (1976 ) used an i_n situ method (Phalen
et al., 1973) to measure the conductive airways of several mammalian  species,
including man, dog, rat, and hamster.  They used casts prepared at autopsy
under conditions simulating end inspiration (Raabe,  1979).  These replica
casts purportedly were more faithful reproductions of the normal airway
orientation than were those obtained with excised  lungs.  After determining
the lengths,  diameters, and branching angles  for  selected segments from  trachea
to terminal bronchioles, Raabe and co-workers (1976b) performed extensive
measurements  on the conductive airways of man and  experimental  animals.  They
demonstrated  that the number of airway branches  in the  human  TB  region from
                                      11-13

-------
trachea to terminal bronchiole can range from 11 to 22.   They also showed that


different lobes have different average numbers of branches to terminal, with


the apical or upper lobes tending to have fewer branches than the other lobes.


These measurements reveal the diversity of branching angles, airway segment


lengths and diameters, and branching patterns in mammalian species.  Other


factors,  such as airway closure, changes in caliber during breathing, bronch-


motor tone and constrictions can alter these dimensions (Slonim and Hamilton,


1971; Hinshaw, 1969).


     The  number of alveoli increases after birth until late childhood, reaching


a maximum of  about 300 million (Charnock and Doeshuk, 1973; Davies and Reid,


1970; Dunnill, 1962).  Schreider and Raabe (1980) made acinus measurements of


casts of  the  respiratory airways.  Although the alveolus usually assumes an


irregular shape because of the thin walls and close packing, alveolar size is


usually described as the equivalent spherical diameter.   Reported diameters


range from 150 to 300 pm for man (Weibel, 1963; Davies, 1961; Crosfill and


Widdicombe, 1961; Kliment, 1973; Von Hayek, 1960).  The alveolar dimensions


vary with degree of inflation (D'Angelo, 1972, Forrest, 1970) and  hydrostatic


pressure  (Glazier et al., 1966, 1967).


     The total surface area of the alveoli in adult man was  reported  by  Von

                    2                        ?
Hayek (1960) as 35 m  in expiration and 100 m  in deep  inspiration.   Weibel
                                       iy
(1963) estimated a surface area of 70 m  for a human  lung  at three-quarters

                                    2
capacity.   This compares with 45.5 m  for 16 kg dogs  (Tenny  and  Remmers,  1963)

         2
and 1.1 m  for guinea pigs (Schreider, 1977).


     The deep lung parenchyma includes several types  of tissue,  circulating


blood,  lymphatic  drainage pathways, and lymph nodes.  In man, the  weight  of


the lung,  including circulating blood, is about 1.4 percent  of the total  body
                                     11-14

-------
weight.  Lung blood is equal to about 0.7 percent of total  body weight (10
percent of total blood volume) (Snyder, 1975).  Because a portion of lung is
occupied by air, the average physical density of the parenchyma is about 0.26
g/cm   (Fowler and Young, 1959).
     Models of the airways, which simplify the complex array of branching and
dimensions into workable mathematical functions, are useful in estimation of
deposition.  An early idealized model of the airways of the human lung was
developed by Findeisen (1935)  for estimating the deposition of inhaled particles
Findeisen's model assumed branching  symmetry within the lung,  with each gener-
ation  consisting of airways of identical size.  Other models based on a symmetry
assumption have been proposed  by Landahl (1950), Davies (1961), Weibel  (1963),
and Horsfield and Gumming (1968).
11.1.4  Respiration
     Both the humidity and  temperature of inhaled aerosols and gases, as well
as the subsequent changes that occur as the aerosol-gas mixture passes through
various parts of the airways,  have important  influences on the inhalation
deposition of airborne particles.  Deposition of inhaled soluble, deliquescent,
and hygroscopic aerosols will  depend in part  on the relative humidity in the
airways, since the growth of such particles (with concomitant  increase  in
aerodynamic size) will directly affect both the site and extent of  inhalation
deposition.
     The relative humidity  of  inhaled air probably  reaches  near saturation in
the nose (Verzar et al., 1953).  Since the human nose  is a  relatively  simple
and short passageway, tranquil diffusion alone  cannot  account  for  rapid  humidi-
fication.  Rather, convective  mixing must play  a role,  suggesting  a mechanism
for enhancing S0? collection in the  nose.  The  lower temperature  of inhaled
                                      11-15

-------
air increases the effectiveness of nasal  humidification by convective mixing.



Unlike humidity,  the temperature of the inhaled air may not reach body tempera-



ture until  relatively deep in the lung.   Deal  et al.  (1979a, b,  c) measured



retrocardiac and retrotracheal  temperatures under different ambient tempera-



tures and found airway cooling associated with breathing cool air.  Raabe et



al. (1976b) found that the temperature of the  air at major bronchi in a nose-



breathing dog averaged 35°C, 4°C less than the body temperature.  The tempera-



ture of exhaled air at the nose of a dog averaged only 31°C (Raabe and Yeh,



1976a).



     Inspiratory flow rate and depth of inhalation influence the deposition of



inhaled particles.  The air inspired in one breath is the tidal  volume (TV).



The average  inspiratory flow rate, (Q), and tidal volume (Bake et al., 1974;



Clement et al., 1973) affect both inertia! and diffusional deposition processes



(Altshuler et al., 1967).   The total air remaining in the  lungs at the end of



normal expiration [functional residual capacity (FRC)] affects the relative



mixing of inhaled particles and, when compared with total  lung capacity (TLC),



is  indicative of the extent of aerosol penetration into the lung  (West, 1974;



Luft, 1958).  Weibel (1972) developed relationships relating human lung capacity



to body weight, and Guyton (1947a, b) and Stahl (1967) developed  interspecies



relationships describing respiratory volumes and patterns.  An  important



difference between man and rodents is that small rodents breathe  by  inhaling



shallowly and rapidly (for rats about 1.5 ml TV at 100 breaths  per minute).



     The inspiratory capacity (1C), the maximum volume of  air that can be



inhaled after a given normal expiration, is contrasted to  the vital  capacity



(VC),  which is the maximum volume of air that  can be expelled from the lungs



with effort after maximum forced inspiration.   Air that  remains  in the conductive
                                     11-16

-------
airways (from nose to terminal bronchioles) at end expiration is  considered  to


occupy the respiratory dead space (VD). since the conductive airways  are  not


Involved in gas exchange (Paiva, 1973; Paiva and Paiva-Verentennicoff,  1972;

Palmes, 1973).


     Gas flow dynamics within the upper airways may be expected to be turbulent


1n humans and dogs but laminar everywhere in the airways of small rodents


(Dekker, 1961; Fry, 1968; Schroter and Sudlow, 1969; Olson et al., 1973;


Martin and Jacobi, 1972; West, 1961).  The larynx introduces an important air


flow disturbance  that can influence  trachea! deposition (Bartlett et  al.,


1973; Schlesinger and Lippmann,  1976).  In the smaller human bronchi  and


bronchioles, where fluid flow is relatively tranquil, laminar flow prevails,


but branching patterns, filling  patterns (Grant et al. 1974). flow reversals


with varying  velocity profiles,  and  swirling complicate a description of  flow


in the small  airways  (Silverman  and  Billings, 1961; Cinkotai, 1974).   Because


actual flow  in the respiratory airways is difficult to describe, simplifying


assumptions,  such as  laminar  or  bulk flow and uniform velocity profiles,  are


usually  incorporated  into analytic descriptions.


     Representative values  for normal  human  respiratory parameters (Snyder,


1975)  are  frequently  used for deposition and  dosimetric prediction although it


is understood  that these  values  may  not describe  any  particular  person.   It


should be  noted  that  considerable  variability in  respiratory parameters  may


occur  among  individuals  in  the population,  particularly when healthy adults


are contrasted with children, aged,  and  ill  individuals.   For a  young  adult

                                                                       2
weighing 70  kg with a height  of  175  cm and a body surface area of 1.8 m  ,


Snyder  (1975)  assumed a  breathing  rate of  12 breaths  per  minute  with minute


volume of  7.5 liters/minute.  Morrow et  al.  (1966) assumed three sets of
                                      11-17

-------
representative tidal  volumes,  750 ml  at rest,  1450 ml  during  moderate  activity,
and 2150 ml during strenuous exercise with 15  breaths  per minute for deposition
calculations.
11.2 DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS
11.2.1  Insoluble and Hydrophobic Solid Particles
     The behavior of inhaled airborne particles in the respiratory airways and
their alternative fate of either deposition or exhalation depend upon aerosol
mechanics under the given physiological and anatomical condition (Yeh et al.,
1976; DuBois and Rogers, 1968).   To understand the basic physiological and
anatomical factors influencing deposition, initial consideration must be given
to nonreactive stable spherical  particles whose physical properties do not
vary during the breathing cycle.  When deposition measurements and calculations
are confirmed for these ideal  insoluble particles, it  is possible to develop
an understanding of the more complex behavior  of hygroscopic  and deliquescent
particles.
     Figure 11-2 illustrates the five primary  physical processes that lead to
aerosol particle contact with the wall of the  airways.  Contact of particles
with moist airway walls results  in attachment  and irreversible removal of the
particle from the airstream.  The contact process can  occur during inspiration
or expiration of a single breath or subsequently if a  particle has been trans-
ferred to unexhaled lung air (Engel et al., 1973; Davies, 1972; Altshuler,
1961).   Deposition increases with duration of  breath holding and depth of
breathing (Palmes et al., 1973;  Palmes et al., 1967; Altshuler, 1961).
     Electrostatic attraction  of particles to  the walls of the respiratory
airways is probably a minor mechanism of deposition in most circumstances.
Pavlik (1967)  predicted that light air ions (which would include some
                                     11-18

-------
I

VO
                                INTERCEPTIONV
                       ELECTROSTATIC
                       ATTRACTION
                           GRAVITATIONAL
                              SETTLING
                                                            IMPACTION
BROWN! AN
DIFFUSION
   FIGURE  11-2.   Representation of five major mechanisms of  deposition  of inhaled  airborne  particles  in the
   respiratory tract (from Raabe, 1979).

-------
atmospheric aerosol nuclei) would be deposited by electrostatic attraction in



the mouth and throat and suggested that the tonsils were naturally charged for



this purpose.  Fraser (1966) found that an average of 1000 electronic units of



charge per aerosol particle doubled the inhalation deposition 1n experimental



animals.  Melandri et al. (1977) reported enhanced deposition of Inhaled



monodisperse aerosols by people when the particles were charged. Longley



(1960) and Longley and Berry (1961) found the charge of the subject to have an



influence on deposition.  Similar observations have been made in j_n vitro



studies  (Chan et  al., 1978).  However, the airways are covered by a relatively



conductive electrolytic  liquid that probably precludes the buildup of forceful



electric fields.  Charged particles are therefore collected primarily by image



charging as  they  near the wall of an airway or by mutual repulsion from a



unipolarly charged cloud with a high concentration of particles (Yu, 1977).



The charge-to-size ratio (and associated electrical mobility) of an aerosol



particle determines the  extent to which the mechanism may play a role in



deposition.  Hence, the  role of this mechanism may depend on particle source,



age, and special  electrical phenomena in the environment.  It is reasonable to



expect this mechanism to have a small role, if any, in the deposition of



atmospheric environmental aerosols.



     Interception consists of noninertial incidental meeting of a particle  and



the lining of the airway and thus depends on the physical size  of the particle



This process would have a zero probability if the particles were only points



rather than extended bodies.   It is important primarily for particles with



large  aspect ratios,  such as long fibrous particles of asbestos (Harris and



Fraser,  1976).   Interception may be expected to play a negligible role  in  the



inhalation  deposition  of most environmental aerosols.
                                     11-20

-------
     Impaction dominates deposition of particles larger than 3 urn D    in  the
                                                                  3 r


nasopharyngeal and tracheobronchial regions (Rattle,  1961a;  Bohning  et al.,



1975).  In this process, changes in airstream direction or magnitude  of air



velocity streamlines or eddy components are not followed by  airborne particles



because of their inertia.  For example, if air is directed toward an airway



surface (such as a branch carina) but the forward velocity is suddenly reduced



because of change in flow direction, inertial momentum may carry larger particles



across the air streamlines and into the surface of the airway.  Impaction at



an airway branch has been likened to impaction at the bend of a tube,  providing



theoretical estimates of the impaction probability (P.) (Johnston and  Muir,



1973; Yen, 1974; Cheng and Wang, 1975).  Aerodynamic separation of this type



is satisfactorily characterized in terms of the particle aerodynamic diameter.



If impaction  in the airways is likened to collection of aerosols in  a  round-jet



impactor, the 50 percent collection efficiency would occur at a particle



aerodynamic diameter of 18 urn D   for the human trachael bifurcation for a
                               or


volumetric flow rate of 45 liter/minute and would have little effect on



particles smaller than 6 urn D  .  However, the airflow in the trachea  and
                             O i


major bronchi in man is turbulent and disturbed by the larynx so that  turbulent



impaction plays a role in deposition in these  larger airways  (Schlesinger and



Lippmann, 1976).  Breathing patterns involving higher volumetric flow rates



would tend to impact smaller particles.   In contrast, the passages of the nose



contain smaller airways, and the convective mixing spaces of  the nasal turbi-



nates would be expected to collect some particles as small  as  1  or 2  um  Dflr by



impaction.  Hence, impaction is an important process affecting  the inhalation



deposition in the human airways of environmental  aerosol  particles greater




than 1 um in  aerodynamic diameter.
                                      11-21

-------
     Gravitational  settling occurs  because of the influence  of  the  earth's



gravity on small  particles.   Deposition of particles  by this mechanism can



occur in all  airways except those very few that are vertical.   The  probability



of gravitational  deposition (P )  is usually estimated with equations describing



gravitational  settling of particles in an inclined cylindrical  tube of diameter



(d) under laminar flow conditions (Wang,  1975;  Heyder and Gebhart,  1977).



This deposition depends on the particle concentration distribution  in the



airway segments,  the incline angle  with respect to gravity,  and the aerodynamic



resistance diameter (D  ) of the  particle.   Deposition by gravitational settling
                      Q i


is therefore characterized in terms of the particle aerodynamic diameter.



This mechanism has an important influence on the deposition of  particles



larger than 0.5 urn D  .  Settling has an important role in the  deposition of
                    G I


environmental  aerosols in the distal region of the bronchial airways.  Settling



plays an equally important role in  the pulmonary deposition and is  responsible



for part of the deposition of particles in this region during mouth breathing.



     Deposition by diffusion results from the random (Brownian) motion of very



small particles caused by bombardment of the gas molecules in air.   The magni-



tude of this motion can be described by the diffusion coefficient for a given



physical particle diameter.   Since  larger particles have relatively small



diffusional mobility compared with  inertia, diffusion primarily affects depo-



sition of particles with physical diameters smaller than 1 urn.   For a 0.5 urn



particle with  a physical  density  of about 1 g/cm3, the influences of  inertia!



properties and diffusional properties on lung deposition are about equal.



Accurate calculation of the diffusional deposition of aerosols in the airways



requires information concerning the three-dimensional velocity profile  of air



flow in each airway segment.   If  the flow of a given segment is laminar and
                                     11-22

-------
approximately Poisueille, the probability of deposition by diffusion (PQ)



might be approximated using the Gormley-Kennedy (1949) equation for a



cylindrical pipe.  However, this assumes the aerosol is mixed at the entrance



of the cylinder and it might overestimate deposition in lung segments where



there is minimal mixing between branches and laminar flow between segments.



     It is important to note that the diffusivity, electrical mobility,  and



interception potential of a particle depend on its physical size, while  the



inertial properties of settling and impaction depend on its aerodynamic  diam-



eter.  These two measures of size may be quite different, depending on particle



shape and physical density.  Because the main mechanism of deposition is



diffusion for particles whose physical (geometric) size is less than 0.5 urn D



and  impaction and  settling above 0.5 um D   , it is convenient to use  0.5 um
                                         sr


as the boundary  between two regions. Although this convention may lead to



confusion in the case of very dense particles, most environmental aerosols



have densities below 3 g/cm  , and the deposition probability tends to have a



minimum plateau  between 0.5 um and  1 um D   (the equivalent sizes for a spherical
                                         u i


particle with physical diameter 0.5 um and  D   with density 3 g/cm  , respec-
                                            a r


tively).  Of course, a comparison of deposition probabilities is desirable



between the aerodynamic diameter and physical diameter of  submicrometer pa"-



tides.



     Thus, it is possible to use the available information concerning breathing



patterns and respiratory physiology, the anatomical and geometrical  characteris-



tics of the airways, and the physical behavior of  insoluble  spherical particles



to develop theoretical models of regional deposition  (Landahl,  1963;  Findeisen,



1935; Beeckmans, 1965; Landahl et al., 1951).  In  these models,  deposition  of



inhaled aerosols in a given region  of the respiratory  tract  or  in  the entire
                                      11-23

-------
tract is expressed as a fraction of inhaled particles.   Deposition fraction is



the ratio of the number or mass of particles deposited in the respiratory



tract to the number or mass of particles inhaled.   The undeposited fraction



represents those particles that are exhaled after inhalation.  For example,



pulmonary deposition (sometimes called alveolar deposition) 1s the ratio of



the number or mass of particles deposited in the unciliated small airways and



gas exchange spaces of the parenchyma of the lung to the number or mass of



particles entering the nose or mouth.   The fraction not deposited in the



pulmonary region is either deposited in some other region or exhaled. Similarly,



deposition fractions can be defined for the nasopharyngeal and tracheobronchial



regions  of the  respiratory airways.



     The theoretical probability of deposition can be calculated as the dif-



ference  between unity and the product of the probabilities of transmission



through  a given duct or series of ducts.  Hence, the probability of deposition



for a monodisperse aerosol of a given particle size for the combination  of



impaction, settling, and diffusion for a single segment region is given by:



     P = 1 - (1 - PT)(1 - Ps)(l - PD)                  (4)



where P  is the  combined deposition probability, P, is the impaction deposition



probability, P$ is the settling deposition probability, and PQ is the diffusion



deposition probability.




     Most model calculations treat the various mechanisms of deposition as



independently occurring phenomena.   However, such processes as Brownian dif-



fusion and gravitational  settling will interfere with each other when their



effects are of comparable magnitude, and that  interference can reduce the



combined deposition to less than the sum of the separate depositions (Goldberg



et al.,  1978).   Taulbee and Yu (1975a) have developed a theoretical deposition
                                     11-24

-------
model which allows for the combined effects of the primary deposition
mechanisms and features an imaginary expanding tube model of the airway system
(Weibel 1963) based on cross-sectional areas and airway lengths.
     The most widely used models of regional deposition versus particle size
were developed by the International Commission on Radiological Protection Task
Group on Lung Dynamics under the chairmanship of P. E. Morrow (Morrow et a!.,
1966).  Although the purpose of these models was to determine radiation exposure
from inhaled radioactive aerosols, the ICRP aerosol deposition and clearance
models are broadly applicable  to environmental aerosols.  The ICRP Task Group
used the anatomical model and  general methods of Findeisen (1935) and Landahl
(1950, 1963) for calculating deposition  in the tracheobronchial and pulmonary
regions.  The Gormley-Kennedy  (1949) equation for cylindrical tubes was used
for calculating diffusional deposition.  Particles were assumed to be insoluble,
stable, and spherical with physical densities of 1 g/cm  .  Regional deposition
was calculated for a breathing rate of 15 breaths per minute (BPM) for three
tidal volumes (TV):  (a) TV 750 ml, at rest (Figure 11-3), (b) TV 1450 ml,
moderate activity  (Figure 11-4), and (c) TV 2150 ml, fairly strenuous activity.
     The ICRP Task Group used  the  calculated deposition  fractions for individual
particle sizes to  predict deposition of  log-normally distributed aerosols
consisting of unit density spherical particles with geometric  standard devia-
tions (o ) as high as 4.5.  When the results were  expressed  in  terms of the
mass median diameter (MMD) for these various sized distributions of  unit
density of aerosols  (equivalent to the MMAD), the  loci  of the  expected depo-
sition values spanned relatively narrow  limits  (Figure  11-5).
     The ICRP Task Group on Lung Dynamics  (Morrow  et  al., 1966) compared  the
calculated regional and total  deposition fractions  for  inhaled particles  with
the available human data.  Those data were primarily  total  deposition  values
                                      11-25

-------
O\
                              M m

                                                                              I5BPM
                                                                            750 ml  TV
                                                                i   i  i liiti
0.01               O.I                  1.0                100
DIAMETER OF SPHERICAL  PARTICLE WITH DENSITY EQUAL TO ONE
                                                                                           100.0
   FIGURE  11-3.   Total and  regional deposition fractions  in the human respiratory  tract  for various  sizes  of
   inhaled  airborne  spherical  particles  with  physical  density  of  one g/cm   as  calculated  by  the  ICRP  Task
   Group  on Lung  Dynamics  (Morrow  et  al.,  1966)  for  hreathing  rate  of  15  breaths  per minute  (BPM)  and  a
   tidal volume (TV) of 750 ml (from Raabe, 1979).

-------
N>
•vl
                                                                             I5BPM
                                                                          1450 ml  TV
0.01                O.I                 1.0                100
DIAMETER OF SPHERICAL PARTICLE. WITH DENSITY EOUAL TO ONE
                                                                                            1000
   FIGURE  11-4.   Total  and regional  deposition  fractions  in  the  human  respiratory  tract  for various si/cs of
   inhaled  airborne spherical  particles with physical  density  of one g/cm  as calculated  by  the  ICRP  Task  Group
   on Lung Dynamics  (Morrow et  al., 1956)  for  a  breathing  rate of  15 breaths  per  minute (BPM) and a tidal  volume
   (TV)  of  1450 ml  (from Raabe,  1979).

-------
                0.01
  l  O.I   0.5 1.0      5  10     50 ICD

MASS MEDIAN DlAVITER-W'CRDfo
FIGURE 11-5.   The  range  of  regional deposition  fractions  (shaded areas) for
log-normally distributed  spherical  aerosols in human  nose  breathing at 15 BPM
and  1450  ml  TV.   Geometric  standard  deviation   ranges  between  1.2  and 4.5;
particle physical  density is one g/cm  so that MMD = MMAD (Morrow  et
                                              al.,  1966)
                                     11-28

-------
for polydisperse and sometimes unstable aerosols (Morrow, 1970b;  Landahl  and



Herrmann, 1948; Davies, 1964b; Van Wijk and Patterson, 1940; Brown et al.,



1950; Dautrebande and Walkenhurst, 1966; Morrow et al., 1958; Landahl and



Black, 1947; Landahl and Hermann, 1948).  Since then, the deposition 1n humans



of monodisperse insoluble, stable aerosols of different sizes has been measured



under different breathing conditions.  The most extensive of these studies  are



those of Lippmann and Albert, (1969), Heyder et al. (1975), and Giacomelli-Maltoni



et al. (1972).  Additional useful data are reported by Palmes and Wang (1971),



Shanty (1974), George and Breslin (1967), Altshuler et al. (1967), Hounam et



al.  (1971a  and 1971b), and Foord et  al. (1976), among others (Pavia et al.,



1977; Muir  and Davies, 1967; Taulbee et al., 1978; Hounam, 1971;  Heyder,  1971;



Heyder and  Davies,  1971; Fry and Black, 1973.)



     These  human deposition data have been collected from volunteers inhaling



test aerosols through either mouthpieces or nose tubes.  Differences between



those artificially  controlled inhalations and normal, spontaneous mouth breathing



or nose  breathing are possible.  Also, the particular breathing rate (BPM),



respiratory functional residual capacity (FRC), and tidal volume (TV) used in



the  experiments affect deposition.



     If  the quantity of aerosol exhaled is compared with that inhaled, the



data can be expressed as total deposition, but  regional  involvement  cannot be



distinguished (Heyder et al., 1975).  By tagging the test aerosols with  radio-



labels,  investigators can separate deposition by region, beginning with  either



nasopharyngeal deposition for nose breathing or pharyngeal  deposition for



mouth breathing (Albert et al., 1967a).  The measurement  of  clearance of the



radiolabeled aerosol from the thorax can be used to  separate early  clearance,
                                      11-29

-------
indicative of tr^cheobronchial (TB) deposition,  from more slowly cleared
pulmonary (P) deposition (Lippmann and Albert, 1969).
     Selected portions of the available data on total  and regional aerosol
deposition have been compared with the calculated deposition values of the
ICRP Task Group on Lung Dynamics (Morrow et al., 1966) (Figures 11-6 to 11-10).
In these comparisons, the predicted values either agree well with or represent
the upper limit of the observed deposition values.   The greatest overall
discrepancy between actual and calculated values occurs for particles smaller
than 0.2 urn; fractional pulmonary deposition measured for those particles
during mouth breathing is about 0.1 to 0.2, compared with the predicted 0.3 to
0.6.  However, actual data for these smaller particles are based on few experi-
ments.
     The most extensive and generally useful comparison of the effects of
respiratory parameters on aerosol deposition have been conducted by Heyder and
coworkers (1975, 1980) in systematic experiments comparing deposition of different
sized monodisperse aerosols in human volunteers at different tidal volumes,
flow rates, and breathing frequencies.  For particles between 0.1 urn and 4.0
urn  in diameter, Heyder et al. (1975) measured only total respiratory depo-
sition during either nose or mouth breathing.  They sequentially maintained a
given tidal volume and tested different selected breathing rates, inspiratory
flow rates, and particle sizes.   They then maintained a fixed breathing  rate
and studied deposition at different tidal volumes and inspiratory flow  rates.
Likewise, they held respiratory flow rates constant and measured  deposition at
different tidal volumes and breathing rates.  They demonstrated several
important features of aerosol deposition in the human respiratory airways.
With volumetric flow rate held at 15 liter/minute, the particle size yielding
                                     11-30

-------
I
to
o
V-
o
<
oc
u.

z
o
CO
o
OL
LJ
Q
 1.0

0.9


0.8

0.7


0.6

0.5

0.4


0.3


0.2


O.I

  0
  0
                             TOTAL DEPOSITION FOR NASAL BREATHING
                          O M/VLTONI,    1500ml  J?BPM(I972)

                          O HEYDER,    1000 ml  I3BPM(I975)

                          A GEORGE, 350-76O ™1  (4 BPM (1967 )

                          • SHANTY,    1150 ml  18 BPM( 1974)
                   U  th
                                   JL
                             i   i  I  i  t  i  I
                                                          TV 750 ml
JL
JL
t   i  i  i  I
       |         0.2   0.3     0.5   0.7    1.0         2.0    30     5.0   7.0

          PHYSICAL DIAMETER  |-	AERODYNAMIC DIAMETER, D0r t^m)-
                                                                                           10.0
   FIGURE 11-6.  Selected data (Giacomelli-Maltoni et al.,  1972; Heyder et al., 1975; George and Breslin, 1967;

   Shanty, 1974) reported for the deposition in the entire  respiratory tract of monodisperse aerosols inhaled

   through the nose by people are compared with predicted values calculated by the ICRP Task Group on Lung Dynamics

   (Morrow et al., 1966) (from Raabe, 1979).

-------
CJ
ro
    1.0
    0.9

z  0.8
o
P  0.7
o
g  0.6
U.
^  0.5
o
t  0.4
CO
g  0.3
LJ
0  0.2

    0.!
     0
      0,
                            TOTAL DEPOSITION FOR  MOUTH BREATHING
                             T
T
T
                    T	1—I  I  I I	
1=ICRP-DEPOSITION AFTER NP REGION (1966)
 O MALTONI,    lOOOTnl I2BPM(I972)
 • ALTSHULER,  500^1 I5BPM(I957)
              1000 ml 15 BPMCI975)
              760ml II BPM(I967)
              1000 ml IO-I5BPMII976)
              II4O ml I8BPM( 1974)
XT'
                         O HErDER,
                         A GEORGE,
                         O FOORD,
                         • SHANTY,
                         A LIPPMANN, -1400ml |4BPM(I969)

                                       TV!450m1
                                                                  TV 750  ml
                                                                                    i  a  i
                            0.2   0.3
                     PHYSICAL DIAMETER
             0.7   1.0        2.0    30      5.0  7.0
             — AERODYNAMIC DIAMETER, D0f f pm) -
                                                   10.
    FIGURE 11-7.   Selected data (Giacomel1i-Maltoni et al., 1972; Altshuler et  al., 1957; Heyder et al., 1975;
    George and Breslin, 1967; Foord et al.,  1976; Shanty,  1974; and Lippmann and Albert,  1969) reported for the
    deposition in  the respiratory tract of monodisperse aerosols inhaled through the mouth by people are compared
    with predicted values calculated by the ICRP Task Group on Lung Dynamics (Morrow et al., 1966)  (from Raabe, 1979).

-------
i
OJ
OJ
                               NASOPHARYNGEAL(NP)  DEPOSITION

                       AERODYNAMIC DIAMETERfDor(,im) FOR TV 1450 ml  AND15BPM

                        0.7     1.0      1.5   2.0     3.0   4.0  50 60   80  fO.O
                         ICRPU966)

                       It MOUNAM U9TI)

                       A UPPMANN (1970)
                                                                         I	•   •  • •
                                                                               4000     10000
                                                         (//mln)
      FIGURE  11-8.   Selected data (Hounam et al., 1971; Lippmann, 1970 ) reported for the deposition fraction of
      monodisperse aerosols in the?human nasopharyngeal (NP) region of the respiratory tract are plotted against
      the characteristic term (D   Q,  where Q is the average inspiratory flow in 1/min) that controls inertial
      impaction; for reference, ?fie calculated value (Morrow et al., 1966) is shown for 15 BPM at  1450 ml  TV

      (from Raabe,  1979).

-------
       TRACHEOBRONCHIAL (TB) DEPOSITION
               1.0'
              0.9

           z  °-8
           £0.7
           o
           g  0.6
           L-
           z  0.5
           o
           b  0.4
           CO
           8  0.3
           LJ
           0  0.2

              O.I

                0
I  I ITT
I  I I I I I
 — ICRP (1966)
  OFOORD,     1000 ml 10 BPW
  • FOORD,     1000 ml 15 BPW j

  ALIPPMANN', »i600 ml I4BPW/-

       TV 750cm3

   TV 1450 ml
                         1.0
                     5.0     10.0
                    AERODYNAMIC DIAMETER, D
                                                Qr
FIGURE 11-9.  Selected data  (Foord et a!., 1976; Lippmann and Albert, 1969)
reported for tracheobronchial (TB) depositionjtof monodisperse aerosols inhaled
through the mouth by people  are compared with  predicted values calculated by
the  ICRP Task Group on Lung  Dynamics^Morrow et al., 1966) (from Raabe,  1979).
                                 11-34

-------
I
U)
en
1.0
0.9 h
0.8
                    PULMONARY (P) DEPOSITION FOR MOUTH BREATHING
                                                                           I  I
               ICRP -FOR PflRITCLES EVTEWW5
               ALTSHULER,  500 ml 13 BPM (1967 )
                                                      ( »9G6)
              A GEORGE,
              0 FOORO.
                SMANTY
              A UPPMONN,
                                   760 ml II BPMU967)
                                   lOOOtnl IS BPM (1976)
                                         IBBPM(t974)
                                   1400ml
                0.2   0.3     0.5
         PHYSICAL DIAMETER
                              0.7   1.0       2.0   30
                              — AERODYNAMIC DIAMETER,
                                                                       50  7.0   10.0
11-10.
                Selected data (AHshuler et al   1967 George .n- Bresl In

-------
the lowest deposition changed from 0.66 urn at TV 250 ml  to 0.46  urn at TV  2000



ml.  Breathing at TV 1000 ml  changed this minimum deposition size from 0.58 urn



at 30 BPM to 0.46 urn at 3.75  BPM.   Hence, the particle size of minimum depo-



sition was reduced with increased residence time of particles in the lung and



the net deposition for all particles was increased.   In fact, as the breathing



rate went from 3.75 BPM to 30 BPM, the deposition at 1 urn D   went from 0.08
                                                           O T



to 0.4, an increase of a factor of 5.



     When Heyder et al. (1975) kept the breathing frequency constant while



changing the flow rate, the deposition for particles smaller than 1 urn remained



essentially unchanged, indicating that inertial  impaction was of little impor-



tance  in the deposition of submicrometer aerosols.   On the other hand, the



deposition of particles larger than 1 urn D   was enhanced at high flow rates,
                                          O I


indicating the influence of inertial impaction on the deposition of larger



particles.



     Alveolar and total deposition of particles  for mouth breathing was



evaluated by Heyder et al. (1980) as a function  of their aerodynamic diameter



for  two breathing patterns.  Keeping the mean volumetric flow rate constant at



250  ml/sec and allowing the mean residence time  to vary between 2 and 8 sec,



they observed a decrease of the particle size for maximum alveolar deposition



from 4 mm to 3.2 mm as the mean residence time increased.  With this mean



flowrate particles smaller than about 2.3 mm aerodynamic diameter were



exclusively deposited in the alveolar region, indicating their  inertia was  not



sufficiently high for impaction loses.  When the mean flow  rate was  increased



to 750 ml/sec and the mean residence time was 2 sec, particles  with  an aero-



dynamic diameter smaller than about 1.5 mm were exclusively  deposited  in the



alveolar region of the respiratory tract.  From the data of  Heyder  et  al.
                                     11-36

-------
(1980) it can also be seen that alveolar deposition and the particle size for



maximum deposition decrease as the mean flow rate increases.   In the above



studies the maximum of alveolar deposition was shifted from 3.5 wn to 3 mm in



aerodynamic diameter.




     Considering the limitations of the models used by the ICRP Task Group on



Lung Dynamics (Morrow et al., 1966) and the inherent variability between



individuals, their results for deposition of insoluble hydrophobic particles



provide generally useful guidance for environmental assessment purposes,



especially since they do not underestimate deposition fraction for the chosen



respiratory conditions.  These models may represent other breathing conditions



as well, considering that individuals can exhibit differences in deposition



depending on the physiological parameters and the influence of cigarette



smoking and lung disease alterations (Lippmann, 1977).



     When aerosols are inhaled through the nose the relatively efficient



filtration action of the nasopharyngeal region eliminates the passage of



particles larger than 10 urn D   to the lung and markedly limits the pulmonary
                             a I


deposition of particles between 2 urn D,,. and 10 um D,^ (Figures 11-3-11-5).
                                      Q I             G l


An active person breathing at 15 BPM and a tidal volume of 1450 ml  (Figure



11-4) would be  expected to deposit in the deep lung about 35 percent, 25



percent, 10 percent, and close to 0 percent of inhaled aerosols of  unit



density spherical particles of 0.2 um, 1.0 m, 5.0 um, and 10 um,  respectively,



during nose breathing.  Likewise, the tracheobronchial deposition would  be



expected to be  about 2 percent, 3 percent, 6 percent, and 0 percent for  these




sizes, respectively.



     Mouth breathing markedly alters the deposition of inhaled  particles in



humans (Lippmann, 1977; Miller et al., 1979; Heyder et al.,  1980) in that
                                      11-37

-------
larger particles can enter both the tracheobronchial  region (Figure 11-9)  and



the pulmonary region (Figure 11-10).   The deposition  in the deep lung would be



expected to be about 35 percent, 30 percent, 55 percent, and 10 percent for



inhaled aerosols of unit density spherical  particles  of 0.2 urn, 1 urn, 5 urn,



and 10 urn, respectively, for a person breathing at 15 BPM with a tidal volume



of 1450 ml.  This demonstrates the greater importance of the pulmonary



depositions of larger particles during mouth breathing.   In addition, some



larger particles that normally are all collected in the nasopharyngeal region



during nose breathing may pass the glottis and deposit in the upper part of



the tracheobronchial tree during mouth breathing (Figure 11-9; Morrow et al.,



1966; and  Lippmann, 1977).  Lippmann (1977) calculated that about 10 percent



of particles as  large as 15 urn unit density spheres might enter the tracheo-



bronchial  tree during mouth breathing (Q = 30 liter/minute).  The rest and



larger particles are deposited in the mouth and oral  pharynx.  Miller et al.



(1979) used this finding in suggesting that an "inhalable" particle sampling



procedure  consider  particles as large as 15 urn aerodynamic diameter, capable



of penetrating to the tracheobronchial region.



      Since much  information concerning inhalation toxicology is collected with



beagles or small rodents, it is important to consider the comparative regional



deposition in these experimental animals.  Cuddihy et al. (1973) measured the



regional deposition of polydisperse aerosols in beagles with TV about 170 ml



at about 15 BPM and expressed the results as mass deposition percentage versus



mass median aerodynamic resistance diameter (MMAD  ) that ranged from 0.42 urn
                                                 u I


to 6.6 m with geometric standard deviation o  = 1.8.   These  results  are



summarized in Figure 11-11 and compared with the Task Group  Values  for man



with TV 1450 ml, integrated to account for a a  = 1.8.
                                     11-38

-------
   LO-
CI
UJ
t  0.5-

00
S. o
o >-
K C 02-
   0.10
                                  l    I  I   I i  t

       DC; ?ra£
       noc- .'t y-
       ooc ,'e-/J
      .I     02
           ACTIVITY
                           10      2
                         i^3CDr-NAWlC Dl-WE TE R («
                                           i i  i r^
                                           5      10
                                                         0>0
                                                         OOJ
                                                       tf?
£ tr
o
UJ
t OC.^n


I?  1
                                                       o
                                                       »-
                                                       u
                                                                                             B
                                                                       05     LO
       ACTIVITY
    00
                                                  I.O-
                                                z
                                                o
                                                5
                                                z
                                                o

                                                a Q2
                                                z
                                                o
                                                S oio-
                                                a
                                                z
                                                o
                                                  .03
                  05    10
            ACTIVITY MEDIAN AEcOOYNAMiC
                                                    01
                                                                                        \
                                                                   0.5     10              S     ICO

                                                             ACTIVITY MEDIAN AERODYNAMIC DIAMETER (,.m.
       FIGURE  11-11.  Deposition of inhaled polydisperse  aerosols of lanthanum oxide
       (radiolabeled with  140La) in beagle  dogs exposed  in  a nose-only  exposure
       apparatus showing (a)  the deposition fraction  in  the total dog,  (b)  the deposition
       fraction in the tracheobronchial  region, (c) the  deposition fraction in the
       nasopharyngeal region,  and (d)  the  deposition  fraction in the pulmonary region
       (from Cuddihy et al.,  1973).   The dashed lines  indicate the range  of observed
       values.
                                               11-39

-------
     Raabe et al.  (1977) have measured the regional  deposition  of  0.1  um to



3.15 m D,  monodisperse aerosols in rats (TV about 2 ml,  70 BPM)  and Syrian
        or


hamsters (TV about 0.8 ml at about 40 BPM).   Their results are  summarized in



Figure 11-12.  The deposition of particles 3 urn D   or less 1n  small rodents



Is about one-half the ICRP (Morrow et al., 1966) estimates for  humans, although



some comparable deposition values have been reported for  humans by Heyder et



al. (1975).  The distributions among the respiratory regions during nose



breathing follow a pattern that is very similar to human  regional  deposition



during  nose  breathing.  The use of rodents or dogs in inhalation toxicology



research for extrapolation to humans does not seem to entail significant



problems associated with differences in regional deposition of  inhaled aerosols



based on particle sizes  less than 3 urn D__ for inert insoluble  particles
                                        a r


during  nose  breathing.



     Deposition calculations usually group lung regions without regard to



nonuniformity of the pattern of deposited particles within the  regions.



Schlesinger  and Lippmann (1978) found that nonuniform deposition in the trachea



could be caused by the air flow disturbance of the larynx.  Bell and  Friedlander



(1973)  and Bell (1978) observed and quantified particle deposition  as  it



occurs  at a  single airway bifurcation and found it to be highly nonuniform  and



heaviest around the carinal arch.  Raabe et al. (1977) observed that  the



relative lobar pulmonary deposition of monodisperse aerosols was up to  60



percent higher in the right apical lobes of small rodents  (corresponding to



the human right upper lobe) and that the difference was greater for 3.15 um



and 2.19 um  Dar particles than for smaller particles.  In  addition, Raabe et



al. (1977) showed that these differences in relative lobar deposition were



related to the geometric mean number of airway bifurcations between trachea
                                     11-40

-------
                             r	1	1
                           RAT  HAMSTER
                      N-P   A        A
                      T-B   n        o
                        P    o
                      RAABE, et ol. (1977)
O.I          0.2     0.3
    PHYSICAL DIAMETER
                                                  0.7    1.0          2.0    3.0
                                                    AERODYNAMIC DIAMETER •
                                                             Dor(/im)
5.0
FIGURE 11-12.  Deposition of inhaled monodisperse aerosols of fused aluminosi1icate spheres  in small rodents
showing the deposition  in the nasnpharynqeal (nasal) region, the  tracheo-bronchia1 (T-B) region, the pulmonary
region and in  the total respiratory tract based  upon Raahe et al. (1977).

-------
and terminal bronchioles in each lobe for rats and hamsters.  Since  similar
morphometric differences occur in human lungs, nonuniform lobar deposition
should also occur.   Schlesinger et al.  (1977) found nonuniform deposition in
the lobar branches  of a hollow model  of the tracheobronchial  airways with
enhanced carinal deposition and were  able to demonstrate a correlation of
higher lobular deposition and the reported incidence of bronchogenic carcinoma
in different human lung lobes.
11.2.2  Soluble, Deliquescent, and Hygroscopic Particles
     Most deposition studies and models tend to focus on insoluble and stable
test aerosols whose properties do not change during the course of inhalation
and deposition.  However, environmental aerosols usually consist of deli-
quescent or hygroscopic particles that may grow in the humid respiratory
airways.  That  growth will affect deposition (Scherer et al., 1979).  The ICRP
Task Group  on  Lung Dynamics (Morrow et al., 1966) addressed this problem  by
considering the equilibrium diameter for deliquescent materials at relative
humidities  near, but less than, 100 percent.  However, the residence times  in
the respiratory tract may be too short for large particles to  reach their
equilibrium size (Nair  and Vohra, 1975; Charlson et al., 1978).  Also,
environmental  aerosols  may consist of a combination of components,  including
complex mixtures that may not behave like pure substances.
     Perron (1977) has  described the factors affecting soluble particle  growth
in the airways  during breathing.  Basically, his results suggest that  particles
1 urn in aerodynamic diameter will increase by a factor of three  to  four  in
aerodynamic diameter during passage through  the airways.  Nasopharyngeal,
tracheobronchial, and pulmonary deposition of the enlarged particles  would  be
greater than the deposition expected for the  original particle size.   Submi-
cronic particles, including those as small as 0.05  urn, will  grow by a  factor
                                     11-42

-------
of two in physical diameter, with relatively little effect on deposition;



particles smaller than 0.3 urn Dar may even have some reduced pulmonary depo-



sition with growth because of reduced diffusivity.



     Acid sulfates and sulfuric acid formed by the oxidation of S02 1n the



environment may be reduced in acidity by naturally occurring ammonia (NH3) to



form ammonium sulfate (NH4)2$04 and ammonium bisulfate (NH4HS04).   Larson et



al. (1977) made short-term measurements that suggest that endogenously gener-



ated ammonia (NI-L) gas in the human airways may rapidly and completely neutra-



lize sulfuric acid aerosols  in the concentrations that are normally



encountered in the ambient environment.  Further, it is useful to note that



ammonia  is generated  from food and excreta in  inhalation chambers used to



expose experimental animals  to sulfuric acid (I-LSO.) so that some neutrali-



zation of sulfuric acid  in these  test atmospheres may also occur.



     Because of SO- oxidation, most environmental aerosols have a major ammo-



nium sulfate (NH4)~S04 or NHLHSO- constituent  and possibly some hygroscopic



H~SO., especially  in  the submicrometer  size range.  Growth of these particles



will occur in the  respiratory airways during breathing.  This growth  involves



chemical  dilution  of  the electrolyte or acid with absorbed water.  A  particle



growing  a factor  of three in physical diameter must absorb a  volume of wale""



equal to 26 times  its original particle volume.   Also, the increased  size  will



enhance  losses by  inertia! mechanisms,  including  impaction  in the  upper  airways



A  1 urn D  particle of H2$04 or  (NH4)2$04  may  grow  to  nearly  3  urn  Dar in  the



nasal region, increasing both nasal deposition and  tracheobronchial deposition



by a factor of 2  or more over the deposition  expected  for  a  1 urn  Dar  particle,



with the net result that pulmonary deposition  is  reduced  (see Figure  11-3).



Particle growth  in the airways may be  a protective  mechanism,  since (a)  the
                                      11-43

-------
deposition in the upper airways is probably less potentially harmful  than in
the pulmonary regions; and (b) the reduced electrolyte or acid concentration
will probably reduce the level of local toxicity.
11.2.3  Surface Coated Particles
     Some environmental particles may consist of a relatively insoluble core
coated with various chemical  species including metallic salts, (NH^SO^,
(NH4)HSO., H?SO., organic compounds including polynuclear aromatic hydrocarbons
(PAH), and small particles of other sparingly soluble materials.   Some surface
growth due to water adsorption may occur in the airways but will  be limited by
the availability of deliquescent or hygroscopic components on the particle
surface.  In general, the increase in aerodynamic diameter that may occur
would be much  less for coated particles than for more pure forms.
      Important  examples of coated particles are the fly ash, soot, or other
residual solid  particle aerosols released to the environment by fossil fuel
combustion.  The exact chemical form of the relatively inert core of these
particles will  vary from nearly pure fused aluminosilicate particles produced
during the combustion of coal to carbonaceous or metal oxide particles produced
by  internal combustion engines.  Volatile trace metal compounds and organic
compunds condense on  these particles during the cooling of the effluent  stream-
in  the power plant smoke stack or engine exhaust  line and during  release  to
the atmosphere.  In addition, gases such as SCL can adsorb to the particle
surfaces or finer aerosols can aggregate onto the particle surfaces.   If  these
processes are diffusion limited, the condensation and coagulation will be
quantitatively  proportional to particle diameter  for particles larger  than  0.5
pm D and to particle  surface for smaller particles.   In  either case  the
                                     11-44

-------
fractional mass of the surface coating material will be greater on smaller



particles than on larger ones.  In other words, the condensed material  coats



the particles with a relative mass concentration that increases with decreasing



particle size.  Important elements such as Se, Cd, As, V, Zn, Sb,  and Be have



been found to exhibit this size dependence in coal fly ash aerosols (Davison



et al., 1974; Natusch et al.  , 1974; Gladney et a!., 1976).  Therefore,  the



growth of such surface-coated particles in the airways should be expected to



be much less than for pure deliquescent particles.  Such growth should  be only



a minor influence on the deposition of large particles.  On the other hand,



small submicrometer coated particles may be principally composed of a deli-



quescent surface coating and  subject to more extensive relative growth.   (See



also Chapters 3, 5, and 6.)



11.2.4  Gas Deposition



     The major factors affecting the uptake of gases in the respiratory tract



are the morphology of the respiratory tract, the physicochemical properties  of



the mucous and surfactant layers, the route of breathing and the depth and



rate of airflow, physicochemical properties of the gas, and the physical



processes which govern gas transport.  A brief discussion of these factors



serves to illustrate their general role in the deposition of gases and convey



some aspects specific to the  uptake of SO-.



     The complex morphological structure of the human  respiratory tract has



been discussed in section 11.1.3.  The nature  and  structure of  the respiratory



tract in man and animals critically influences the deposition  of  gases since



the relative contribution of  gas transport processes varies as  a  result of



this morphology.  The human  tracheobronchial tree  is more symmetric, with
                                     11-45

-------
respect to diameter ratios and branching angles,  than that of  dogs,  rats,  or

hamsters, but is closest to that of the dog (Phalen et al.,  1974).   The

structure of the tracheobronchial  tree is variable from species to  species,

from lobe to lobe within a given lung, and from one depth to another in the


lung.

     The amount of a gas acting on a given area of the respiratory  tract is

reflected by the airway concentration at that level.   In general, the more

soluble  a gas is the higher it is removed in the respiratory tract.   However,

the  resultant tissue dose and observed toxicity do not necessarily  correlate

with this removal.  The gas must first come in contact with the mucous or

surfactant  layer lining the airway, depending upon which level of the respi-

ratory tract the gas has reached.   Chemical reactions with components in these

layers can  occur, thereby increasing the total absorption of the gas, but can

also reduce the amount of the gas penetrating to the tissue.  Thus, knowledge

of  the biochemical composition of the mucous and surfactant layers  is needed

to  identify components of these fluids which may react with the gas, influenc-

ing  deposition and the resulting toxicity

     Various reviews are available on the physical and chemical properties  of

bronchial secretions (Barton and Lourenco, 1973; Charman et al., 1974) on  the

structure and function of tracheobronchial mucosa  (Kilburn, 1967).  on the

surface  lining of lung alveoli (Rattle, 1965), and on the chemical  mechanisms

of action of gases, such as 03 and N02, in biological systems  (Menzel , 1976).

     Although respiratory surface area differs greatly among  various vertebrate

species, the amount of surfactant correlates well  with the  amount of dipalmitoy'

lecithin in lung parenchyma and with alveolar surface area  (Clements et al  ,
mo
•19-&9).   Dipalmitoyl lecithin has been found to constitute 90-95  percent of
                                     11-46

-------
recoverable lipid (Balis et a!., we-; Hurst et al.,  1973).   Thus,  the  alveolar



region is normally lined with saturated lecithin and  is mostly free of  other



lipids, proteins and carbohydrates.  Ecanow et al.  (1967) suggested a possible



role of alveolar surfactants in the uptake of inhaled gas related to the



formation upon inspiration of micelles which can readily solubilize non-polar



gases or inhaled anaesthetics.   With release of pressure during expiration,



the micelles return to the subphase, disaggregate,  and release the anaesthetic



or molecular gases for absorption by the blood stream.



     Physicochemical properties of a gas relevant to  respiratory tract  depo-



sition are its solubility and diffusivity in mucus, surfactant, and water and



its reaction-rate constants in mucus, surfactant, water, and tissue.  Henry's



law relates the gas-phase and liquid-phase interfacial  concentrations and is  a



function of temperature and pressure.  The solubility of most gases in  mucus



and surfactant is not known.  However, Henry's law constant for many gases in



water is known, the value for SO- being 59.7 mole fraction in air per mole



fraction in water at 37°C and one atmosphere of pressure (Washburn, 1928).



The diffusivities of most gases in mucus, surfactant, tissue, and water are



also unknown, thereby complicating efforts to model gas uptake in the



respiratory tract.  Diffusivity may be much smaller in a viscous mucous fluid



than in water, but ciliary activity effectively increases the diffusion coeffi-



cient.  In the general case, transport rates of the gas across the



mucus-tissue interface, tissue layer, and the tissue-blood interface are



needed to fully understand the absorption and desorption of gases  in the



respiratory tract.  However, knowledge on the biochemical mechanisms of action



of a given gas may enable one or more of these compartments to be  ignored.
                                     11-47

-------
     The major processes affecting gas transport involve  convection,  diffusion,
and chemical  reactions.   The bulk movement of inspired gas  in the  respiratory
tract is induced by a pressure gradient and is termed convection.   Molecular
diffusion due to local  concentration gradients is superimposed on  this bulk
flow at all times,  with the transport of the gas being accomplished by the
coupling of these two mechanisms.   Convection can be decomposed into the
processes of advection and eddy dispersion.   Advection is the horizontal
movement of a mass of air that causes changes in temperature or in other
physical properties, while eddy dispersion occurs when air is mixed by turbu-
lence so that individual fluid elements transport the gas and generate the
flux.  Due to the morphology of the respiratory tract and respiratory airflow
patterns, the relative contribution of the various processes to transport and
deposition is a function of location.
     During the respiratory cycle, the volumetric flow rate of air varies from
zero up to a maximum (dependent upon tidal volume, breathing frequency, and
breathing pattern) and then back to zero.   Usually expiration is longer than
inspiration, and intervening pauses may occur.  The net result of these
variables is to impart complicated flow patterns and turbulence in some
portions of the respiratory tract.
     The complex anatomical structure of the nose is well suited for
humidification, regulation of temperature, and removal of many particles and
gases.   The air deflecting channels of the posterior nares cause impaction  of
large airborne particles and create turbulent air flow conditions.  As  the
cross-sectional area expands beyond the entrance flow separation occurs.  This
results in turbulence and eddies which continue as the air traverses  the
passages around the turbinates.   Proctor and Swift (1971) studied  the flow  of
                                     11-48

-------
water through a clear plastic model of the walls of the nasal  passages  and
constructed charts of the direction and linear velocity of airflow in the
model.  With a steady inspiratory flow of 0.4 I/sec, they found that the
linear inspiratory velocity at the nasal entrance reached at least 4.5-5
m/sec and at most 10 - 12 m/sec, values which are significantly greater than
the 2 m/sec peak linear velocity in the tracheobronchial tree during quiet
breathing.
     Schroter and Sudlow (1969) studied a wide variety of flow patterns and
rates in  large scale symmetrical models of typical tracheobronchial  tree
junctions.  For both inspiration and expiration and irrespective of entry
profile form, they observed secondary flows at all flow rates in their single
bifurcation model.  When a second bifurcation was added a short distance
downstream of the first, the entering flow profile was found to influence the
resulting flow patterns.  Also different results were obtained depending upon
the plane in which the second bifurcation was located relative to the first
bifurcation.
     Olson et al. (1973) studied convective airflow patterns in cast replicas
of the human respiratory tract during steady  inspiration.  They showed that
the effect of the larynx is such that flow patterns typical of smooth bifur-
cating tubes do not occur until the lobar bronchi are reached.  Small eddies
were observed as far down as the sublobar bronchi with  200 ml/s flows  in  the
trachea.  In man the glottis of the larynx acts as  a variable orifice  since
the position of the vocal cords changes.  During  inspiration a jet  of  turbu-
lent air  enters the trachea and is directed against its  ventral wall imparting
additional turbulence over that associated with the corrugated walls and
length of the trachea.
                                      11-49

-------
     In the tracheobronchial  tree with its many branches,  changes  in caliber
and irregular wall  surfaces,  it is difficult to establish  exactly  where flow
is laminar, turbulent,  or transitional.   Viscous forces predominate in laminar
flow and streamlines persist  for great distances,  while with turbulent flow
there is rapid and  random mixing downstream.   As the flow  rate Increases,
unsteadiness develops and separation of the streamlines from the wall can
occur leading to the formation of local  eddies.   This type of flow is termed
transitional.  The  Reynolds number, the ratio of inertial  to viscous forces,
is useful  in describing whether flow is laminar or turbulent.   Values between
approximately 2000  and 4000 are ascribed to transitional flow with smaller
Reynolds numbers reflecting laminar flow and larger ones turbulent flow.
Fully developed laminar flow probably only occurs in the very small airways;
flow is transitional in most of the tracheobronchial tree, while true turbu-
lence may  occur in  the trachea, especially during exercise when flow veloci-
ties are high (West, 1977).
     Turbulence will gradually decay in any branch in which the Reynolds
number is  less than 3000 (Owen, 1969).  Decays of 15 percent, 16 percent, and
10 percent are predicted to occur in the first three generations of bifurcation
respectively, using the theory of Batchelor (1953) for the change in turbulent
energy at  regions of rapid flow contraction.   While these decay calculations
neglect the possible effects  of the strong secondary flows generated at  the
bifurcation, their  validity is supported by the data of Pedley et al.(1971)
which shows that the boundary layer remains laminar in the daughter-tube for
Reynolds numbers in the parent-tube up to at least 10,000.  Hence,  the turbu-
lent eddies are localized in  the core.
                                     11-50

-------
     Flow oscillations in the segmental bronchi  attributed to beating  of  the


heart are only detectable during breathholding or during pauses  between


inspiration and expiration (West, 1961).   A peak oscillatory flow rate of 0.5


l/»in was measured, which is about 20 percent of the peak flow rate in the


segmental bronchi during quiet breathing.   Gas mixing is improved by these


oscillations.


     Diffusion in the lung normally involves at least three gases and  the


governing laws are Stefan-Maxwell equations rather than the more familar


Pick's law (Hirschfelder et al., 1954).  In a multicomponent mixture,  the


transfer of one component is a function of its own concentration as well  as  of


the concentration of the other components; in the binary case diffusivity is


dependent on the total pressure and temperature of the mixture,  the molecular


weights of the two species and is independent of the composition of the

                If $7
mixture.   Toor (-1-951-) showed that a ternary gas mixture may exhibit one  of the


following phenomena:  1) diffusion barrier - when a component gas diffusion


rate is zero even though its concentration gradient is not zero, 2) osmotic


diffusion - when a component gas diffusion rate is not zero even though  its


concentration gradient is zero, and 3) reverse diffusion - when a component


gas diffuses against the gradient of its concentration.  An exact solution to


the Stefan-Maxell equation is extremely difficult to obtain and in respiratory


physiology, diffusion in the lung has always been assumed mathematically to be


binary.  Chang et al. (1975) used a simple gas film model to examine  differ-


ences between binary and ternary diffusion.  Their results  indicate that for


air breathing under normal conditions, gas transport diffusion  problems  in the


lungs may be examined using binary laws.  However, significant  errors may


occur if binary laws are used to examine diffusion involving gases, such  as


helium, or high pressures.
                                     11-51

-------
      In  studying the nature of gas mixing in the tracheobronchial tree and  its



 effects  on gas transport there have been numerous modeling efforts utilizing



 an  approach  in which all pathways from the mouth or trachea to the alveoli  are



 combined into one effective pathway whose cross-sectional area is equal to  the



 summed cross-sectional area of all bronchial tubes at a given distance from



 the mouth or trachea (Davidson and Fitz-Gerald, 1974; Paiva, 1973; Pedley.



 1970; Yu, 1975; Scherer et al., 1972).  In this formulation, the mechanical



 mixing imparted by  tube bifurcations, turbulence, and secondary flows and the



 mixing due to molecular diffusion are represented by the function form of the



 effective axial diffusion coefficient (Scherer et al, 1975).  Thus, this



 coefficient  of diffusion incorporates the effect of axial convection.  The



 effective axial diffusion coefficient is a constant equal to the molecular



 diffusivity  only in the alveolar region where gas velocity is very small.



 However,  in  other regions of the tracheobronchial tree, the local average gas



 velocity and the tube geometry will jointly determine the value.   Various



 functional forms have been proposed in the studies cited above for an appro-



 priate expression for the effective axial diffusion coefficient.



      Utilizing two dimensionless parameters, Wilson and Lin (1970) showed that



 pure  convection is the dominant mechanism of gas transport through the 7th



 generation of branching in the human lung.   Based upon their analyses they



 suggested that roughly between generations 8 and 12 Taylor laminar diffusivity



 (Taylor,  1953) for parabolic flow in a straight tube would apply.  For this



type of diffusion,  radial  diffusion and axial convection are coupled to pro-



duce an effective  block flow with axial  diffusion.   Block flow convection with



axial diffusion  dominates  in generations beyond the 12th.  Turbulent pipe flow



diffusivity  (Taylor, 1954)  has been used in the case where flow is turbulent
                                     11-52

-------
over part of the bronchial tree (Davidson and Fitz-Gerald, 1974; Pedley,
1970).
     By constructing individual streamline pathways from the trachea to the
alveoli, Yu (1975) derived an expression for the effective axial diffusion
coefficient which equalled the algebraic sum of the molecular diffusion
coefficient and an apparent diffusion coefficient.   The apparent diffusion
coefficient arises from two independent mechanisms:  1) the nonhomogeneous
ventilation distribution  in the lung, and 2) the interaction of nonuniform
velocity and concentration profiles due to Taylor's mechanism in individual
airways.  Using an average standard deviation of airway lengths based upon the
data of Weibel (1963) and various flow theory limiting values, Yu (1975)
demonstrated that Taylor  diffusion is everywhere in the tracheobronchial tree
dominated by the apparent diffusion due to nonhomogeneous distribution of
ventilation, rather than  being a major mechanism for gas transport in some
airways as claimed by Wilson and Lin (1970).
     In all of the previously described studies the diffusivity expressions
used assume fully developed flow in straight pipes to describe gas mixing, a
condition not truly applicable over most of the tracheobronchial tree.  Since
flow patterns at tube bifurcations are different for inspiration and expiration
(Schroter and Sudlow, 1969), the mixing process and hence the effective
diffusivities are different.   To obtain diffusivities applicable to the tracheo-
bronchial tree, Scherer et al. (1975) used airway  lengths and diameters from
Weibel (1963) and branching angles from Horsfield  and Gumming (1967) to con-
struct a five-generation symmetrical branched tube model and to experimentally
determine effective axial diffusivity for laminar  flow of a gas as a function
of mean axial  velocities up to 100 cm/s in the zeroth generation tube.  The
                                     11-53

-------
relationship was approximately linear and diffusivities for expiration were
about one-third those for inspiration.   The values obtained by Scherer et al
(1975) for steady flow can be applied to oscillating flow in the tracheo-
bronchial tree provided the oscillating flow can be considered quasi-steady,
i.e., steady at any instant of time.   This condition should hold in the first
ten generations whenever flow rates are approximately greater than 0.1 1/s
(Jaffrin and Kesic, 1974).
     As computational models of gas transport,  such as that of Pack et al.
(1977), become more refined to include effective diffusion, fluctuating lung
dimensions, etc., one can obtain a better understanding of the effects of
various factors affecting the transport and removal in the lung of gases, such
as SO-.  The deposition of SO,, in the respiratory tract depends upon the
transfer of the gas from the air to the liquid  coating or mucus membrane
surfaces of the airways and subsequent reaction of the sulfite anion with
constituents of body fluids or cells.  Since SO- dissolves readily in water at
or near neutral pH, the moist walls of the airways should readily collect SO-
and diffusion to the surface of the airways from inhaled air should be an
irreversible and efficient process (Balchum et  al. , 1960).  The rate at which
SO- comes in contact with the walls of the airways is therefore controlled by
the diffusion (Aharonson, 1976).
     The theoretical diffusivity of SO- at body temperature (sea level) is
       2
0.20 cm /sec.   This diffusivity in combination  with high solubility in body
fluids is responsible for high deposition in the nasopharyngeal region and
upper airways.   Frank et al.  (1969) surgically  isolated the upper airways of
anesthetized dogs with separate connections for the nose and mouth.  Sulfur
dioxide labeled with 35S was passed through this isolated nasopharyngeal
                                     11-54

-------
region for 5 min, and nearly complete removal was observed for concentrations



of 2.62 mg/m  to 131 mg/m  (1 to 50 ppm) at a flow rate of 3.5 liter/minute



through the nose.  Uptake of the mouth averaged more than 95 percent at 3.5



liter/minute with SO^ levels of 2.62 mg/m3 and 26.2 mg/m3 (1 and 10 ppm).



Strandberg (1964) made similar measurements for rabbits with trachea!  cannulas



He observed 95 percent absorption in the respiratory tract at 524 mg SO^/mg



(200 ppm) but at 0.13 mg SO./m  (0.05 ppm) absorption was lowered to about 40



percent during inspiration, demonstrating an apparent concentration effect.



Absorption of SO- at expiration was 98% in the 524 mg/m  (200 ppm)



studies compared to 80% for experiments using 0.13 mg/m  (0.05 ppm).



Dalhamn and Strandberg (1961) found that rabbits exposed to 262-786 mg



S02/m3 (100 - 300 ppm) absorbed 90% - 95% of the S02-  They noted that



absorption was to some extent dependent upon the technique whereby



tracheal air samples were obtained.



     Corn et al. (1976) studied the upper respiratory tract deposition



of SO- in cats and computed mass transfer coefficients which can be used



with surface area data to calculate the amount of SO,, removed in various



parts of the respiratory tract.  Utilizing a theoretical approach,



their own empirical data, and information available  from the  literature,



Aharonson et al. (1974) examined the effect  of respiratory  airflow rate



on nasal removal of soluble vapors.  The only assumption made regarding



factors affecting local uptake was that there was no back pressure  in  the



blood.  Hence, whether the rate of uptake is  limited by  diffusion  through



the gas phase, diffusion through the tissue,  chemical  reactions  in  the



tissue, or local blood flow in the tissues,  the  analytical  approach  is



valid, as long as the rate of uptake is proportional to  the gas  phase
                                      11-55

-------
pressure of the vapor.   Their analysis for acetone,  ether,  ozone,  and
sulfur dioxide showed the. the uptake coefficient,  which defines the
average flux of soluble vapors into the nasal  mucosa per gas-phase unit
partial pressure, increases with increasing airflow rate.
     In experiments described by Brain (1970)  there was a 32-fold
increase in the amount of S0~ present in the trachea of dogs when the
air flow-rate was increased 10-fold.   However, had  the uptake coefficient
not changed with the flow rate, Aharonson et al.  (1974) pointed out that
penetration would have increased 500-fold.   If the  uptake coefficient for
SO- is concentration dependent, as the data of Strandberg (1964)
suggests, increasing airflow rate may increase uptake due to higher
levels of SOp being present along the center of the inspired airstream
for the same input levels.
     The deposition and clearance of sulfur dioxide also has been
studied in jm vitro and model systems.  In a model  of the tracheobron-
chial airways lined with a simulated airway fluid (bovine serum albumin
dissolved in saline), it was observed that S02 was  primarily absorbed in
the upper third of the simulated airway with only a small fraction of
the SO- reaching the simulated alveolar or bronchiolar regions (Kawecki,
1978).
     Uptake and release of S02 in the nose of  human subjects breathing
42.2 mg/m  (16.1 ppm) through a mask during a  30 minute exposure period
was studied by Speizer and Frank (1966).   During inspiration the con-
centration of S02 had dropped 14% at a distance 1-2 cm within the nose
and was too small to detect at the pharynx with the analytical method
used.   Expired gas in the pharynx was also virtually free of SO-, but
                                     11-56

-------
in its transit through the nose the expired air acquired SO- from the nasal


mucosa.  The expired S02 concentration at the nose was 5.2 mg/m  (2.0 ppm),  or


about 12% of the original mask concentration.  In most subjects the nasal


mucosa continued to release small amounts of SO- during the first 15 minutes


after cessation of the SO- exposure.


     Melville (1970) exposed humans to SO- levels ranging from 4 mg/m  to  9


mg/m  (1.5 ppm to 3.4 ppm) for periods up to 10 min.  Extraction of SO- during


nose breathing was significantly greater (p < 0.01) than during mouth breathing


(85% versus 70%, respectively) and was independent of the inspired concen-


tration of S02.  Andersen et al.  (1974) found that at least 99% of 65.5 mg

     3
S02/m  (25.0 ppm) was absorbed in the nose of subjects during inspiration.


Values obtained after one to three hours of exposure were not different from


those obtained after four to six hours of exposure, thereby indicating there


was no saturation effect during this period of time.


11.2.5  Aerosol-Gas Mixtures


     Gases readily diffuse to the surface of aerosol particles and can partici-


pate in a variety of surface interactions.  Surface absorption related to


temperature and gaseous vapor pressure occurs if residence sites for the gas


molecules are present on the particles.  Such physical adsorption can be


described by the Longmuir or more complex isotherms (Gordieyeff, 1956).   In


addition chemical adsorption can occur involving chemical transformations and


bonds that enhance transfer of gaseous materials to the particulate  phase.


Such transformations can include both inorganic and organic vapors  (Natusch,


1978).  In addition aerosols of liquid droplets can collect and  carry volatile
                                     11-57

-------
are dissolved in the droplets.   In these cases,  aerosols  can serve  as  vectors
carrying molecules of various substances deeper  into the  airways  than  would
occur if the substances were in their gaseous forms.
     Since SO- is found in the  gas phase in various environmental aerosols,
the reactions that occur between SO- and aerosols,  and the gas-to-particle
conversions that may occur, can greatly influence the regional  deposition of
biologically active chemical species.   Since SO- is highly soluble in  water,
droplet aerosols, including those formed by delinquescent particles, will
collect dissolved SO- and can carry the resulting sulfurous acid deep  into the
lung.  The presence of certain  sulfite species formed by  such reactions in
environmental aerosols has been suggested (Eatough et al., 1978).  SO- is also
known to be converted to sulfate by reactions catalyzed by some aerosols,
including those containing iron or manganese.  The simple adsorption of SO- to
aerosol surfaces by chemical reaction may lead to the aerosol's acting as a
vector for transporting SO- to  the deep lung.  These types of S0--aerosol
behaviors are apparently responsible for the so-called synergism in biological
response found in experiments using SO- in combination with certain aerosols
(Goetz, 1960; Frank et al., 1962). However, in a study in which rabbits were
exposed to a mixture of SO- and carbon particles that adsorbed SO- on their
surface, the presence of carbon particles in the SO- mixture did not affect
absorption in the respiratory tract to any appreciable extent (Dalhamn and
Strandberg, 1963).
     The deposition of the aerosol and gaseous fractions  of the  sulfur species
can be predicted from the properties of these fractions.   Hence, the problem
of estimating deposition (and subsequent biological effects) requires  an
                                     11-58

-------
understanding of the proportion of sulfur species associated with the aerosol



fraction and their chemical properties.  Since these reactions are dynamic



processes, the rate and mechanics of the gas-particle chemical reactions,



especially as they may occur in the airways, must be understood.



11.3 TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT



     Particulate material deposited in the respiratory tract may eventually be



cleared by the tracheobronchial ciliary mucus conveyor or nasal mucus flow to



the throat and is either expectorated or swallowed.   Other deposited material



may be cleared by either the lymphatic system or transfer to the blood.   SO-



probably reacts rapidly with biological constituents to produce S-sulfonate



(Gunnison, 1971).  The role of clearance as a protective mechanism for the



respiratory tract depends on the physicochemical characteristics of the  particles



(or gaseous species), the site of deposition, and respiratory physiology   If



the particles are soluble in body fluids, their deposition in the nasal  turbi-



nates with subsequent absorption into the blood may be more important than



pulmonary deposition, and total deposition of soluble particles may be more



important than regional deposition.  For relatively inert and insoluble parti-



cles, deposition  in the pulmonary region, where they may be tenaciously retained,



would be more hazardous.  The  deposition by dissolution of SO, in the naso-



pharyngeal region may be protective, since  it probably  involves  less  serious



biological effects than deposition in  the bronchial or  pulmonary  airways.



Mouth breathing would eliminate the nasal absorption and  increase the S02



levels entering the lung.   If  the particles or  SO-  chemically  react  with  body



fluids, transformations of  the material can affect  clearance.   In all respi-



ratory regions, the dissolution of particles  competes with  other clearance




processes.
                                      11-59

-------
11.3.1  Depor ,ted Particulate Material
     Because clearance from the three respiratory tract regions (NP, TB, and
P) is physiologically and temporally different, by region of deposition and
characteristic  chemical  classes of particles (i.e., by relative solubility in
body fluids) (Morrow et al., 1966).   An understanding of regional deposition
is requisite to an evaluation of respiratory clearance and a description of
the retention of deposited particulate materials.  In addition, there may be
significant differences between the relative importance of clearance mechanisms
in different mammalian species.
     Particle deposition in the nasopharyngeal (NP) region is limited primarily
to the larger particles deposited by inertia! impaction.  Deposition of various
aerosol particles may lead to specific biological effects associated with this
region.  For particles that do not quickly dissolve or that react with body
fluids, clearance from this region is mechanical.  The anterior third of the
human nose  (where most particles >5 urn may deposit) does not clear  except by
blowing, wiping, sneezing, or other extrinsic means, and particles  may not be
removed until 1 or more days after deposition (Proctor and Swift, 1971;
Proctor et  al., 1969; Proctor and Wagner, 1965 and 1967; Proctor et al.,
1973).
     The posterior portions of the human nose, including the nasal  turbinates,
have mucociliary clearance averaging 4 to 6 mm/min with considerable variation
                           a^cj. 1$&qu,
-------
Group (Morrow et al., 1966) adopted a 4-minute half-time for physical



clearance from the human NP region by mucociliary transport to the throat and



subsequent swallowing.



     Soluble particles or droplets are readily assimilated by the mucous



membranes of the NP region directly into the blood.   Solubility is graded frorr,



extremely insoluble to instantly soluble, and the dissolution rate constant



for the particles must be considered for each aerosol.



     Since the tracheobronchial region includes both very large and very small



conductive airways, particles of various sizes can be deposited.   If deposited



in sufficient quantity over a sufficiently  long period, some of these particles



can lead to biological responses in the bronchial airways (Ulmer, 1967; Nadel



et al., 1967).  The retention of deposited  materials in this region can differ



markedly among individuals and can be affected by such factors as cigarette



smoking, pathological abnormalities, or responses to inhaled air pollutants.



Clearly, the more  rapid  the clearance, the  less time available for untoward



responses or latent injury.   In mouth breathing of aerosols, such as during



smoking or under physical exertion, the beneficial filtering of  large particles



in the NP region is lost, and a greater fraction of these large  particles can



be deposited in the TB region.



     An important  characteristic of the TB  region is that it  is  both ciliated



and equipped with  mucus-secreting  cells.  Mucociliary  clearance  mechanisms has



been reviewed by Schlesinger  (1973).  For relatively insoluble and  inert



particles, the primary clearance mechanism  for the TB  region  is  mucociliary



transport to the glottis, with subsequent expectoration  or  swallowing  and



passage through the gastrointestinal  tract.  Mucus  flow influences  the  ciliary



mucus conveyor (Van As and Webster,  1972; Besarab and  Litt,  1970; Oadaian Jt74fj
                                      11-61

-------
     The rate of mucus movement is slowest in the finer,  more  distal  airways



and greatest in the major bronchi  and trachea.   In addition,  coughing can



accelerate tracheobronchial  clearance by the mucociliary  conveyor.   The size



distribution of particles affects  their distribution in the tracheobronchial



tree.  The clearance of small  particles, usually deposited deep in the lung,



is slower than for larger particles,  which tend to deposit in the larger



airways (Albert et al., 1967b; Albert et al., 1973; Camner et al., 1971;



Luchsinger et al. , 1968).



     The clearance of material in the TB compartment cannot be described by a



single  rate.  Data from experimental  studies imply that the larger airways



clear with a half-time of about 0.5 hours, intermediate airways with a



half-time of 2.5  hours, and finer airways with a half-time of 5 hours (Morrow



et al., 1967a; Morrow, 1973).   There is also considerable variability among



individuals  (Camner et al., 1972a, 1972b, Camner et al. 1973a, 1973b; Albert



et al., 1967b).   Material with slow dissolution rates in the TB compartment



will  usually not  persist for  longer than about 24 hours in healthy humans.



Cigarette smoking has been reported under various conditions to either  increase



decrease, or have little effect on the efficiency and speed of TB clearance



(Camner e-t-aT;1972a; LaBelle et al., 1966; Bohning et al., 1975; Albert  et
                     i /}


al.,  1974; Thomson^1973^



      Particles smaller than about 10 urn D    are deposited to some extent  in
                                         Q T*


the  pulmonary region of the lung upon inhalation  (Figures 3, 4,  and  10),



although the deposition of particles much smaller  than 0.01 pm may be  quite



limited because of the competing diffusional deposition  in the NP and  TB



regions. Particles that deposit in the pulmonary  region  land on  surfaces  kept



moist by a complex liquid containing pulmonary  surfactants  (Blank et al.,
                                     11-62

-------
1969; Balis et al., 1971; Rattle, 1961b; Kott et al.,  1974;  Henderson  et al.,



1975).   There are no ciliated cells in the epithelium  of this region,  and flow



of liquid from pulmonary airspaces into the tracheobronchial  region is minimal



in humans (unlike murine species; Gross et al., 1966).   Insoluble materials



that deposit in the human pulmonary region are usually retained for extended



periods.



     A description of the clearance of particles from  the pulmonary region



should characterize particle distribution and redistribution.  Usually,



relatively insoluble particles are rapidly phagocytized by pulmonary macro-



phages (LaBelle and Brieger, 1961; Sanders and Adee, 1968; Green, 1971;  Green,



1974; Ferin, 1965; Camner et al., 1973a; Camner et al., 1974; Camner et  al.,



1973b; Chapman and Hibbs, 1977).   Smaller particles may not be as efficiently



or rapidly collected as larger particles (Hahn et al.,  1977); some particles



may enter the alveolar interstitium by pinocytosis (Strecker, 1967).   Chemo-



toxic processes have been identified in phagocytosis (Metzger, 1968),  and some



particles may be cytotoxic to macrophage cells (Allison et al., 1967).  Migra-



tion and grouping of macrophages  laden with particles  can lead to redistri-



bution of evenly dispersed particles into clumps and focal aggregations of



particles in the deep lung.   Some macrophages containing particles may enter



the boundary region between the  ciliated bronchioles and the respiratory ducts



and then can be carried with the  mucociliary flow of the TB  region.



     Some insoluble particles deposited in the lung are eventually trapped in



the pulmonary interstitium (Strecker, 1967), impeding mechanical  redistri-



bution or removal (Felicetti et  al., 1975).  Only the very smallest particles



(smaller than 10 nm in physical  diameter) can  readily diffuse  through pores



directly into the blood, passing  intact through the air-to-blood cellular
                                     11-63

-------
barrier of the gas-exchange regions of the lung (Raabe et al.,  1978a;  Raabe et
al., 1978b; Gross,  1954;  Raabe,  1979).
     Another possible clearance  route for migrating particles and particle-laden
macrophages is the  p'/imonary lymph drainage system with translocation to the
tracheobronchial  lymph nodes (Thomas, 1968; Lauweryns and Baert, 1977; Leeds
et al., 1971).  Little information is available about the clearance rates for
transfer from lung  to lymph nodes in man, but half-times of 1 to 2 years have
been estimated from data on dogs and monkeys (Leach et al., 1970).  Like
transfer to the TB  region with clearance by the mucociliary escalator, transfer
to  lymph nodes may affect only a portion of the material deposited in the
lung.
     Waligora (1971) studied the pulmonary clearance of extremely insoluble
                                                         95
and  inert  particles of zirconium oxide radiolabeled with   Nb.   Although his
results were  not precise, the biological clearance half-life in man was about
1 year, a  value about the same as for beagles.   By contrast, murine species
have a more rapid pulmonary clearance (Morgan et al., 1977).  Leach et al.
(1970, 1973)  exposed experimental animals to insoluble UO. (MMAD  of about 3.5
urn)  and observed lung retention half-times of 19.9 months for dogs and 15.5
months for monkeys.  Ramsden et al. (1970) measured the retention of  acci-
dentally inhaled, relatively insoluble 239PuCL (plutonium dioxide) in a man's
lungs and  found the clearance half-time to be about 240 to 290  days;  some  of
that material was dissolved into blood and excreted in the urine.  Pulmonary
clearance half-times as long as  1000 days have been reported for  extremely
insoluble particles of plutonium dioxide in dogs (Raabe and Goldman,  1979).
Cohen et al. (1979) reported an apparent half-time of about  100 days  for
nonsmokers and about 1 year for smokers for pulmonary clearance of magnetite
particles.
                                     11-64

-------
     Because of the slow clearance by the various mechanical pathways,  dis-



solution and associated physical and biochemical transformations are often the



dominant mechanisms of clearance from the pulmonary region (Morrow, 1973).



The term "dissolution" is taken in its broadest context to include whatever



processes cause material in a discrete particle to be dispersed into the lung



fluids and the blood (Green, 1975).  Many chemical compounds deposited in the



lung in particulate form are mobilized faster than can be explained by known



chemical properties at the normal  lung fluid pH of about 7.4 (Kanapilly,



1977).  Raabe et al. (1978a) suggested that the apparent dissolution of highly



insoluble PuO- actually may be due to fragmentation into particles small



enough to move readily into the blood, rather than to true dissolution.



     Mercer (1967) developed an analysis of pulmonary clearance based on



particle dissolution under nonequilibrium conditions.  If the dissolution rate



constant (k) is known for a material, the time required to dissolve half the



mass of (monodisperse) particles of initial physical diameter (D ) is given



by:





          = 0.618 a  pD /or k                           (5)
with p the physical density of the particles and a  and a  the volume and



surface shape factors, respectively  (for spherical particles a$/av = 6).



The particles would be expected to be completely dissolved at a time, tf,



given by:





     tf = 3av p D0/ask                                 (6)
                                      11-65

-------
Mercer (1967) also calculated the expected dissolution half-time for poly-



disperse particles when their mass median (physical)  diameter in the



lung is known:






     Tl/2 = °'6 °v




Further, he showed that the resulting apparent lung retention function R(t)



could be described as the sum of two exponentials of  the form:





     R(t) = M/MQ =





where f1 = (l-f2), 0 = agKt/avp(MMD) and f-l,  f2,  A^  and \2 are functions of



the geometric standard deviations as defined  by Mercer (1967).   Therefore,  for



dissolution-controlled pulmonary clearance, smaller particles will exhibit



proportionately shorter clearance half-times.   When the dissolution half-times



are much shorter than the half-times associated with  the translocations of



particles to the TB region or to lymph nodes  (i.e., much less than 1 year),



dissolution will dominate retention characteristics.   Materials usually thought



to be relatively insoluble (such as glass) may have high dissolution rate



constants and short dissolution half-times for the small particles found in



the lung; the dissolution half-time for 1 urn  D glass  spheres is about 75 days



(Raabe, 1979).   Changes in structure or chemical  properties, such as by



heat treatment of aerosols (Raabe, 1971), can lead to important changes  in



dissolution rates and observed pulmonary retention.



     Since respiratory tract clearance may begin immediately after the  initial



deposition,  the dynamics of retention can become quite complicated when  addi-



tional  deposition is superimposed on clearance phenomena.  Extended  or  chronic
                                     11-66

-------
exposures are the rule for environmental aerosols,  and particulate material



may accumulate in some portions of the lung (Davies,  1963;  Walkenhorst,  1967;



Davies, 1964a; Einbrodt, 1967).



     Usually the retention time of material in the  respiratory tract is  measured



(such as with radiolabeled aerosols) rather than the  clearance rates (Sanchis



et al., 1972; Camner et al., 1971; Edmunds et a!.,  1970; Luchsinger et al.,



1968; Aldas et al., 1971; Ferin, 1967; Barclay et al., 1938; Morrow et al  ,



1967a; Morrow et al., 1967b; Friberg and Holma, 1961; Holma, 1967, Kaufman and



Gamsus, 1974).  The lung burden or respiratory tract  burden can be represented



by an appropriate retention function with time as the independent variable



(Morrow, 1970a; Morrow, 1970b).  For models based on  simple first-order  kinetics



the lung burden (y) at a given time during exposure is controlled by the



instantaneous equation (Raabe, 1967):
        - E - V
where E is the  instantaneous deposition rate of particulate material deposited



in the lung per unit time during an inhalation exposure and X, is the fraction



of material in  the  lung cleared from the  lung per unit time.  For an exposure



that lasts a time t  , the lung burden from the exposure is given by:






                 'Ve
     ye = (E -  Ee   l e)/\1                                    (10)





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



is governed by:





     dy_ _    A,y                                              (11)

     dt "
                                      11-67

-------
and the lung burden is given by:

             -At
     y = ye e  i                                              (12)
where y  is the lung ourden at the end of the exposure period (t ).   Hoi linger et
al. (1979) used this simple model to describe the deposition and clearance of
inhaled submicronic ZnO in rats (Figure 11-13) where the concentration of zinc
(as Zn) in the lungs (as described by Equations 10 and 12) is superimposed on
the natural background concentration of zinc in lung tissue.   The normally
                                                                  '   ~1
insoluble  zinc has  only a 4.8-hour dissolution half-time (A,  = 0.21 h  ) for
this  aerosol.  Of course, environmental aerosol exposures continue so that a
steady state  lung burden may be expressed by:

      yss = EAi                                               d3)
      If several deposition and  clearance regions, subregions, or special pools
are  involved,  a more complicated multicompartmental model may be required to
describe  lung  or respiratory tract buildup and retention of inhaled aerosols.
If each compartment can be described by first order kinetics, as given in
Equations  10 and 12, the lung burden during exposure is given by:
           n      n          -At
      y =  Z y. = Z  (E. - E.e  1 e)/i                            (14)
       e  i=l n  i=l  1    1

where  the  subscript i is the index associated with each of the n different
clearance  compartments.   The steady state value for environmental aerosols is:
                                     11-68

-------
(O
              1000

               800
            LJ  600

            !  500

            £  400
            X

            ui  300
            tr
            0  200
            c
            M
i  100

    60

    60
    50
- EXPOSURE PERIOD
             r
T
i—r
                                                T
          CLEARANCE PERIOD
                                       LUNG     I DotoVofuc+SE
               Controls
                   >
 Base Level  114±3(SE)
                      JL
        JL
JL

                                      L
 -20  -10  -10  -5
                                         0   5    10    15   20  25  30
                                       TIME (HOURS) POST EXPOSURE
                                     35   40   45   50
  FIGURE 11-13.   Single exponential model,  fit by weighted least-squares, of the buildup (based on text equation  10)
  and retention  (based on  text Equation 12) of zinc  in rat lungs (data from Hoi linger et al.  1979).

-------
    yss = !Ei/Ai                                             (15)

           1=1



Likewise,  the retention,  when  exposure  ends,  is  given  by (Raabe,  1967):


         n     -A.t
y
       = I (y,e  1  )                                           (16)
where each of the X. values translates  to a clearance rate for each of the
compartments given by half-time T,^ = 1n 2/Ai  (Figure 11-14).

     For chronic exposures where the several  pools are in complex arrays of

change, a simple power function may serve as  a  satisfactory model of pulmonary

retention (Downs et al . ,  1967).  In such a model,  the pulmonary region is

treated as one complex,  well-mixed pool  into  which material is  added and

removed during exposure,  as given by the instantaneous equation:
     dy_
     dt = E - Apy/t [y = 0 at t = 0]                          (17)
where y is the total lung burden at a given time (t), E is the average deposi-

tion rate of inhaled particulate material  in the lung, and A  is the fraction

of available lung burden being cleared.   Unlike the A. of the exponential

retention models, A  is dimensionless.   The time coordinate is not arbi-

trary;  time is taken as zero only at the beginning of the inhalation exposure,
                                     11-70

-------
                100.0-3
                                 NxE|r l.4mg/doy
                                   \Ti=50d
                                    » •»
                        EXPOSURE       \
                        PHASE
                        te=20doys
0         200        400       600       800
                               TIME, days
                                                                            1000
1200
MOO
FIGURE 11-14.   Example  of  the  use  of  the  sum of exponential  models  for  describing lung uptake during  inhalation
exposure   (Equation  14)  and  retention  (clearance  phase)  after  exposure  ends   (Equation  16)   for  three lung
compartments with half-lives 50 d,  350 d, and 500 d, and twenty-day exposure rates  of  1.4 mq/d (Ej).  1.7 mq/d (E?),
and 2.1 mq/d (E3), rpspectively (from Raabe,  1979).

-------
when the lung burden is nil.   Thus, during an exposure lasting until  time (te),



the pulmonary burden (yfi) is  given by (Raabe, 1967):





     ye = Ete/(\p + i)                                        (18)





On this basis, no steady-state concentration is reached even though



clearance is progressing and  the lung concentration continues to increase



during chronic exposures to environmental  aerosols.  This model is therefore



not applicable to relatively  soluble species.  The lung burden (y) after the



exposure ends is given by (Raabe, 1967):







     y = ye te*p t Xp = At  P [t = te + tp]                   (19)





where time  (t) is reckoned from the beginning of exposure and is equal to



the sum of  the exposure time  (t ) and the time after exposure (t ).  This



model is illustrated  in Figure 11-15.



     Deposited particulate material cleared from the lung is usually trans-



formed  chemically and transferred to other tissues of the body.  The injurious



properties  of a toxic material translocated from the lung may therefore  be



expressed in other organs.  Identification of the potential hazards associated



with inhalation exposures to  toxicants is compounded when the respiratory



tract is not the only target  for injury but still  serves as the portal of



entry into  the body.  The metabolic behavior and excretion of  inhaled  toxi-



cants after deposition in the lung could define the probable  target organs  and



indicate potential pathogenesis of resulting disease.



     Multicompartmental models that describe biological  behavior  can  become



extremely complex.   Each toxicant or component of  aerosol particles deposited
                                     11-72

-------
                  100.0 F
I
*»J
OJ
               en
               E
           u.   -
           o  -J

           LU  CC
           Q  LU
            CD

            O  O
               c
               o
               CL
               LU
               O
 100         1,000

TIME^doys
                                                                              lopoo      100,000
  FIGURE 11-15   Example of  the use of  the power function model for describing lung uptake during inhalation exposure

  (text Equation 18) and retention (clearance phase) after exposure ends  (text Equation  19) for a twenty-day exposure

  at 8.5 mq/d (E) (adapted  from Raabe  1967).

-------
in the respiratory tract may need to be described by a separate rate constant



and pool or compartment.  A general  model  of the metabolic behavior of inhaled



particles (Figure 11-16) shows 39 different places where rate constants may



need to be determined.   In this general model,  the pulmonary region of the



lung is visualized as consisting of  three  independent clearance compartments,



and the particles are presumed to be converted  from their original  particulate



state to some other physicochemical  form or transformed state prior to clearance



from the respiratory tract.  Such a  transformed state can be used to describe,



for example, the behavior of hydrolytic aerosols in the respiratory tract.



     A  more specific model of the systemic metabolism of inhaled aerosols is


                                             144
shown  (Figure 11-17) for cerium trichloride (   CeCU) contained in particles



of cesium chloride (CsCl) with a MMAD   of about 2 urn (Boecker and Cuddihy,
                                     3 i


1974).  The resultant pattern of combined uptake and retention in various



organs  after inhalation exposure is  illustrated in Figure 11-18.   In this



case,  the exposure is acute; the fate of relatively insoluble materials in



chronically inhaled environmental aerosols may  involve more complex relation-



ships.



11.3.2  Absorbed S02



     S02 coming in contact with the  fluids lining the airways (pH 7 4) should



dissolve into the aqueous fluid and  form some bisulfite (HSO,-) and considerable

            2~

sulfite (S03  ) anions.   Because of  the chemical reactivity of these anions,



various reactions are possible, leading to the  oxidation of sulfite to sulfate.



     Clearance of sulfite from the respiratory  tract may involve several



intermediate chemical  reactions and  transformations.  Gunnison (1971)  has



identified S-sulfonate  in blood as a reaction product of inhaled SO-.  The



reaction rate  is rapid,  if not nearly instantaneous, so that there  is  no
                                     11-74

-------
FTPURF 11-16   Model of the multicompartmental deposition, clearance, retention
tJanslocation  and excretion of inhaled particulate material in the respiratory
tract and Ussues of the body; the numbered circles represent the transfer
rate constants (from Cuddihy, 1969).
                                     11-75

-------
                    Re&pifQtory    Environment
         5
        •t;
^  £
0.65

I
Cow
>C'1-
[ff^r *
N
re
> c
b
c
0

39
70
7?
4 1
3*
2«






                                                           So''
02-
-i »•
•^
-OOOOi
-OOOOi
- Oi
O.O4-
       fccet
Oi —
-oo4_:
~^*~
-0000:
                                                Tronsfer Ro»e Con»1or.!s
                                                Eiprettvd 0» Free lion o?
                                                Comporlmtnlol Content
                                                per Doy
FIGURE 11-17.   Multicomponent  model  of  the  deposition,  clearance  retention,
U^slocation  and excretion  of an  example  sparingly soluble metallic compound
(   CeCl3 continued in CsCl  particles)  inhaled by man or experimental animals;
the rate constants are based upon  first order kinetics  as in text Equation 11
(from Boecker  and Cuddihy, 1974).
                                     11-76

-------
•00
0'
                             J-.

                           DAYS POST-INHALATION EXPOSURE
*oc
 FIGURE  11-18.   Example  of  the  organ  retention  of  an  inhaled sparingly soluble
 metallic  compound  assuming a single  acute exposure demonstrating the trans-
 location  from  lung and  build-up  and  clearance  from other organs (from Boecker
 and Cuddihy, 1974).
                                      11-77

-------
long-term clearance to characterize.   However,  intermediate and potentially
toxic products may be formed.   These  products  may have residence times that
are long enough to demonstrate an elevation of  the sulfur content of the lung.
Potentially detrimental  reactions are most likely to be of biological concern
when they occur in the pulmonary and  bronchial  regions of the lung.
     Desorption from the upper respiratory tract may be expected whenever the
partial pressure of SO- on mucosal  surfaces exceeds that of the air flowing
by.  Desorption of SO- from mucosal  surfaces was still evident after 30 minutes
of flushing with ambient air the airways of dogs which had breathed 2.62 mg/m
(1.0 ppm) for 5 min. (Frank et al.,  1969).   Frank et al.  (1967) reported S02
in the  lungs  of dogs that apparently was carried by the blood after nasal
deposition.   In human subjects breathing 42.2 mg/m  (16.1 ppm) through a mask
for  30  minutes, 12% of the SO- taken up by the tissues in inspiration reentered
the  air stream in expiration and another 3% was desorbed during the first 15
minutes  after the end of SO- exposure (Speizer and Frank, 1966).  Thus, during
expiration, SO- was desorbed from the nasal mucosa in quantities totaling
approximately 15% of the original inspired concentration.
     The effects of SO- on tracheobronchial clearance in 9 healthy, nonsmoking
adults  was studied by Wolff et al.  (1975).   Technetium Tc 99m albumin aerosol
(3 |jm MMAD, o  = 1.6) was inhaled as a bolus under controlled conditions.  A
three hour exposure to 13.1 mg S02/m  (5.0 ppm) had no significant effect on
mucociliary clearance in resting subjects, except for a small transient  increase
(p < 0.05) after 1 hour.  A significant decrease in nasal mucus flow  rates
during a six hour exposure of 15 young men to 13.1 mg S0-/m3  (5.0 ppm) and
65.5 mg S02/m  (25.0 ppm), but not 2.62 mg S0-/m3 (1.0 ppm), was observed by
Andersen et al.  (1974).   Decreases were greatest in the anterior nose and  in
                                     11-78

-------
subjects with  initially slow mucus flow rates.  Newhouse et al. (1978)



assessed the effect of oral exposure to SCL on bronchial clearance of a radio-



active aerosol (3 urn MMAD) in healthy nonsmoking males and females who exer-



cised periodically during exposure at an exertion level sufficient to keep the



heart rate at 70% - 75% of the predicted maximum.  After a 2 hour exposure to



13.1 mg SOp/m  (5.0 ppm), clearance was increased.



11.3.3  Particles and SO- Mixtures



     The presence of adsorbed SO- or other sulfur compounds on aerosol sur-



faces may alter the clearance processes of both.   Chemical  reactions involving



sulfur compounds on particle surfaces may enhance the apparent solubility  of



the aerosol particles.  These aerosol particles may also undergo reaction  with



sulfite or other species upon contact with body fluids.



     The formation of sulfate anions by oxidation of SO- to SO, may be



catalyzed by manganese, iron, or other aerosol components.   The S03 reacts



immediately with water to form sulfuric acid that can react with other mate-



rials, such as metal oxides on fly ash aerosols,  to produce sulfate compounds.



Since sulfate is a normal constituent of body fluids (Kanapilly, 1977),  the



clearance of sulfate anions probably involves simple dissolution and



diffusional dilution into body fluids.



11.4  DISCUSSION AND SUMMARY



     When aerosols or S0? are inhaled by man or experimental animals, different



fractions of the inhaled materials deposit by a variety of mechanisms in



various locations in the respiratory tract.  Particle size distribution,



particle chemical properties, S02 diffusivity, respiratory tract anatomy,  and



airflow patterns all influence the deposition.  The predicted regional
                                     11-79

-------
deposition percentages for man given by the Task Group on Lung Dynamics are in



reasonable agreement with available experimental measurements and provide



useful  general  guidelines for estimating particle deposition for environmental



assessment.   Nose breathing and mouth breathing provide somewhat contrasting



deposition patterns.   During nose breathing nearly all particles larger than 8



urn in aerodynamic diameter are usually collected in the nasopharyngeal region,



while this natural filtration can be circumvented during mouth breathing so



that some particles as large as 15 urn aerodynamic diameter may enter the



tracheobronchial region.   After deposition, the inhaled material will be



translocated by processes that depend on the character of the particles and



their site of deposition.  If the material is quite soluble in body fluids, it



will readily enter the bloodstream.  Relatively insoluble material that lands



on  ciliated epithelium,  either in the nasopharyngeal region or tracheobronchial



airways,  will be translocated with mucus flow to the throat and will be



swallowed or expectorated.  Depending on particle size, relatively insoluble



material  that deposits on nonciliated surfaces  in the pulmonary region may  be



phagocytized, may enter  the interstitium and remain in the  lung for an extended



period,  or may  be translocated by lymphatic drainage.  Some material  from  the



pulmonary region may  enter the TB region and be cleared by  the mucociliary



conveyor.




     Both deposition  and retention play roles in determining  the  effects of



inhaled  particulate toxicants and SO-.  Everyone is environmentally  exposed to



a variety of dusts, fumes, sprays, mists,  smoke, photochemical  particles,  and



combustion aerosols,  as well as SCL and other potentially  toxic  gases.   The



particle  size distribution and chemical and physical  composition  of  airborne



particulate material  require special attention  in  toxicological  evaluations
                                     11-80

-------
since a wide variety of physicochemical properties may be encountered in both



experimental and ambient inhalation exposures.   Sulfur dioxide may deposit



directly in the airways or enter into a variety of gas-to-particle conversions



or gas-particle chemical and physical reactions.  SO- must be considered with



aerosol  behavior in the atmosphere and during inhalation deposition, as well



as in relation to respiratory responses.



     The three functional regions (NP, TB, and P) of the respiratory airways



can each be characterized by major mechanisms of deposition and clearance



(Table 11-1).   Besides being a target of inhaled particles and gases, the



respiratory tract is also the portal of entry by which other organs may be



affected.   An understanding of the mechanisms and patterns of translocation to



other organ systems is required for evaluation of the potential for injury or



response in those organs.
                                      11-81

-------
      TABLE 11-1.   SUMMARY OF THE RESPIRATORY DEPOSITION  AND  CLEARANCE
                OF INHALED AEROSOLS (FROM RAABE,  1979)
    REGION                     DEPOSITION                   CLEARANCE


                               IMPACTION                    MUCOCILIARY
      NP                       DIFFUSION                    SNEEZING
NASOPHARYNGEAL                 INTERCEPTION                 BLOWING
                               ATTRACTION                   DISSOLUTION
                               IMPACTION                    MUCOCILIARY
                               DIFFUSION                    COUGHING
      TB                       SETTLING                     DISSOLUTION
TRACHEOBRONCHIAL               INTERCEPTION
                               ATTRACTION
                               DIFFUSION                    DISSOLUTION
      P                        SETTLING                     PHAGOCYTOSIS
PULMONARY                      ATTRACTION                   LYMPH FLOW
                               INTERCEPTION
                                  11-82

-------
11.     RESPIRABLE AEROSOL SAMPLING
    A fundamental principle in inhalation toxicology is  that  it  is  the  deposi-
tion of inhaled particulate materials in sensitive regions of the  respiratory
tract or subsequent transformations and translocations to  sensitive organs  or
cells that leads to potentially deleterious biological responses.   Particles
(or gases) that deposit neither in sensitive regions of  the airways nor in
regions conducive to translocation to sensitive organs are cleared  with rela-
tively low probability of causing injury or disease (Morrow,  1964-).  For
example, large insoluble particles that deposit almost exclusively  in the nose
are prevented from reaching the lung during nose breathing and are  less likely
to lead to injury than smaller particles having appreciable lung deposition.
    This principle was early observed in coal  mining in  Europe; it  was  found
that the air concentration of dust in mines didn't necessarily correlate to
the incidence of respiratory disease.  However, a meaningful  comparison was
possible when samples were aerodynamically fractionated  to provide  a separate
measure of the respirable dust levels.  This led to the  use of "respirable"
dust samples in the coal mining industry (Walton, 1954).   Further,  the
repeated practice of collecting respirable dust samples  is necessary, since
there is variability in the aerodynamic size distribution  of  dust depending on
age and source.
    On this basis the principle of "respirable" dust sampling was developed
(Lippmann, 1970b).  In this context the word "respirable"  means broadly "fit
to be breathed."  The objective is to collect samples that have been purposely
biased in favor of the smaller, more respirable sizes.   Only  the smaller size
fraction is measured to yield the "respirable" aerosol concentration.   No
specific "cut-size" was defined, since it is clear that  there is no size for
                                  ll-82a

-------
which all particles smaller are respirable and all  larger are not.   Instead,
weighting functions were defined that simulated the size  classification
normally afforded by the human naso-pharyngeal deposition during  nose
breathing.  Another factor involved in describing a respirable fraction  was
the availability of a simple instrument that would provide a  practical means
for collection of these size-classified samples.
    Two weighting functions have been generally used as criteria  for respir-
                        
-------
           o.
           w
           c
           111
          o_
                                   BMRC curve
                                   LASL curve
               0     2     4     6     8    10
                    Diom unit density sphere —


                      FIGURED  /H9

Respirable aerosol  sampling criteria for penetration of
repirable aerosols  through a size-classifier to provide for
collection of particles that have the greatest potential for
pulmonary deposition if inhaled (from Raabe,1979).
                          ll-82c

-------
efficiently deposited in the pulmonary region during mouth breathing  (Fig. &
                                fl-3
than during nose breathing (Fig.^-) are weighted more than would be justified
by the ICRP Task Group nose breathing models.
    It is important to note that the "respirable" dust sample is thus  not
intended to be a measure of the lung deposition but only a measure of  aerosol
concentration for particles that are the primary candidates for lung deposi-
tion.  Clearly, the respirable dust sample is only biologically relevant  for
aerosols whose upper respiratory deposition is not expected to be of major
health impact.  Soluble aerosols of toxic substances can enter the blood
directly from the nasal mucosa or the gastrointestinal tract during clearance
from the nose, and the deposition of particles as large as 100 ym or even
larger in the nose may be the .primary hazard for such aerosols.
                                   ll-82d

-------
11.5  REFERENCES

Adams, R. , L. Davenport.  The  technique  of  bronchography  and  a  system  of
     bronchial nomenclature.   JAMA  _118:111,  1942.

Adler, K. B.  , 0.  Wooten, and M. J.  Dulfano.   Mammalian  Respiratory Mucociliary
     Clearance.   Arch.  Environ. Health.  22:364-369.  1973.

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

Ahronson, 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. Physio!. £7:654, 1974.

Alavi, S. M.  , T. E. Keats, W.  M.  O'Brien.   The angle of tracheal  bifurcation:
     its normal mensuration.   Am.  J.  Roentgenol.  108:547,  1970.

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.

Albert,  R. E., M.  Lippmann, H. T.  Peterson, J.  Berger,  K.  Sanborn, and D.
     Bohning.  Bronchial deposition and  clearance of aerosols.   Arch.  Intern.
     Med.  131:115,  1973.

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.   I_n:   Inhaled Particles and  Vapours II.  C. N.  Davies,  ed.,  Pergamon
     Press,  Oxford, 1967b.  p  361.

Albert,  R. ,  M. Lippmann, J. Spiegelman,  A.  Liuzzi, and  N.  Nelson.   The deposition
     and clearance  of radioactive particles in the human  lung.   Arch.  Environ.
     Health  14:10,  1967a.

Aldas, J.  S., M. Dolovich,  R.  Chalmers,  and M. T. Newhouse.   Regional  aerosol
     clearance in  smokers and  nonsmokers.  Chest 5_9:25, 1971.

Allison, A.  C., J.  S. Harington,  M. Birbeck, and T.  Nash.   Observations on the
     cytotoxic action of  silica  on macrophages.  J_n:   Inhaled Particles and
     Vapours II.   C.  N. Davies,  ed. ,  Pergamon Press, 1967.  p 121.

Altshuler, B.  Calculation  of  regional deposition in the  respiratory tract.
     Bull.' Math. Biophys. 21:257, 1959.

Altshuler, B.  The  role of  the mixing of intrapulmonary gas  flow in the
     deposition of  aerosols.   I_n:  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 respiratory  tract.  I_n:   Inhaled  Particles and  Vapours II.  C.
     N.  Davies, ed. ,  Pergamon  Press.  1967.   p. 323.
                                    11-83

-------
AHshuler, B. ,  E.  D.  Palmes, L.  Yarmus, and N.  Nelson.  Intrapulmonary mixing
     of gases studied with aerosols.   J.  Appl.  Physiol.  14:321, 1959.

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

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

Anderson, 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.  1.4:243, 1971.

Barclay,  A. E., and K. J. Franklin.  The rate of excretion  of Indian ink
     injected into the lungs.  J. Physiol.  90:482-484, 1937.

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.

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

Barton,  A. D., and R. V.  Lourenco.  Bronchial  secretions and mucociliary
     clearance.   Biochemical charactersitics.   Arch.  Intern. Med. 131:140-144,
     1973.

Batchelor, G. K.  (Symmetrical contraction on isotropic turbulence),  p.  74.   In
     The  Theory of Homogeneous Turbulence.   London:   Cambridge University
     Press, 1953.

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

Bell, K.  A.  Local particle deposition in respiratory airway  models,  pp.
     97-134 (Chap.  6).  In:   Recent Development in Aerosol  Science.   D.  T
     Shaw, ed.,  John Wiley and Sons,  New York,  1978.

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

Berg, A., M.  E.  A.  Boyden, and F. R.  Smith.  An analysis  of the  segmental
     bronchi of the left lower lobe of fifty dissected  and ten injected lungs.
     J.  Thor.  Surg. 18:216,  1949.
                                   11-84

-------
Besarab, A., and M.  Litt.  Model studies on the adhesive properties of mucus
     and similar polymer solution.  Arch.  Intern. Med.  L26:504,  1970.

Blank, M., A. B. Goldstein, and B. B.  Lee.  The surface properties of  lung
     extract.  J. Coll. Int. Sci. 29:148,  1969.

Boecker, B. B., and  R. G. Cuddihy.  Toxicity of 144Ce  inhaled  as 144CeCl, by
     the beagle:  Metabolism and Dosimetry  Radiation  Res. 60:133, 1974

Bohm'ng, 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.  The uptake of inhaled gases  by the nose.  Ann. Otol  79-529-539
     1970.                                                          "~

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.

Balchum, 0. J., J.  Dybicki, and G. R.  Meneely.  The  dynamics of  sulfur dioxide
     inhalation.  AMA Archives of Industrial Health  21:84-89,  1960.

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

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

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

Camner,  P., K.  Strandberg,  and K. Philipson.   Increased mucociliary transport
     by  adrenergic stimulation.  Arch. Environ. Health  79: March/April,  1976.

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

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

Camner,  P., P.  Hellstrom, and M.  Lundborg.  Coating  5 mm particles  with  carbon
     arid metals  for  lung clearance studies.  Arch.  Environ. Health  27:331,
     1973a.

Carson,  S., R.  Goldhamer, and R.  Carpenter.  Mucus  transport  in  the respiratory
     tract.  Am. Rev.  Resp. Dis.  93  (suppl.):86-92,  1966.

Chang  H.,  R. C. Tai,  and L. E.  Farhi.  Some  implications  of  ternary diffusion
     in  the  lung.  Respir.  Physiol.  2_3:109-120.  1975.
                                    11-85

-------
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.

Chapman,  M.  A.,  and J. B. Hibbs.  Macrophage tumor  killing:  Influence of  the
     local environment.  Science 1^7:279, 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.

Charman, J., M.  T. Lopez-Vidriero, E. Keal,  and L.  Reid.  The  physical and
     chemical properties of bronchial secretion.  Brit. J.  Dis.  Chest  68:215-227,
     1974.

Charnock, E. L., and  C.  F.  Doershuk.  Developmental aspects  of the  human lung.
     Pediatr. Clin. North Am.  20:275, 1973.

Cheng, Y  S. , and  C.  S.  Wang.   Inertia! 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 pleura! pressure.  Respir.  Physiol.
     18:222, 1973.

Cohen, D., S. F. Arai, and  J.  D. Brain.   Smoking  impairs  long-term  clearance
     from the lung.   Science £04:514, 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.

Crosfill, M. L. , and  J.  G.  Widdicombe.  Physical  characteristics of the  chest
     and  lungs  and the work of breathing  in  different mammalian  species.   J.
     Physiol. 158:1.  1961.

Cuddihy,  R. G.  Analog simulation  of the  biological  behavior of  inhaled
     radionucl ides.   I_n:  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 deposition  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 respiratory  tract.   Am. Rev.  Respir.  Dis.  103:808,  1971.
                                    11-86

-------
Dalhamn, T.  Mucous flow and ciliary activity  in the trachea of healthy cats
     and rats exposed to respiratory irritant  gases (SO-, H,N, HCHO):  A
     functional and morphologic  (light microscopic and electron microscopic)
     study, with special reference to technique.  Acta Physio!.  Scand. 36:Suppl.
     123, 9-161, 1956.                                                 ~~

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

Dalhamn, T. , and L. Strandberg.   Synergism between sulfur dioxide and carbon
     particles.  Studies on adsorption and on  ciliary movements in the rabbit
     trachea j_n vivo.   Int. J. Air Water  Pollut. 7:517, 1963.

D'Angelo, E.  Local alveolar size and transpulmonary pressure j_n situ and in
     isolated lungs.  Resp. Physiol.  14:251,  1972.

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 CL along a model pathway
     through the respiratory region of the lung.  Bull. Math. Biol.  36:275-303,
     1974.                                                           ~~

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

Davies,  C.  N.   A formalized anatomy  of the human respiratory tract.   In:
     Inhaled Particles  and Vapours.   C.  N.  Davies, ed.,  Pergamon Press, Oxford,
     1961.  p.  82.

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

Davies,  C.  N.   Deposition  of  inhaled  particles in  man.   Chemistry  and Industry
     441:    June  1,  1974.

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

Davies,  G., and L.  Reid.   Growth of  the  alveoli and  pulmonary arteries  in
     childhood.  Thorax 23:669,  1970

Davison,  R. L.,  D.  F.  S.  Natusch, and J.  R. Wallace.   Trace elements in fly
     ash.   Environ.  Sci.  Technol. 8:1107, 1974.
                                    11-87

-------
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.  Physio!:   Respirat.  Environ. Exercise Physio!. 46:476,  1979b.

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

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. Physio!:  Respirat. Environ.  Exercise  Physiol
     46:467, 1979a.

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

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. Physio!.  5_:34,  1968.

Dungworth, D. L., L. W. Schwartz, W.  S. Tyler, and  R. F. Phalen.   Morphological
     methods for evaluation of pulmonary  toxicity in animals.   In:   Annual
     Review of  Pharmacology and Toxicology.  H. W.  Elliott, ed. , Annual Reviews,
     Inc. , Palo Alto, 1976.  p. 381.

Dunm'll, 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.

Ecanow,  B., R.  C. Balagot, and V. Santelices.  Possible role  of alveolar
     surfactants in the uptake of inhaled gases.  Nature 215:1400-1402, 1967.

Edmunds, L. H. , P.  D. Graf, S.  S. Sage!,  and R. H.  Greenspan.  Radiographic
     observations of clearance of tantalum and barium  sulfate particles from
     airways.   Invest. Radio!.  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.  3_5:18,  1973.

Evans, J. W., D. G.  Cantor, and J. R. Norman.  The  dead space in a compartmental
     lung model.  Bull.  Math.  Biophys. 29:711, 1967.

Ewert, G.  On the mucus flow rates in the human  nose.   Acta Otolarynq., Suppl.
     200, 1965.
                                    11-88

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

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

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

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 Science 8:251-267, 1977.

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

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.                                                             ~~

Forrest,  J. B.   The effect of changes  in  lung volume on the  size and shape of
     alveoli.  J. Physiol. 210:533, 1970.

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

Frank, N.  R., and R. E. Yaeder.   A  method of making a  flexible cast  of the
     lung.  J. Appl. Physiol. 21:1925.  1966.

Frank, N.  R., M. 0.  Amdur, J. Worcester,  and J.  L. Whittenberger.  Effects of
     acute controlled  exposure  to S0?  on  respiratory mechanics in  healthy male
     adults.  J. Appl.  Physiol. 17:252-258,  1962.

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

Frank, N.  R., R. E.  Yoder, E. Yokoyama, and  F.  E.  Speizer.   The  diffusion of
     S09  from tissue fluids  into  the lungs  following  exposure  of  dogs  to  SO--
     Health  Physics 13:31-38,  1967

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.  6.
     Saunders Co.,  Philadelphia,  1971.

Fn'berg.  L., and B.  Holma.   External measurement of  lung clearance.   Arch.
     Environ. Health 3:56, 1961.
                                    11-89

-------
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, G. Maltoni,  C. Melandri, V. Prodi, and G. Tarroni.  Deposition
     efficiency of monodisperse particles  in human respiratory tract.   Am.
     Ind. Hy. Assoc.  J.  33:603, 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.

Glazier,  J. B., J. M. B. Hughes, J. E. Maloney, and J. B. West.  Vertical
     gradient of alveolar size  in  lungs of dogs frozen intact.  J.  Appl.
      Physio!.  21:416, 1966.

Glazier,  J.  B., J. M. Hughes, J. E. Maloney, and J. B. West.  Vertical  gradient
      of  alveolar size  in lungs  of  dogs  frozen intact.  J. Appl. Physio!.
      23:694,  1967.

Goetz,  A.   On the  nature of the  synergistic action of aerosols.   Inter. J.  Air
      Pollution 3:78, 1960.

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.  A5_2:163,  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.  Alveolobronchiolar Transport Mechanisms.   Arch  Intern   Med.
     131:109, 1973.
                                    11-90

-------
Green, G. M.  In defense of  the  lung.  Am.  Lung  Assoc.  Bull. £0:4,  1974.

Green, J. F.  The pulmonary  circulation.   In:  The  Peripheral  Circulations.
     R. Zelis, ed. , Grune and  Straton, New York,  1975.   p.  9.

Gross, P., and M. Westrick.  The  Permeability  of Lung  Parenchyma  to Particulate
     Matter.  Am. J. of Pathol.  30:195-213,  1954.

Gross, P., E. A. Pfitzer, and  T.  F.  Hatch.   Alveolar clearance:   Its  relation
     to lesions of  the respiratory  bronchiole.   Am. Rev.  Resp.  Dis.  94:10.
     1966.                                                          —

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.   Analysis of respiratory patterns  in  laboratory  animals.  Am.  J.
     Physio!. 150:78, 1947b.

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

Hahn,  F.  F.,  G.  J.  Newton, and P. L.  Bryant.   In vitro phagocytosis of  respirable-
     sized monodisperse particles by alveolar  macrophages.   I_n:   Pulmonary
     Macrophage  and Epithelial Cells.  CONF-760927.  U.S.  Department  of Commerce,
     Springfield, VA, 1977.  pp.  424-435.

Hamilton, R.  J.,  and W. H. Walton.   The  selective sampling of  respirable  dust.
     _In:  Inhaled Particles  and Vapours.   C. N.  Davies, ed.,  Pergamon Press,
     Oxford,  1961.   p. 465.

Hansen,  J.  E.,  and  E. P. Ampaya.  Human  air space,  shapes, sizes, areas,  and
     volumes.   J. Appl. Physiol.  38:990,  1975.

Hansen,  J.  E.,  and  E. P. Ampaya.   Lung morphometry:   a fallacy in the use o*
     the  counting principle.   J.  Appl.  Physiol.  37:951, 1974.

Hansen,  J.  E.,  E. P. Ampaya, G.  H.  Bryant, and J. J.  Navin.   Branching  pattern
     of  airways and air spaces of a single human terminal bronchiole.  J.
     Appl.  Physiol.  38:983,  1975.

Harris,  R.  L.,  and  D. A. Fraser.  A model  for  deposition of fibers in the
     humans  respiratory system.   Amer.  Indus.  Hyg.  Assoc. J.  3_7:73, 1976.

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

Heyder,  J. ,  J.  Gebhart, and  W. Stahlhofen.  Inhalation of Aerosols.
     Particle Deposition and Retention,   pp. 65-103.    in Generation  of
     Aerosols and Facilities for Exposure Experiments, ed. by K.  Willeke,
     Ann. Arbor Science, Ann Arbor, Michigan,  1980.
                                    11-91

-------
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 §3:261, 1975.

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.,  and J. Gebhart.   Gravitational deposition of particles from laminar
     aerosol flow through inclined circular tubes.  J. Aerosol Sci. 6:289,
     1977.

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.

Hinshaw,  H.  C.  Diseases of the Chest, 3rd Ed., W. B. Saunders Co., Philadelphia
     1969.

Hirschfelder, J.  0.,  C.  F. Curtis, and R. B. Bird.  Molecular theory of gases
     and  liquids, John Wiley and Sons, New York, p. 718, 1954.

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. and Applied 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.

Horsfield, K.  Analysis and Modeling of Branching  Systems.  Dissertation.
     University of Birmingham.  Department of Medicine, England,  1972.

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. Cumming.  Morphology of the  bronchial tree  in  man.
     J. Appl.  Physio!. 24:373, 1968.

Horsfield, K. , G.  Dart, D.  Olson,  G. Filley, and G.  Cumming.   Models  of  the
     human bronchial tree.   J. Appl. Physiol. 31:207,  1971.

Hounam, R. F.   The deposition  of atmospheric condensation  nuclei  in  the
     nasopharyngeal  region of  the  human respiratory  tract.  Health Physics
     20:219,  1971.
                                   11-92

-------
Hounam, R. F., A. Black, and M. Walsh.  The deposition of aerosol particles in
     the nasopharyngeal 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 nasopharyngeal region of the human respiratory tract.  In:  Inhaled
     Particles III.  W. H. Walton,  ed., Unwin Brothers Limited, Surrey England,
     1971b.   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.

Hurst, D. J.,  K. H.  Kilburn, and W. S.  Lynn.  Isolation and  surface activity
     of soluble alveolar components.  Respir. Physiol. 17:72-80,  1973.

Jacobi, J. W.  Particle loss in sampling  conduits.  _In:  Assessment of Airborne
     Radioactivity.   International  Atomic Energy Agency, Vienna,  1967.  p.
     701.

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

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

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.

Kanapilly, G.  M.,  0. G. Raabe, and  H. A.  Boyd.  A method for determining  the
     dissolution characteristics of accidentally released radioactive aerosols.
     In:  Proceedings  of the Third  International Congress of the  International
     "Radiation Protection Association.  U.S.  Atomic Energy Commission, Oak
     Ridge,  TN, 1974.  p. 1237.

Kanapilly, G.  M.,  0.  G. Raabe, C. H.  T. Goh,  and R. A. Chimenti.   Measurement
     of j_n vitro dissolution of aerosol particles  for comparison  to  i_n vivo
     dislolution in  the lower  respiratory tract after inhalation.  Health
     Phys. 24:497,  1973.

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.

Kilburn,  K.  H. Cilia and mucus  transport  as  determinants  of  the response  of
     the  lung to air pollutants.  Arch.  Environ.  Health.  14:77-91, 1967.

Kliment,  V.   Similarity and  dimensional analysis,  evaluation of aerosol  deposi-
     tion  in the lungs of  laboratory  animals  and  man.  Folia Morphologies
     21:59,  1973.
                                    11-93

-------
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.    Particle removel   by the respiratory  system.   Bull. Math.  Biophys.
     25:29, 1963.

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

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

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.

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.

Laurenzi, G.  A., S.  Yin,  and J.  J.  Guarneri.   Adverse  effect of  oxygen on
     tracheal mucus  flow.   New Eng. J. Med. 279:333-339, 1968.

Laurenzi, G.  A., S.  Yin,  B. Collins, and  J. J. Guarneri.   Mucus  flow in the
     mammalian  trachea.   U.S.   Public Health Service Pub. No.  1787.  10th Aspen
     Emphysema  Conf.  pp.  27-40, 1967.

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

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  (UOp)  dust  - I.   Retention  and biological effect  in  the
     monkey dog and  rat.  Health Phys. 18:599,  1970.
                                    11-94

-------
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.

Liebow, A.  A., M. R. Hales, E. L.  Gustaf, and W. E. Bloomer.  Plastic
     demonstrations of pulmonary pathology.  Bull  Int  Assoc  Med. Mus
     27:116, 1947.

Lippman, M.   Regional Deposition of Particles in the Human Respiratory Tract,
     pp. 213-232 in 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.

Lippman, 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.  "Respirable" dust sampling.  Amer. Ind. Hyg. Assoc. J. 31:138,
     1970b.                                                           ~~

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

Lippmann, M., and W. B. Harris.  Size  Selective Samplers for Estimating
     Respirable Dust Concentration.  Health Phys.  8:155,  1962.

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.

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., M. F. Klimek,  and C.  J.  Borowski.   Deposition and  clearance
     of  2 m particles  in  the  tracheobronchial tree of  normal  subjects  -  smokers
     and nonsmokers.   J.  Clin.  Invest. 50:1411, 1971.

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

Machlin, C.  C.  The alveoli  of  the mammalian  lung:  an anatomical study with
     clinical correlations.   Proc.  Inst.  Med.  18:78,  1950.
                                    11-95

-------
Marin, M.  G.,  and P.  E.  Morrow.   Effect of changing inspired 0- and CO- lev*
     on trachea! mucociliary transport rate.   J. Appl. Physiol. 27:385-388,
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. 23:23-29, 1972.

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.  I_n:   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 SO-.  W.  I. Med.  J. 19:231-235,
     1970.

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

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

Metzger,  G.  Some Environmental Factors Influencing the I_n  Vitro Phagocytosis
     of  Inert Test  Particles.   Doctoral Dissertation.  University of  Rochester.
     Biophysics,  Rochester, NY, 1968.

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,  A.,  J.  C. Evans,  and  A. Holmes.  "Deposition  and clearance  of inhaled
     fibrous minerals  in  the  rat:  Studies using radioactive tracer techniques."
     pp.  259-274  in  INHALED PARTICLES IV,  (W. H. Walton, Ed.) Pergamon Press,
     1977.

Morrow,  P.  E.   Alveolar Clearance  of Aerosols.  Arch.  Intern. Med.  131:101,
     1973.                                                          	

Morrow,  P.  E.   Evaluation of  inhalation hazards based upon the respirable dust
     concept and  the philosophy and application of  selective sampling.  Am.
     Ind. Hyg.  Assoc.  J.  25:213, 1964a.

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.   Theoretical and experimental models  for dust deposition  and
     retention  in man.  Rev.  Environ. Health  1:186,  1974.

                                   11-96

-------
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 participate 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,  Jji:   Inhaled
     Particles and Vapours.   S.  C.  N. Davies, ed. , Oxford, Pergamon Press,
     1967b.   p. 351.

Morrow, P. E., F. R. Gibb, and  L. Johnson.   Clearance of insoluble  dust from
     the  lower respiratory tract.   Health  Phys.  10:543, 1964b.

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

Muggenburg,  B. A.,  S. A.  Felicetti, and S. A. Silbaugh.  Removal of inhaled
     radioactive  particles by lung  lavage  -  A review.  Health Phys. 33:213,
     1977.                                                          ~~

Muir,  D.  C.   Clinical Aspects of Inhaled Particles.  William Heinemann Medical
     Books,  London, 1972.

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.

Nadel, J. A., M.  Corn, S.  Zwi,  and  G. P. Flesch.  Location and mechanism  of
     airway  constriction after  inhalation  of histamine aerosol and  inorganic
     sulfate aerosol.  Ir\:   Inhaled Particles and Vapours  II.  C. N. Davies,
     ed., Pergamon  Press,  Oxford, 1967.  p.  55.

Nagashi,  C.   Functional  Anatomy and Histology of the Lung.  University  Park
     Press,  Baltimore, MD, 1972.

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, Ozone and Other  Photochemical Oxidants,  Committee
     on Medical  and Biologic  Effects of Environmental  Pollutants,  National
     Academy of  Sciences,  Washington, D.C.,  1977, pp.  719.

Natusch,  D.  F. S.   "Potentially carcinogenic species emitted  to  the atmosphere
     by fossil-fueled power  plants." Environ.  Health Perspectives. 22:79,
     1978.

Natusch,  D.  F. S.,  J. R.  Wallace, and C. A.  Evans,  Jr.   Toxic trace elements:
     preferential concentration in  respirable particles.   Science 183:202,
     1974.
                                    11-97

-------
Newhouse, M.  T.,  M.  Dolovich, G. Obminski, and R. K. Wolff.  Effect of TLV
     levels of SCL and H2SO. on bronchial clearance in exercising man.  Arch.
     Environ.  Health 33:24-32, 1978.

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.

Owen, P. R.  Turbulent flow and particle deposition in the trachea, pp. 236-252.
     In G. E.  W.  Wolstenholme and J. Knight, Eds. Circulatory  and Respiratory
     Mass Transport.  A CIBA Foundation Symposium.  Boston:  Little,  Brown  and
     Co., 1969.

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. Physio!.  35:401,  1973.

Paiva,  M., and I. Paiva-Veretennicoff.  Stochastic  simulation  of the  gas
     diffusion in the air phase of  the  human lung.  Bull. Math.  Biophys.
     34:457, 1972.

Palmes,  E. D.  Measurement of pulmonary air spaces  using  aerosols.  Arch.
      Intern. Med. 131:76, 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.

Palmes,  E. D., B. Altshuller, and N. Nelson.   Deposition  of  aerosols  in the
      human  respiratory tract  during breath holding.  In:   Inhaled  Particles
      and Vapours  II.  C.  N.  Davies,  ed.,  Pergamon  Press,  Oxford, 1967.   p.
      339.

Palmes,  E., C. Wang,  R. Goldring, and  B.  Altshuller.  Effect of depth of
      inhalation  on  aerosol persistence  during  breath holding   J.  Appl   Physicl.
      34:356, 1973.

Parker,  M., K. Horsefield, and  G. Gumming.  Morphology  of distal airways  in
      the human lung.  J.  Appl.  Physio!.  31:386,  1971.

Pattle,  R. E.  Surface lining of lung  alveoli.   Physiological  Reviews 45-48-78,
      1965.                                                             —

Pattle,  R. E.  The  lining complex of the  lung  alveoli.   I_n:   Inhaled Particles
     and Vapours.   C. N.  Davies, ed.,  Pergamon Press, Oxford,  1961b.   p.  70.

Pattle,  R. E.  The  retention  of gases  and particles in  the human nose.   I_n:
     Inhaled Particles and Vapours.  C.  N. Davies,  ed. ,  Pergamon Press, Oxford,
     1961a.  p.  302
                                    11-98

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

Pavia, M.  Gas transport in the human  lung.  J. ADD. Physiol. 35:401-410,
     1973.                                    "          	  ~

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 combus-
     tion by-products.  J. Microscopy  310:87, 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.~6~5, 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.

Phalen, R. F., and 0. G. Raabe.  Aerosol particle size  as a factor in pulmonary
     toxicity.  Proc. 5th Conf. on Environ.  Tox.  AMRL-TR-74-125.  Aerospace
     Medical  Research Laboratory, Wright-Patterson Air  Force Base, Ohio, 1974.

Phalen, R. F., H. C. Yeh, and D. J. Velasquez.   Bronchial tree structure in
     the human, beagle, rat, and hamster, pp. 289-292.   In 1973-1974  Annual
     Report  of the Inhalation Toxicology Research Institute.  LF-49.
     Albuquerque, N.M.:  Lovelace Foundation for Medical Education and Research,
     1974.

Phalen, R. F., H. C. Yeh, 0. G. Raabe, and  D. J. Velasquez.  Casting  the lungs
     in situ.  Anat. Rec. 177:255, 1973.

Proctor, D.  F., and  D.  Swift.   The nose  - A defence  against  the  atmospheric
     environment.  Inhaled Particles  III.   V.   1 W.  H.  Walton,  ed.,  Unwin
     Brothers.  Limited.  Surrey, England,  1971.  p.  59.

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

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  H.  N. Wagner.  Mucociliary clearance in  the human nose.
     In:   Inhaled Particles  and Vapours  II.   C.  N.  Davies,  ed.,  Pergamon
     T>ress,  Oxford,  1967.  p. 25.

Proctor, D.  F., I. Andersen, and  G.  Lundquist.   Clearance of inhaled particles
     from  the human  nose.  Arch.  Intern. Med.  131:132,  1973.
                                    11-99

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

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

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.   Generation and characterization of aerosols.  Inhalation
     Carcinogenesis.  M. G. Hanna, Jr., P. Nettesheim, and J.  R. Gilbert,
     eds., CONF-691001.  U.S. Atomic Energy Commission.  Division of Technical
     Information, 1970.  pp. 123-172.

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

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

Raabe, 0.  G., and H. C. Yeh.  Principles for  inhalation exposure systems  using
     concurrent  flow spirometry.  J. Aerosol  Sci. 7:233, 1976a.

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

Raabe, 0.  G., G. J. Newton, C. J. Wilkinson,  and S. V. Teague.  Plutonium
     aerosol characterization inside safety enclosures at a demonstration
     mixed-oxide fuel  fabrication facility.    Health Phys. 3_5:649, 1978b.

Raabe, 0.  G.  , H. A. Boyd, G. M.  Kanapilly, C. J. Wilkinson, and G. J. Newton.
     Development at^guse of a system for the  routine production of monodisperse
     particles of    PuCL and evaluation of gamma emitting  labels.   Health
     Phys. 28:655,  1975.

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 YoTk,  1977.
     p. 3.

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

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,  1978a.
                                   11-100

-------
Ramsden, D., M. E. D. Bains, and D. C. Fraser.  In vivo and bioassay results
     from two contrasting cases of plutonium-239~Tnhalation.  Health Phys.
     19:9, 1970.

Ryan, S. F.  The structure of the primary  lobe  lobule.  Ann. Clln. Lab Sci.
     3:147, 1973.

Sanchis, J. , M. DoTovich, R. Chalmers, and M. Newhouse.  Quantitation of
     regional aerosol clearance in the normal human  lung.  J. Appl. Physio!.
     33:757, 1972.

         C. L. , and  R. R. Adee.  Phagocytosis of  inhaled plutonium oxide  -
        Pu particles by pulmonary macrophages.  Science 162:918,  1968.

Santa Cruz, R. , J. Landa, J. Hirsch,  and M.  Sackner.  Tracheal mucus velocity
     in normal man and patients with  obstructive  lung disease; effects of
     terbutaline.  Am. Rev.  Resp. Dis.  109:458,  1974.

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.

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.

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

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

Schlesinger, R. B.,  D. E. Bohning, T. L. Chan,  and  M.  Lippmann.   Particle
     deposition in a hollow  cast of the human tracheobronchial  tree.   J.
     Aerosol Sci.  8:429, 1977.

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

Schreider,  J.  P.   Lung anatomy and characteristics  of  aerosol  retention  of the
     guinea pig.   Ph.D. Thesis, University of Chicago,  1977.

Schreider,  J.  P.,  and 0. G.  Raabe.  Morphology  of pulmonary acinus.   Submitted
     to Anatomical Record,  1980.

Schroter,  R. C., and M. F.  Sudlow.   Flow patterns in models of the human
     bronchial airways.  Respir. Physiol.  7:341,  1969.
                                    11-101

-------
Scrimshire, D.  A., P.  J.  Tomlin, and R.  A.  Ethridge.   Computer simulation of
     gas exchange in human lungs.   J.  Appl.  Physio!.  34:687, 1973.

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.

Silverman,  L., and C.  E.  Billings.  Pattern of airflow in the respiratory
     tract,  lr\:   Inhaled Particles and Vapours.  C.  N. Davies, ed. , Pergamon
     Press, Oxford, 1961.  p. 9.

Slonim, N.  B., and L.  H.  Hamilton.  Respiratory Physiology, 2nd Ed., The C. V.
     Mosby Co., St. Louis, 1971.

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 SO- by the human
     nose.    Arch. Environ. Health. 12:725-728,  1966.

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

Stober, W. ,  H. J. Einbrodt,  and W. Klosterkolter.  Quantitative studies  of
     dust  retention in animal and human lungs after chronic inhalation,  _In:
     Inhaled Particles and Vapours II.  C.  N. Davies,  ed. ,  Pergamon Press,
     Oxford, 1967.  p. 409.

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

Strandberg,  L. G.  SO, absorption in the respiratory  tract.   Arch. Environ.
     Health  9:160-1667 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.   In:   Inhaled Particles
     and Vapours  II.  C. N.  Davies, ed., Pergamon  Press, Oxford,  1967.   p.
     141.

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

Taulbee, D.  B., and C. P. Yu.   Simultaneous diffusion and  sedimentation of
     aerosols  in  channel flows.   J. Aerosol  Sci.  6:433,  1975b.

Taulbee, D., C. Yu, and J. Heyder.  Aerosol  transport in the  human lung from
     analysis  of  single breaths.  J. Appl.  Physiol.  44:803, 1978.
                                    11-102

-------
Taylor, G. I.  Dispersion of soluble matter in solvent flowing through a
     pipe.  Proc. Roy. Soc. , London, Ser. A. £19:186-203. 1953.

Taylor, G. I.  The dispersion of matter  in turbulent flow through a pipe.
     Proc. Roy. Soc. London, Ser. A. 223:446-468, 1954.

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

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

Thomas, J. W.  Particle  loss in sampling conduits.   I_n:  Assessment of Airborne
     Radioactivity.  International  Atomic Energy  Agency, Vienna, 1967.  p.
     701.

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

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

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

Tompsett,  D.  H.  Anatomical  Techniques.   E. and S.  Livingstone,  Ediburgh  and
     London,  UK, 1970.

Toor, H.  L.   Diffusion  in three-component gas  mixtures AlCh J. 3:198-207,
     1957.

Ulmer, W.  T.   Reaction of the  lungs to various broncho-irritating  substances.
     In:   Inhaled Particles  and Vapours  II.   C. N.  Davies,  ed.,  Pergamon
     Fress,  1967.  p. 87.

Van As, A.,  and  I. Webster.  The morphology of mucus in  mammalian  pulmonary
     airways.  Environ.  Res. 7:1, 1974.

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.  25J7:400, 1953.

Von Hayek, H.  The Human Lung.   Hafner  Publishing Co.  Inc., New York, 1960.
                                    11-103

-------
Waligora, S. J., Jr.  Pulmonary retention of zirconium oxide  (  Nb)  in man and
     beagle dogs.  Health Phys. 20:89, 1971.

Walkenhorst, W.  Untersuchungen an einem nach teilchengrossen geordneten
     mischstaub  im atembarden  korngrossenboreich.   In:   Inhaled Particles  and
     Vapours II.  C. N. Davies, ed., Pergamon Press, Oxford,  1967.   p. 563.

Walton, W.  H.  Theory of size  classification of  airborne dust clouds by
     elutriation.  Brit. J. Appl. Phys.  Suppl.  3:529, 1954.

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

Wanner, A., J. A. Hirsch, D. E. Greeneltch, E. W. Swenson, and T.  Fore.
     Tracheal  mucous velocity  in beagles after chronic exposure to cigarette
     smoke.  Arch.  Environ. Health. 27:370-371,  1973.

Washburn,  E. W., Ed.  National  Research Council  of  the U.S.A. International
     Critical  Tables of Numerical Data, Physics, Chemistry and Technology.
     Vol.3.   New York:  McGraw-Hill,  1928.  444pp.

Weibel,  E.  R.  Morphometric estimation of pulmonary diffusion capacity.   Resp.
     Physio!.  14:26, 1972.

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

Weibel,  E.  R., and  H. Elias.   Introduction  to  stereologic principles.   In:
     Quantitative Methods  in Morphology.  E. R.  Weibel,  and  H. Elias, eds.,
     Springer-Verlag, Berlin,  1967.  p. 89.

West, J.  B.  Observations  on gas flow  in the human  bronchial  tree.  In:
     Inhaled Particles  and Vapours.  C. N.  Davies,  ed. ,  Pergamon  Press,  Oxford,
     1961.  p. 3.

West, J.  B.  Observations  on gas flow  in the human  bronchial  tree, pp.  3-7.
     In  C.  N.  Davies, Ed.  Inhaled Particles and  Vapours.  Proceedings of an
     International  Symposium organized by the  British  Occupational Hygiene
     Society,  1960.  New York:  Pergamon Press,  1961.

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

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

Whimster, W. F.  The microanatomy of the alveolar duct system.   Thorax 25:141,
     1970.                                                              —

Whitby, K.  T.  The physical characteristics of  sulfur  aerosols    Atmos.  Environ
     12:135, 1978.
                                    11-104

-------
      Additional References Recommended for Consideration in Chapter 11

Bar-Ziv, J., and G. M. Goldberg.  Simple Siliceous pneumoconiosis  in Negev
     Bedouins.  Arch. Environ. Health 29:121-126, 1974.

Brambilla, C., J. Abraham, E.  Brambilla, K. Benirschke, and C. Bloor.  Comparative
     pathology of silicate pneumoconiosis.  Am. J. Pathol. 96:149-170, 1979.

Camner, P. and K. Philipson.  Human alveolar deposition of 4 urn Teflon particles.
     Arch. Environ. Health 33(4):181-185, 1978.

Chan, L. T. and M.  Lippman.  Experimental measurements and empirical modeling
     of the regional deposition of inhaled particles in humans.  Am. Ind. Hyg.
     Assoc. J., 1980.  (in press)

Dejours, P.  Oxygen Demand and Gas Exchange in Evolution of Respiratory Processes:
     A Comparative Approach.  Stephen C. Wood and Claude Lenfant,  eds., Volume
     13 of Lung Biology in Health and Disease (executive editor:   Claude
     Lenfant).  Marcelu Dekker, Inc. New York, 1980.  pp. 1-49.

Heyder, J. , J. Gebhart, and W. Stahlhofen.  Inhalation of Aerosols:  Particle
     Deposition and Retention.  In: Generation of Aerosols and Facilities for
     Exposure Experiments.  K. Willeke, ed., Ann Arbor Science Publishers,
     Inc., 1980.

Hyde, D. M., N. E.  Robinson, J. F. Gillespie, and W. S. Tyler.  Morphomety of
     the distal air spaces  in lungs of aging dogs.  J. Appl. Physiol. 43(1):86-91,
     1977.

Lippman, M., D. B.  Yeates, and R. E. Albert.  Deposition, Retention and Clearance
     of Inhaled Particles.  Br. J. Ind. Med., 1980.  (in press)

Richards, D. W.    Pulmonary Changes Due to Aging.  In: Handbook of Physiology
     Respiration (Volume  II).  W. 0. Fenn and H. Rahn, eds., American Physiological
     Society. Washington, DC, 1965. pp.  1525-1529.

Sherwin, R. P., M.  L. Barman, and J. L. Abraham.  Silicate Pneumoconiosis of
     Farm Workers.   Laboratory Investigations 40(5):576-582, 1979.

Stauffer, D.  Scaling Theory for Aerosol Deposition in the Lungs of Different
     Mammals.  J.  Aerosol Sci. 6:223-225, 1975.

Weibel, E. R.  Morphometrics of the lung.  In:  Handbook of Physiology Respiration
     (Volume I).   W. 0. Fenn and H. Rahn, eds. American Physiological Society,
     Washington, DC, 1964.  pp. 285-307.

Weibel, E. R.  Oxygen Demand and Size of Respiratory Structures in Mammals.
     In:  Evolution of Respiratory Processes:  A Comparative Approach.  Steven
     C7 Wood and Claude Lenfant, eds., Volume 13 of Lung Biology In Health  and
     Disease (executive editor Claude Lenfant).  Marcel Dekker, Inc., 1980.

-------
11.      RESPIRABLE AEROSOL SAMPLING
    A fundamental  principle in inhalation  toxicology  is  that  it  is  the deposi-"
tion of inhaled participate materials  in sensitive  regions  of the  respiratory
tract or subsequent transformations and translocations to sensitr^organs  or
cells that leads to potentially deleterious  biological responses.   Particles
(or gases) that deposit neither in sensitive regions  of  the airways nor in
regions conducive to translocation to  sensitive  organs/are  cleared  with rela-
tively low probability of causing injury or  disease^(Morrow,  1964).   For
example, large insoluble particles that deposit/almost exclusively  in the nose
are prevented from reaching the lung during  ifose breathing  and are  less likely
to lead to injury than smaller particles/having  appreciable lung deposition.
    This principle was early observed /in coal  mining  in  Europe;  it  was found
that the air concentration of dust ;fn  mines  didn't  necessarily correlate to
the incidence of respiratory disease.   However,  a meaningful  comparison was
possible when samples were ae|7bdynamically fractionated  to  provide  a separate
measure of the respirable d-dst levels.   This led to the  use of "respirable"
dust samples in the coal/mining industry (Walton, 1954).  Further,  the
                      /
repeated practice of jebllecting respirable dust  samples  is  necessary, since
there is variability in the  aerodynamic size distribution of dust depending  on
                 ity
age and source./'
              /
    On this basis the principle of "respirable"  dust  sampling  was  developed
(Lippmann,/1970b).   In this context the word  "respirable" means  broadly "fit
to be b/eathed."  The objective is to  collect  samples  that  have  been purposely
biased in favor of the smaller, more respirable  sizes.  Only the smaller size
fraction is measured to yield the "respirable" aerosol  concentration.   No
specific "cut-size" was defined, since it  is  clear  that there  is no size for
                                 ll-82a

-------
                 Missing reference page 11-105 from first printing
                              Chapter 11 - PM/SO
                                                />

    Wilson, T.  A., and K. Lin.  Convection and diffusion in the airways and the
         design of the bronchial tree.  In:  Airway Dynamics Physiology and
         Pharmacology.  A. Bouhuys, editor.  Springfield, 111.  Thomas 1970.
         pp. 5-19.

    Wolff, R. K., M. Dolovich, C. M. Rossman, and M. T. Newhouse.  Sulfur dioxide
         and tracheobronchial clearance in man.  Arch. Environ. Health 30:52.1-527,
         1975.                                                          ~

    Yeh, H. C.   Use of a heat transfer analogy for a mathematical model of
         respiratory tract deposition.  Bull. Math. Biol, 35:105, 1974.

    Yeh, H. C,, A. J. Hulbert, R. F. Phalen, D. J. Velasquez, and T.  D. Harris.  A
         steroradiographic technique and its application to the evaluation of lung
         casts.  Invest. Radiol. 10:351, 1975.

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

    Yus C. P.  An equation of gas transport in the lung.  Resp. Physiof.  23:257,
         1975.

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


                                Chapter 11 - PM/SO?
                                      Errata
                            REFERENCE LIST CORRECTIONS

Page   Par/Line           Delete                            Insert

11-86  After       ~                                  Clements, J. A., J. Nellenbogen,.
       8th Ref.                                       anc' H. J. Trahan,  Pulmonary
                                                      surfactant and evolution of
                                                      the lungs.  Science 169:
                                                      603-604, 1970.

11-93  After       ~                                  Kawecki, J. M.  Emmission of
       llth Ref.                                      Sulfur-Bearing Compounds
                                                      from Motor Vehicle and Air-
                                                      craft Engines, A Report to
                                                      Congress.  EPA-600/9-78-028,
                                                      U. S. Env. Prot. Agency.
                                                      Aug. 1978.

11-96  After       -                                  Menzel,  D. B.  The role  of
       5th Ref.                                       free radicals  in the  toxicity
                                                      of air  pollutants  (nitrogen
                                                      oxides  and ozone).   In:
                                                      Free Radicals  in Biology,
                                                      Vol. II, Academic  Press,
                                                      New York,  1976.  pp.  181-202.

-------
                          12.  TOXICOLOGICAL STUDIES






12.1  INTRODUCTION



     This chapter describes j_n vitro and j_n vivo studies of sulfur oxides and


particulate matter.   The toxic effects of sulfur oxides and of atmospheric


aerosols overlap because a major component of atmospheric aerosols are salts


of sulfuric acid (ammonium sulfate, sodium sulfate, zinc ammonium sulfate, and


related compounds) (see Chapters 3 and 5).  The toxicology of all forms of


sulfur oxides must be considered as a whole.   For example, in the ambient air


sulfur dioxide (S02) may interact with aerosols, may be absorbed on particles,


or may be dissolved in liquid aerosols.  To a lesser degree, similar


interactions may occur in the air within the respiratory tract.   Sulfuric acid


aerosols may react with ammonia forming ammonium sulfate [(NH.^SOJ and


ammonium bisulfate (NhLHSO.) in the ambient air, the animal exposure chamber


atmosphere before inhalation, or to a lesser degree simultaneously upon


inhalation.  Biological interaction can also occur, resulting in a situation


where the effect of a mixture of pollutants has additive, synergistic, or


antagonistic health effects compared to the effects of the single pollutants.


     This chapter will also present brief discussions of the toxicology of


organic compounds so far detected as atmospheric particulates.  Unfortunately,



our knowledge of the exact chemical nature and health effects of these


materials is incomplete.  A more complete treatment of this subject can be


found in the health assessment document on polycyclic organic matter (POM).


A similar overview is provided for heavy metals.  Individual documents and


                                               275-283
reviews have covered this topic in more detail.
                                   12-1

-------
     Because of the relative toxicity of various particles and their
interaction with S0?, this Chapter should be taken as a whole and not as
artificially segregated major topics.  Discussions of the deposition and
clearance are limited; the reader, therefore, should be familiar with the
content of Chapter 11 which presents this subject in detail.
12.2  EFFECTS OF SULFUR DIOXIDE
12.2.1  Biochemistry of Sulfur Dioxide
     Much of the discussion under 12.2.1 relates to i_n vitro experiments,   ^n
vitro studies are those in which the potential target (i.e., cells, enzymes,
other molecules, etc.) is exposed to the toxicant outside the body.  In  such a
culture system, some homeostatic or  repair mechanisms are absent.   In some
cases, pollutants act by  indirect mechanisms.  For example, the pollutant
affects target A which in turn alters target B.  Thus, if only target B  were
present, the effect would not be observed.  In addition, the dosimetric
relationships of j_n vitro studies to i_n vivo studies are not defined.
Therefore,  effective concentrations  cannot be extrapolated  from j_n  vitro to
j_n  vivo studies.  For the above reasons, there is some controversy  as to whether
these iji vitro reactions  can be extrapolated to mechanisms  of toxicity.
Nonetheless, sound jln vitro investigations can show whether a given pollutant
has  the potential of altering a given target.  I_n vitro studies  are best used
to  provide  guidance for j_n vivo investigations or when j_n vivo  results  have
been observed.  In the latter case,  the relatively simplified _i_n  vitro  system
can  sometimes elucidate the potential mechanisms of toxicity.   To  these  ends,
they can be useful.
     Knowledge of the chemistry of sulfurous acid and S02  is  necessary  to
understand the physiological and toxicological properties  of  SO,.   Sulfur
                                   12-2

-------
dioxide is the gaseous anhydride of sulfurous acid.  It dissolves readily in
water; and at physiological pH near neutrality, hydrated S02 readily dis-
sociates to form bisulfite and sulfite ions as illustrated by Equations 12-1
and 12-2.  The rate of hydration of S02 is very rapid; the rate constant of
hydration, k^ is 3.4 x 10  M*1 sec"1, and the rate constant of the reverse
reaction is 2 x 10  M"1 sec"1 at 20°C (Equation 12-1).1  The dissociation
constants of sulfurous acid are 1.37 and 6.25 (in dilute salt solutions),1 so
at pH 7.4 sulfite ions are present at about 14 times those of bisulfite, but
in rapid equilibrium.  Hence, SOp can be treated as bisulfite/sulfite and
conversely.
      S02 + H20   ^	    H2S03                                    12-1
                            H+ + HSO~     ^    ^    H+ + S0=3           12-2
     Sulfur dioxide reacts readily with all major classes of biomolecules.
Reactions of S02 or bisulfite with nucleic acids, proteins, lipids, and other
biological components have been repeatedly demonstrated j_n vitro.
12.2.1.1  Chemical Reactions of Bisulfite with Biological Molecules-- The
chemical reactions of bisulfite with biological molecules are discussed in
detail in Appendix I.  Briefly, there are three important reactions:  sulfonation,
autoxidation, and addition to cytosine.
     Sulfonation results from the nucleophilic attack of bisulfite  on
disulfides:
                       RSSR'  «• HSO,           N  RSSO," * R'SH
                                  3  -s;	      3                  12-3
                                   12-3

-------
This reaction is also known as sulfitolysis.  The products of the reaction are
S-sulfonates (RSSO-") and thiols (R'SH).  Direct evidence for the formation of
plasma S-sulfonates has been found.    Any plasma protein containing a disulfide
group could react to form an S-sulfonate.  Small molecular weight disulfides,
such as oxidized glutathione, can also be reactants.  Generally, analyses of
plasma S-sulfonates have been restricted to diffusable (dialyzable or small
molecular weight) and nondiffusable (nondialyzable or protein) S-sulfonates.
The exact molecular species has not been determined.  S-sulfonates can react
with thiols, either reduced glutathione or protein thiol groups, to form
sulfite and disulfide.  Since this reverse reaction is facile, S-sulfonates
are hypothesized as being transportable forms of bisulfite within the body
(see Appendix I, Section 1.0).
     Similar reversible nucleophilic addition of bisulfite to a variety of
biologically important molecules has been reported (see Appendix I).  The
toxicologies! importance of these chemical species is uncertain.  It is not
likely, for example, that the reactions of bisulfite with pyridine nucleotides
(NAD or NADP), reducing sugars, or thiamine are important to the toxicity of
bisulfite or SCL.
     Autoxidation of bisulfite occurs through a multistep chain reaction (see
Appendix I, Section 2.0).  These reactions may be important because they
produce hydroxyl (-OH) and superoxide (-02~) free radicals as well as singlet
oxygen ('02).  These chemical species of oxygen are highly reactive and are
also produced by ionizing radiation.  Hydroxyl free radicals are theoretically
responsible for the lethal  effects of ionizing radiation.  Autoxidation of
bisulfite could lead to increased concentrations of these reactive chemical
species within the cell and could hypothetically lead to similar adverse
                                   12-4

-------
effects.  The reactive forms of oxygen can also initiate peroxidation of the
lipid bilayer of cells.  Peroxidation of cellular lipids, especially plasma
membrane lipids, is thought to be highly deleterious.    (See Appendix I,
Section 3.0.)  No direct evidence has been presented to support peroxidation
of cellular lipids as a mechanism of toxicity of S02.
     Bisulfite addition to cytosine can result in deamination to form uracil.
The result would be a DNA conversion of GC to AT sites and could be mutagenic.
Transamination of cytosine can occur through reaction of an amine with cytosine-
sulfite adduct.  Since the nucleus is rich in polyamines, transamination is a
likely event.  Deamination of cytosine occurs most readily in high (1 M)
concentrations of sulfite; transamination also requires high sulfite and amine
concentrations.  The decomposition of the cytosine-sulfite adduct is the rate
limiting step in both reactions.
12.2.1.2  Potential Mutagenic Effects of Sulfite and SO,,—At the present time,
no clear evidence exists for mutagenicity caused by S02 or sulfite.   However,
because of the reactivity of sulfite with cytosine, the potential mutagenic
properties of sulfite and S02 have been examined.  Such experiments are detailed
in Appendix I, Section 6.0.  To date, microbial experiments with high concentrations
of sulfite in acid solutions i_n vitro have produced mutations.  These conditions
would be similar to those favoring deamination of cytosine.  Experiments
conducted at low concentrations and neutral pH are less convincing.   For
example, the microbial assays were not done with strains of Salmonella known
to be sensitive to mutagens (Ames Assays).  Negative experiments have been
reported when insects (Drosophila) and mammals (mice) were exposed.  Cytotoxicity,
rather than mutagenicity, appears when cultured animal and human cells are
                                   12-5

-------
exposed to sulfite.  (See Table 12-1 for summary; details in Appendix I,



Section 6.0.)



12.2.1.3  Metabolism of Sulfur Dioxide



12.2.1.3.1  Integrated Metabolism.  There are several studies of the metabolism



of exogenously supplied S02, sulfite, or bisulfite.   Quantitative differences



exist between inhaled and ingested S02 with regard to the rate of clearance of


                                                                69
the  key intermediary in sulfite metabolism, plasma S-sulfonates,   but no



qualitative differences exist in the metabolism of inhaled S02 and injected or



ingested  bisulfite or sulfite.  The importance of the appearance of plasma



S-sulfonates lies in tneir potential ability to serve as a circulating poe1 of



sulfite molecules.  Plasma S-sulfonates represent both protein-bound and small



molecular weight thiol-bound forms of sulfite (Reaction 1 in Figure 12-1).



Continuous inhalation of 26.2 mg/m  (10 ppm) S02 resulted in the attainment of



38 ± 15 nmole of plasma S-sulfonates/ml in rabbits after about 4 days.69  The



clearance of plasma S-sulfonates generated by either inhalation of S0? or



ingestion of sulfite in the drinking water was exponential,  exhibiting only a



single compartment in most rabbits.  The half-life was 4.1 days for S-sulfonates



generated by inhalation vs.  1.3 days for those generated by ingestion.69  The



mechanism for this quantitative difference in clearance rates has not yet been



found.   An integrated scheme is shown in Figure 12-1.



     Inhaled S02 quickly penetrates the nasal mucosa and airways as shown by



the  rapid appearance of 35S  in the venous blood of dogs inhaling 35S02.44  A



significant fraction of the  blood 35S was probably in the form of plasma



S-sulfonates  (RSS03).   Gunnison and Palmes69 have shown that this compound



accumulates  on  long-term inhalation of S02 as well as on ingestion or injection



of sulfite solutions  in rabbits.   These researchers  suggest that tissue or
                                   12-6

-------
                                                  TABLE  12-1.   POTENTIAL HUT4GENIC EFFECTS OF S02/BISULFITE
Concentration SO.



•4

1310 mg/m3
(500 ppm)
Bisulfite
0.9 M HSOl
pH 5.0 J
3 H HSO~
pH 5-6 J
1 M HSO"
pH 5.2 J
5 x 10"3 M HSO"
pH 3.6
0.04 or 0.08 M

Organise
Phage T4-R11 System
Phage T4-R11
Systeit
E. coll K12 &
K15
S. cerevlslae
D. »elanogaster
Hela cells
(Hunan)
End Point
GC+AT or
deamlnatlon of
cysodne
deanlnatlon of
cytocine
GC+AT or
deanl nation of cytoclne
Point Mutation
Point Mutation
Cytotoxiclty
Response Conoents Reference
S-je^-nd
201
i Poor dose Hayatsu and.Blura
response Ilda et al.
+ Mukal et al.203
+ Doranga.and
DupuyZD4
May not be Valencia et «1.205
bioavallsble
«• Thowpson and Pace
13.1 - 105 ng/n
(5 - 40 ppm x 3 «1n)
House flbroblasts &
Peritoneal aacrophages
                                                                                                                                 Nulsen «t al
                                                                                                                                              208

-------
                                                  TABLE 12-1.  POTENTIAL MUTAGENIC EFFECTS OF  S02/BISULFITE
Concentration SO.





1310 mg/m3
(500 pp*0
Bisulfite
0.9 M
pH 5.0
3 M
pH 5-6
1 M
pH 5.2
5 x 10 " 3 M
pH 3.6
0.04 or 0.06 M

Organise
Phage T4-R11 System
Phage T4-R11
System
E. coll K12 &
K15
S. cerevlsiae
D. melanogaster
Hela cells
(Human)
End Point
GOAT or
dean i nation of
cysocine /''
deaml nation of _,,,--^
cytoclne- /-'''
GOAT of
deam'lnatlon of cytoclne
Point Mutation
Point Mutation
Cytotoxicfty
Response ^.- Comments Reference
.,---'' Drake
± Poor dose Hayatsu and^Niura
response Sida et al.
+ Mukal et al.203
norland
May not be Valencia et al.205
bioavallable
207
+ Thompson and Pace
13.1 - 105 nq/wT
(5 - 40 ppM x 3 Din)
Mouse flbroblasts &
Peritoneal aacrophages
Nulsen et al.
                                                                                                                                               208

-------
TABLE 12-1.   (Continued)
Concentration SO. Bisulfite
14.9 mg/m3


0.0001H
0.01N
0.0001M

0. 0040H

^ 0.0025M
ro
Organism
Human lymphocytes


Human lymphocytes

House oocytes

Ewe oocytes

Cow oocytes

End Point
Point Hutation
Chromosomal aberrations
Cytotoxicity
Inhibition of mitosis

Inhibition of meiosis

Inhibition of meiosis

Inhibition of meiosis

Response Comments Reference
.
Kikigawiiqand
+ -S+wHor
* Dose related Harman et al
response
+ Observed Jagiello et
fuzziness of
+ chromosomes may be
due to Cytotoxicity
+



• J- i Z. O

213

al.212





CD

-------
ro
i
10
                                                 Liver
      SO.
HSO!
•SO
                           -?
^
             Plasma         \
             Proteins	^  \

               4            >1
          Low Molecular       ]
          Weight Oisulflde    /
                           Intracellular
                                Pool
         RSSR * SO
          Intracellular Pool

          in Organs
                                                  G5H or RSH
                                NAOPH

                                  NADP*


                                     RSH * SOI2

                                -2       5    J
                      RSH *  RSOj  	^ MS"
                                           Sulflte
                                           0x1dase
                                                                   HSO
                                                       Metabolism
                                                                                Sul fated GlycomHno^lycans
                                                                                and  Glycoprotelns 	_^ Urinary

                                                                                                               Complex
                                                                                           7                    Sulfates
                                                                                                               Kidney
^
                                                                ~'
^ Urinary SOj2
                    Figure 12 1. An integrative scheme for metabolism of sulfur dioxide in mammals.

-------
plasma sulfhydryl compounds can react with plasma S-sulfonates to reverse the



reaction, leading to the establishment of an intracellular pool of sulfite.



Thus, intracellular concentrations of sulfite can occur over a prolonged



period after a single inhalation of SCL.  Such a mechanism may explain the



observation that inhaled 35S02 leads to the presence of   S in various other



organs in dogs besides the lung (e.g., the ovaries).    Distribution of a



mobile source of sulfite through the blood is particularly important because



of  the variety of reactions of S02, sulfite and bisulfite, and because of the



implication that toxic effects are also possible in nonpulmon'ry organs.



      Frank et al.77 found exhaled   S in the breath of dogs exposed to   S02



through  the surgically isolated head and upper airways.  Presumably, the


       35                     35
breath   S was in the form of   S02 and could have occurred through nasal



absorption of S02 and distribution through the circulation.  Breath S02 could



have come either from the desorption of hydrated S02 (bisulfite or sulfite) or



through  reversal of the equilibrium of  sulfite and plasma proteins with plasma



S-sulfonates.  Since plasma S-sulfonates are the dominant form of exogenously



supplied S02 in  the blood, the reversal of Reaction 1 (Figure 12-1) seems to



occur easily and rapidly during the early phases of exposure.



      Most of the inhaled S02 is presumed to be detoxified by the sulfite



oxidase  pathway  in the liver, forming sulfate which is excreted in the urine



(Reaction 3, Figure 12-1).  The dominance of this reaction has been supported



by  studies of sulfite oxidase inhibition3  which are discussed below and by



the appearance of about 85 percent of the inhaled 35S02 as urinary sulfate in


      44                                                        Tt;
dogs.    Once oxidized by sulfite oxidase, most of the inhaled "s derived



from  S02 appears in the urine as 35S-sulfate.44  A small fraction (10 to 15



percent) of the urinary   S was in the  form of sulfuric acid esters and
                                   12-10

-------
       44
ethers.    Sulfate arising from the oxidation of sulfite can enter the sulfate



pool and could be incorporated into sulfate macromolecules including



glycosaminoglycans and glycoproteins.   These macromolecules are actively



synthesized by the respiratory mucosa and could account for the presence of


                                                                     35    44
radiolabeled sulfur in the respiratory tract following inhalation of   SO,,.



Most of the nondialyzable   S detected by Yokoyama et al.44 was bound to the



crglobulin fraction of plasma.  The chemical form of the   S was not


                            44                     3R
determined.  Yokoyama et al.   speculated that the   S present in the



crglobulin fraction was in the form of sulfonated carbohydrates.   The problem


                                                                      69
is  in  need of further clarification. According to Gunnison and Palmes,



plasma S-sulfonated proteins may also have contained the   S.   They have



suggested that the slow clearance of plasma S-sulfonates is an important



factor in determining toxicity.  They have not reported, however,



intracellular levels of S-sulfonates or sulfite.



     Reductive cleavage of S-thiosulfates to a thiol and thiosulfate



(Reaction 4, Figure 12-1) has been reported.    Thiosulfate can be reduced to



hydrosulfide (Reaction 5, Figure 12-1) by rhodonase and reduced lipoate or by


                                              72-74
thiosulfate reductase and reduced glutathione.



12.2.1.3.2  Sulfite Oxidase.   The biochemistry of sulfite oxidase will be



discussed because of its importance as a mechanism of detoxification of



sulfite.  Genetic deficiency of sulfite oxidase occurs in humans.


                                                           42
Dietary factors can, however, alter the enzymatic activity.    Sulfite oxidase



(EC 1.8.3.1) is a metallo-hemo protein with molybdenum and protoheme as the


                  •so                       32~37          38            39~41
prosthetic groups.    It exists in animals,      bacteria,   and plants.



In both plants and animals, the enzyme is located in the mitochondria.



Purified sulfite oxidase can utilize either cytochrome c or oxygen as  the
                                   12-11

-------
                    34                                                   • i
electronic receptor.    When coupled with cytochrome c to the mitochondria I



respiratory chain, sulfite oxidase reduces molecular oxygen to water (Equation



12-24), whereas during oxygen reduction, the product formed is hydrogen




peroxide (Equation 12-25).
      SO'2V   , 2 Cyt c (Fe3+)
                                                                      12-24
       S0~2'  V 2 Cyt c (Fe2+) '    1/2 0,
       S0~2  +  H20 + 02  ->  S0~2+ H20£                                   12-25



 Direct reduction of molecular oxygen by sulfite oxidase is prevented  in  the



 presence  of ferric cytochrome c.  In intact mitochondria, therefore,  sulfite



 oxidation occurs through  the interaction of sulfite oxidase with  the  respira-



 tory chain  of the mitochondria, producing 1 mole of ATP/mole of su"!fite



 oxidase.



      Sulfite  oxidase  is presumed to be necessary for the detoxification  of



 sulfite.   In  three reported cases in humans, a genetic defect  in  this enzyme



 resulted  in severe neurological problems.         Cohen et al.    suggested



 that sulfite  oxidase  is the principal mechanism for detoxifying bisulfite and



 S02-   This  is supported by a study which showed that dogs exposed to  35S02



 excreted  80 to 90 percent of the inhaled 35S in the urine.  Because sulfite



 oxidase requires molybdenum, Cohen et al.   were able to deplete  rats of



 sulfite oxidase by feeding them a low molybdenum diet and treating them  with



 100  ppm of  sodium tungstate in drinking water.  Tungsten competes with moly-



 bdenum and  essentially abolishes the activity of sulfite oxidase  and xanthine



 oxidase (EC 1.2.3.2), the two major molybdo-proteins of rat  liver.
                                   12-12

-------
Similar decreases were observed in the lung and other organs.   The LD50 for



interperitoneally injected bisulfite was found to be 181 mg NaHSO,/kg in the
»                                                                J


sulfite oxidase deficient animals compared to 473 mg/kg in the nondeficient



rats.


                                                             A 0
     The effect of inhaled SO,, on lethality was more complex.     High levels



were used in all cases and two effects of inhaled S02 were observed.   At 1,546



or 2,424 mg/m  (590 or 925 ppm) SO- or less, the principal effect in control



animals was respiratory insufficiency resulting in death by asphyxiation.   At



6,157 mg/m3 (2,350 ppm) S02 or greater (up to 1.3 x 106 mg/m3, 1,310,000 ppm),



the principal effect appeared to be mediated by the central nervous system



(CNS) resulting in seizures and prostration followed by death.  A direct


                                                  42
effect of bisulfite on the CNS has been suggested.     Interperitoneally


                  42
injected bisulfite   also produced CNS effects.  Mortality was observed in



both the control and tungsten-treated animals exposed to greater than 1,554



mg/m  (593 ppm) SO- for 4 hr.  Most of the deaths occurred within 48 hr of



exposure, and no further mortality occurred during the subsequent 2 wk period.



Time before death, however, appeared to be much shorter for those rats treated



with tungsten than for control animals.  To test this finding, rats were



exposed continuously to 1,546, 2,424, or 6,157 mg/m  (590, 925, or 2,350 ppm)



S02.  At 6,157 mg/m3 (2,350 ppm) and 2,424 mg/m3 (925 ppm), but not at 1,546



mg/m  (590 ppm), a clear difference existed between the tungsten-treated



(i.e., deficient in sulfite oxidase) and control animals, with the


                                                     42
tungsten-treated animals dying earlier.  Cohen et al.   suggest that these



differences in survival times are due to the inability of the tungsten-treated



animals to detoxify inhaled S02 to sulfate.  Of those animals exposed  to  2,424



mg/m3 (925 ppm) S02, tungsten-treated animals died of seizures and
                                   12-13

-------
prostration, whereas the control group succumbed to respiratory insufficiency.



The authors concluded that sulfite oxidase mainly alleviates acute systemic



toxicity due to bisulfite and has little or no effect on subacute or chronic



respiratory effects of SCL.  The sulfite oxidase pathway in the rat lung  is



capable of detoxifying bisulfite derived from inspired SO,, at the rate  of 600



umole/day.  The authors suggest that this is equivalent to 52.4 mg/m  (20 ppm)



SCL  in the  atmosphere, assuming complete extraction of S02 by the rat lung.



The  capacity of the rat (200 g) to oxidize bisulfite amounts to 150,000 umole



of bisulfite/day, which is theoretically equivalent to continuous exposure to



13,100 mg/m3 (5,000 ppm) S02-   Since some rats exposed to 2,424 mg/m  (925



ppm) S0?  died  (25 to  38 percent mortality), factors other than oxidation  by


                                   42
 sulfite  oxidase must  be considered.


      Attempts  to  induce higher  levels  of sulfite oxidase through pretreatment


                                                          42
 of the  animals with  S02/bisulfite or phenobarbital  failed.    Since sulfite



 oxidase  is a mitochondria! enzyme with a long half-life, it  is not  likely that



 phenobarbital  or  chronic exposure to SOp would result  in adaptation through



 induction of  higher  levels of  sulfite  oxidase.



 12.2.1.4  Activation  and Inhibition of Enzymes by Bisulfite—Both  inhibition



 and  activation of specific enzymes have been reported.  This may be due to



 formation of  S-thiosulfates  since disulfide bonds often stabilize  the tertiary



 structure of proteins.  Sulfite ions activated several phosphatases  including



ATP-ase    and  2,3-diphosphoglyceric acid phosphatase.47  The mechanism  by



which activation  occurs is not  known.  Inhibition of  several enzymes  has  been



reported;  these include aryl sulfatase,47 choline sulfatase,48  rhodanase,38


                             49
and  hydroxyl amine reductase.    Malic dehydrogenase  was  inhibited by



micromolar concentrations  of bisulfite (Ki = 5 uM).50"51   Other


               52
dehydrogenases   and  flavoprotein oxidases are  inhibited by  bisulfite.
                                    12-14

-------
     Bisulfite effectively inhibits a number of other enzymes including potato


and rabbit muscle phosphorylase.    Bisulfite inhibition was competitive with


respect to glucose-1-phosphate and inorganic phosphate, suggesting that the


bisulfite inhibition was caused by competition of bisulfite with the phosphate


binding site of phosphorylase.  Several important coenzymes. such as


pyrodoxylphosphate, NAD+, NADP+, FMN, FAD, and folic acid, may react with


sulfite to form addition products as discussed above.  As a result, these


coenzymes could theoretically aid in inhibition of a wide variety of critical

                                                      p
enzymic reactions.  Pyridine coenzyme-bisulfite adduct  and


flavoenzyme-bisulfite adduct  '   have been studied in detail, and these


adducts have been shown to be biologically inactive.


     Despite all of the data obtained using j_n vitro systems on the inhibition


of enzymes by bisulfite/SOp, no inhibition or activation has been determined


In vivo with SO- exposure.  Such inhibition may occur, but there has been no


concerted effort to search for inhibition of specific enzymes during S02


exposure.


12.2.2  Mortality


     The acute lethal effects of SOp have been examined mostly in the older


literature and have been reviewed in the previous Air Quality Criteria

                           78
Document for Sulfur Oxides.    In early studies, a  number of different animal


species was examined for susceptibility to SOp.  These data show that


mortality was not observed at exposures of 65.5 mg/m   (25 ppm) for up to 45


days in either rats or mice; this conclusion has been  confirmed by subsequent

        CO
studies.    Statistically significant mortality could  be  associated with


long-term exposure to S02 at 134 mg/m  (51 ppm) or  higher.  The clinical signs

                                                       42
of S09 intoxication appear to vary with the dose rate.    At concentrations
                                   12-15

-------
below approximately 1,310 mg/m   (500 ppm), mortality  is  associated  with

respiratory  insufficiency; above this concentration,  mortality  is ascribed to

central  nervous disturbances producing  seizures  and paralysis of the

extremities.  These clinical signs depend upon the presence  and activity of

sulfite  oxidase as discussed in  Section 12.2.1.3.2  Injections  of histamine or

                                                 230
adrenalectomy can increase the lethality of SO-.

     Matsumura113'114 examined the effect of a 30-min exposure  to several  air

pollutants  on mortality  consequent to the anaphylactic response of  guinea  pigs

to protein  antigens.  Sensitization to  the antigen administered by  aerosol  was

augmented by pretreatment with 786 mg/m  (300 ppm) SO-,  but  not with 472 mg/m

 (180 ppm).   The dyspneic attack  of anaphylaxis was not affected by  as much as

 1,048 mg/m   (400 ppm) S02.

     On  the basis of mortality due to acute exposure,  SO-  is far less toxic

than ozone  and  is similar in toxicity to nitrogen dioxide.   Concentrations

required to produce mortality from SO,,  are far in excess of  those which occur

in the atmosphere due to pollution (Table 12-2).

12.2.3   Tumorogenesis in Animals Exposed to SO-  or SO- and Benzo(a)pyrene

     Tumorogenesis after exposure to SO- alone or to  SO- and an aerosol of
                                        *-            ^^jUJ^^
benzq(a)pyrene  has been  examined.  .Mice, were exposed/ito-  1,310 mg/m   (500
dt**l^4^&&^ SV4/?*#" S0± ^^^-^^^ ^^^^^ ^C_^^/^>0^ ^-<-> ^
^S0,| for  •5"-min/dayHFor 5  days/wk  for lifetimes-    .  Examinations for tumors of

the lung and other organs were undertaken only in mice that  survived longer

than 300 days,  since no  primary  lung tumors had  been  seen  in younger mice.

Primary  pulmonary neoplasias increased  in the males (n = 35) from  31 percent

in the control group to  54 percent in the S02-exposed group  and in  the females

(n = 30)  from 17 to 43 percent.  The incidence of the  next  most  common tumors

in this  strain of mice,  hepatomas and lymphomatoses,  was not affected.   The
                                    12-16

-------
TABLE 12-2.  LETHAL EFFECTS OF SO,  ON  ANIMALS
09 Concentration
3
>: g/ra ppm
26.2
134
275
-1 , 310
1,598
2,392
3,086
5,175
9,165
13,236
5,782
6,571
7,205
786
10
51
105
610
913
1,178
1,975
3,498
5,052
2,207
2,508
2,750
300
Duration
6 hr/day x 5 day/wk
x 113 day
113 days
22 day
5 min/day x 5 day/wk
LJ .7 fi n ft -i i i-t- " j^ 7^
> X JOU flay^ ^e-^££-c^^t-
LTr.n 285.6 min
bO
74. 5 min
38. 7 min
LT5Q 197.6 min
71.7
41.0
LT5Q 68.2 min
28.7
35.5
30 min
Species Remarks . Reference
CO
Rat No mortality in excess of control Laskin et al.
No mortality in excess of control
64% mortality (treated-control)
Mice No increased mortality; tumor formation Peacock and Spence
c found
230
Mice IP injection of 200 to 300 mg histamine/mouse Leong et al
(Connaught Med. increased toxicity
Res. Lab. Strain)

230
Rat (Sprague- IP injection of 200 to 300 mg histamine/rat Leong, et al.
Dawley) or adrenal ectomy increased toxicity


230
Guinea Pig Leong, et al.


Guinea Pig Increased mortality Matsumura
             due  to  anaphylaxis
             from antigen challenge
             to sensitized animals

-------
authors classified only tumors which invaded blood vessels as carcinoma.   In



males, S02 did not affect the incidence of malignant tumors (2/35, 6 percent



in air group; 2/28, 7 percent in S02 group).  However, in females, the



incidence of primary lung carcinoma increased from 0/30 in the controls to



4/30 (18 percent) in the S02-exposed mice.  These were early studies and the



statistical analysis is vague.  The significance of these increases,



therefore, is questionable.   The investigators concluded that the increased



incidence of primary lung tumors was due to the initial inflammatory reaction



to SOp, followed by tolerance, which accelerated spontaneous tumor



development.  They further state that this study does not "justify the



classification of SOp as a chemical carcinogen as generally understood."



      Lung tumors or other significant pathological effects were not observed



in hamsters exposed for 98 wk to 26.2 mg/m  (10 ppm) 50^ for 6 hr/day, 5


                                             3                           3
days/wk for 534 exposure days or to 9.17 mg/m  (3.5 ppm) S02 plus 10 mg/m



benzo(a)pyrene for 1 hr/day, 5 days/wk for 494 exposure days or to a

                              CO           CO

combination of the 2 regimens.    When rats   were exposed to the same



regimen, however, lung squamous cell carcinoma was found in 5/21 (23.8



percent) animals receiving the combined exposure of 26.2 mg/m  (10



ppm)  S02 for 6 hr/day and 9.17 mg/m  (3.5 ppm) S02 plus 10 mg/m3



benzo(a)pyrene for 1 hr/day and in 2/21 (9.5 percent) animals exposed to the



benzo(a)pyrene plus S02 for 1 hr/day.   Renal metastasis also occurred.



Control rats exposed to air (n = 3) or to 26.2 mg/m3 (10 ppm) S02 (n = 3) had



no tumors.



     This study was subsequently extended to lifetime (exact time not



specified) exposures (5 days/wk) of rats.194  Exposure to air alone (n = 15)



or 26.2 mg/m  (10 ppm)  S02 (n = 15) for 6 hr/day caused no cancers  (squamous
                                   12-18

-------
cell carcinoma).  A 1 hr/day exposure to 10 mg/m  benzo(a)pyrene caused cancer



in 1/30 (3.3 percent) rats.  A 6 hr/day exposure to 26.2 mg/m  (10 ppm) SO-



plus a 1 hr/day exposure to 10 mg/m  benzo(a)pyrene resulted in a cancer



incidence of 6.7 percent (2/30).  When animals received a combination of 10



mg/m  benzo(a)pyrene and 10.48 mg/m  (4 ppm) S02, 4/45 (8.9 percent) of the



rats had cancer.  The highest incidence (19.6 percent, 9/46) was found in



animals exposed for 6 hr/day to 26.2 mg/m  (10 ppm) SO- plus a combination of



10 mg/m  benzo(a)pyrene and 10.48 mg/m  (4 ppm) S02 for 1 hr/day.



     The biological significance of these studies (Table 12-3) is complex and



difficult to interpret, particularly since statistical analyses were not



reported in the publications.  Few SOp exposure experiments have been carried



out for the near lifetime of the animal as in the early mouse study   and the


                     194
subsequent rat study.     Most work has centered around short-term acute



studies in which the experimental design and other aspects of the study would



be inadequate to detect a low incidence of tumors.   The incidence of lung



tumors increases as the animals age; but no historical control data are


                                      68 194
available for the colony of rats used,  '    making the increased incidence by



the combined S0--benzo(a)pyrene treatment difficult to interpret.   Tumor



formation may be a multistep process, requiring more than just the initiation



for expression.  Thus, the potential co-carcinogenic activity of SO- may be



real and significant in terms of a human health hazard, but it is not



definitely proven by these experiments.



12.2.4  Morphological Alterations



     Because of the high solubility of SO- in water, morphological and physio-



logical effects have been detected in the upper and lower airways (Table



12.4).  At relatively high concentrations (used in most studies designed to
                                   12-19

-------
                                    TABLE 12-3.  TUMOROGENESIS IN ANIMALS EXPOSED TO S02  OR S02  AND  BENZO(a)PYRENE
       Concentration
                                        Duration
                                                             Species
                                                          Results
                                                                                                                                     Reference
4310 mrjfm* (Ann ppj) 
-------
                                           TABLE 12-4.   EFFECTS OF SULFUR DIOXIDE ON LUNG MORPHOLOGY
       Concentration
                                      Duration
                                                           Species
                                  Results
                                                                                                                                 Reference
0.34. 2.65. or 15.0 mg/m3
 (0.13. 1.01, or 5.72 ppm)
 SO,
0.37. 1.7 or 3.35 mg/m3 (0.14.
 0.64 or 1.28 ppm)

12.3 mg/m3 (4.69 ppm) then
 between 524 and 2620 mg/m3
 (200-1000 ppm) then Gng**3 .
                       /#4'/
13.4 mg/m3 (5.12 pp«)


13.4 mg/m3 (5.1 ppm)
26.2 »g/m3 (10 ppm)
91.7 mg/m3 (35 ppn) (rose on
occasion to 262 mg/m3 (100 ppm))

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


                                  30 wk then 1 hr then
                                   48 wk
                                   18 no, continuous


                                   21 hr/day. 620 days

                                   72 hr, continuous
                                  1 to 6 wk


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

                                                          Cynomolgus
                                                           monkey
Cynomolgus
 •onkey

Dog

Mouse
Pig

Rat





Rat
                                                                                                       QQ
                                     Lungs  of  15.0  mg/m3  (5.72  ppm)  group,  killed  after     Alarie  et  al.
                                      13  or 52 wk of  exposure,  showed  less  spontaneous
                                      pulmonary disease  than  controls.   Controls and  0.34
                                      and 2.64 mg/m3  (0.13  and  1.01  ppn)  animals had
                                      evidence of lung disease.   Tracheitis  present in
                                      all but  15.0  mg/m3  (5.72  ppm)  group.   Survival
                                      greater  in the  latter group
                                                                                                       90 91
                                     No remarkable  morphologic  alterations  in  the  lung      Alarie  et  al.   '
                                     Persistent  changes  in  lung morphomology  including:
                                      alterations  in  the  respiratory bronchioles,
                                      alveolar ducts,  and alveolar  sacs; proteinaceous
                                      material within  the alveoli;  thicker  alveolar
                                      walls  infiltrated with  histocytes and leucocytes;
                                      moderate hyperplasia  of the epithelium  of  the
                                      respiratory  bronchioles; bronchiectasis and
                                      bronchiolectasis; vacuolation of hepatocytes

                                     No alterations  in lung morphology

                                     No alterations  in lung morphology

                                     Pathological  changes in  the nasal mucosa appeared
                                      after  24 hr  of  exposure and Increased in severity
                                      after  72 hr.  Mice  free of upper respiratory patho-
                                      gens were  significantly less  affected than the con-
                                      ventionally  raised  animals.   Morphological altera-
                                      tions  were qualitatively identical in both groups.
                                     Loss  of  cilia  in
                                      goblet  cells, IN
                                                                                        nasal  cavity,  disappearance  of
                                                                                       •taplasia  of  the  epithelium
                                     Trachea)  goblet  cells  increased  in number and size.
                                      Incorporation of  3SSO.    into mucus  increased.
                                      Sialidase  resistant mucus  secreting  cells were
                                      found  much more distally.  Chemical  composition
                                      of  mucus altered
                                                                       Increased mitosis of goblet cells.
                                                                        not lost by 5 wk post-exposure
                                                 Alteration
                                                                   Alarie et al.90'91
                                                                                                                             Alarie  et al.
                                                                                                                                          92
                                                                                                                             Lewis  et al
                                                                                                                                         104
                                                                                                                             Giddens  and Fairchild
                                                                                                                                                  80
Martin and Willoughby
                                                                                                                                                  81
                                                                                                                             Reid
                                                                                              ,83
                                                                   Lamb and Reid
                                                                                                                                          ,82

-------
detect morphological alterations), most of the inhaled SCL is removed by the
nasopharyngeal cavity.   (See Chapter 11, Section 11.2.4 for an expanded
discussion of SCL absorption.)  In rabbits, the concentration of inspired SC^
determines how much is removed in the nasopharyngeal cavity as opposed to the
                                           79
bronchial and alveolar regions of the lung.    At high S02 concentrations,
greater than 26.2 mg/m3 (10 ppm), 90 to 95 percent is removed in the
nasopharyngeal cavity.  A small part, 3 to 5 percent, is removed by the
bronchiolar-alveolar region.  So at concentrations in this range, most of the
dose  is  delivered to the nasal turbinates with only a small percentage going
to  the  lung  parenchyma.  At lower concentrations of inspired SG^, such as 0.13
mg/m3 (0.05  ppm), which is closer to ambient levels, only 40 percent  of the
dose  is  delivered to the nasopharyngeal cavity upon inspiration, while another
40  percent  is  removed  by the  respiratory tract upon expiration.  Thus, at
 lower concentrations,  the actual percentage of S02 removed in specific regions
of  the  respiratory  tract is not  known precisely.  In the dog, over 95 percent
was removed  by the  upper airways and nose  at concentrations between 2.62 and
131 mg/m3 (1 to  50  ppm) S02.77'101
                          80
      Giddens and Fairchild    pointed out that these differences  in removal  of
inspired S0£ could  explain the apparent anomaly of  little damage to the  lower
respiratory  tract at high SO,, concentrations.  They undertook a  study of the
effects  of  inhaled  SO^ on the nasal mucosa of mice.  Two groups  of mice were
used; one group  that was free of specific  upper respiratory pathogens,  and  an
ordinary laboratory group that was presumed to be infected or to  have a  latent
infection of upper  respiratory pathogens.  Mice were exposed  continuously  to
26.2  mg/m (10 ppm) $62 for a maximum of 72 hr.   Pathological changes in the
nasal mucosa appeared  after 24 hr of exposure and increased  in  severity  after
                                    12-22

-------
72 hr of exposure.  Mice free of upper respiratory pathogens were
significantly less affected than the conventionally raised animals.   Giddens
             80
and Fairchild   concluded that resident or acquired pathogens exacerbated the
morphological changes they had observed.  Morphological alterations were,
however, qualitatively identical in both groups of animals.  Cilia were lost
from the nasal mucosa; vacuolization appeared; and the mucosa decreased to
about one half the normal thickness, and a watery fluid accumulated.
Desquamation of the respiratory and the olfactory epithelia was evident.
Alveolar capillaries were slightly congested, but edema and inflammatory cells
                                   81
were absent.  Martin and Willoughby   reported loss of cilia, disappearance of
goblet cells, and metaplasia of the epithelium of the nasal cavity of pigs
exposed to 91.7 mg/m  (35 ppm) SO- for 1 to 6 wk.  This study, however, was
marred by difficulties with the control of the S0?, rising on occasion to 262
mg/m  (100 ppm), and with high relative humidity occurring during cleaning of
the pig pens.
                  82         83
     Lamb and Reid   and Reid   attempted to use S02-exposed rats in a model
of human chronic bronchitis.  They presented favorable arguments that
S02-induced bronchial hyperplasia is analogous to human chronic bronchitis.
Most of their studies have been carried out at high concentrations of SO-
(1,048 mg/m  or 400 ppm S02 for 3 hr/day. 5 days/wk).  Under these conditions,
the trachea! glands clearly increased.  The goblet cell density also increased
in the proximal airways, main bronchi, trachea,  and distal airways, with
proximal airways and main bronchi showing the  largest changes.  The
incorporation of   S-sulfate by goblet cells into mucus also  increased with
exposure, reaching a plateau at approximately  3  wk.  Changes  in the mitotic
index were observed (Figure 12-2).  The effects  of 502 were concentrated  in
                                    12-23

-------
o   4
I
                      Proiimal  airways
                                                     Trachea
                                                           	o
        ^__   Distal  airways
    HON-EXPOSED
      ANIMALS
 234
S02 exposure  (weeks)
Figure 12-2. Mitotic count (four-hour period) after S02 exposure up
to six weeks. Mitoses represented as percentage of total nuclei.83
                            12-24

-------
the central airways, again suggesting that the solubility of SCL in water
limits its accessibility to the periphery.  Mitosis reached a maximum after 2
or 3 exposures and declined rapidly as injured cells were replaced.  On
repeated exposure for periods up to 6 wk, mitosis remained elevated in the
proximal airways compared to the distal airway in which this value returned to
the control level.  The magnitude was proportional to the SCL concentration
(Figure 12-3).  An elevation of the mitotic index occurred at concentrations
as low as 131 mg/m  (50 ppm) when given for 3 hr/day, 5 days/wk.  Major
changes in the goblet cell type or substance produced by the goblet cells were
also detected.  Goblet cells which produced mucous (Figure 12-4) resistant to
digestion by sialidase increased in numbers, and their distribution extended
distally from the upper bronchioles towards the respiratory bronchioles.
Since each molecular type of mucin, sialidase resistant or susceptible, could
be produced by one type of goblet cell, or each goblet cell could produce a
different mucin,  these results can be  interpreted in two ways.  The
elaboration of a  specific type of goblet  cell could occur, or more goblet
cells could be produced but with a change in their biochemical function
towards sialidase resistant mucins.
                  88
     Alarie et al.   examined the tissues of guinea pigs exposed continuously
to 0, 0.34, 2.65, or 15.0 mg/m3 (0, 0.13, 1.01, or 5.72 ppm)  S02 for 1 yr.
The lungs of the  guinea pigs exposed to 15.0 mg/m  (5.72 ppm) and  killed after
13 or 52 wk of exposure showed less spontaneous pulmonary  disease  than the
control group.  The prevalence of pulmonary disease  in the control groups
which was not observed prior to exposure  suggests  that they  acquired pulmonary
                                             88
disease during the exposure period.  In these   and  other  studies  by Alarie
                                    12-25

-------
      SO 100 200 300
        S02PPM
50 100 200 300
  SO2PPM
Figure 12-3. Histogram area covered by PAS sen-
sitive material in tracheal epithelium of rats ex-
posed to 50, 100, 200, and 300 ppm of S02 on
eight rats at each concentration. 1,000 fields
(x20) were evaluated. Counts made with an auto-
mated image analyzer.83
                  12-26

-------
               NORMAL
                             After ROE
            50,  EXPOSED
                              After RDE

Figure 12-4, Increase in goblet cells after expos-
ure to S02- Increase in goblet cells assessed by
comparison of left-hand diagrams; increase and
extension of goblet cells resistant to sialidase
(RDE) in right-hand pair.83
                12-27

-------
               90-92
and co-workers,      light microscopic observations were limited to
conventional hematoxylin-eosin stained paraffin sections.  The control group,
                                              o
as well as those exposed to 0.34 and 2.64 mg/m  (0.13 and 1.01 ppm), had
evidence of lung disease as shown by histocytic infiltration of the alveolar
walls.  Tracheitis was also present in the above three groups, but not in the
15.0 mg/m3  (5.72 ppm) group.  Hepatocyte vacuolation was observed in the
latter  group.  The survival was greater (p <0.05) in the 15.0 mg/m  (5.72 ppm)
group  than  in  the other groups including the air exposed control group.  The
authors do  not address the  significance of the hepatocyte vacuolation.  The
possible effects of  S02 in  this study cannot be accurately determined because
of the disease in the control animals.
                                   90 91
      Subsequently these researchers   '   exposed cynomolgus monkeys
 continuously  to  0.37, 1.7  or  3.35 mg/m3 (0.14, 0.64 or 1.28 ppm) S02  for 78 wk
 but found no  remarkable morphological alterations.  Another group exposed to
 12.3 mg/m  (4.69 ppm) SO^  for 30 wk was accidentally exposed to concentrations
 of S02 not higher than 2,620  mg/m  (1,000 ppm) or lower  than 524 mg/m3 (200
 ppm) for 1 hr, after which  they were placed in a clean air chamber and held
 for 48 more wk.  Persistent changes were noted in this group.  Alterations  in
 the respiratory  bronchioles,  alveolar ducts, and alveolar sacs were found.
 Proteinaceous  material was  found within the alveoli.  The distribution of such
 lesions was focal, but was  observed within all lobes of  the  lung.  Alveoli
containing  proteinaceous material were generally those which arose directly
from respiratory bronchioles.  Alveolar walls were thicker and were
infiltrated with histocytes and leukocytes.  Macrophages were present within
these  foci.  Moderate hyperplasia of the epithelia of the respiratory
bronchioles was  found, and  frequently the lumina of the  respiratory
                                   12-28

-------
bronchioles were plugged with proteinaceous material, macrophages, and
leukocytes.  Bronchiectasis and bronchiolectasis were present in 8 of 9
animals.  Vacuolation of hepatocytes was also observed, as with the guinea pig
group exposed to 15.0 mg/m  (5.72 ppm) in the prior study.88
     In a replication of this study, cynomolgus monkeys were exposed to 13.4
    3                                       92
mg/m  (5.12 ppm) S02 continuously for 18 mo.    No alterations in lung
morphology were reported to be due to SO-.  The morphological alterations
reported in the control group included lung mite infections and associated
"slight subacute bronchiolitis, alveolitis, and bronchitis."  Pulmonary
                                                              88 90~92
function measurements were made in the above mentioned studies  '      and are
described  in Section 12.2.5.
     The absence of S02~induced morphological alterations as reported by
Alarie  et  al.88'90"92 and Lewis et a!.104 who exposed dogs for 620 days (21
hr/day) to 13.4 mg/m  (5.1 ppm) SOp is not  in conflict with the broncho-
constriction induced by acute SO^ exposure  reported by Amdur and her
           qo                                                             go
co-workers   at lower concentrations  (see Section 12.2.5).  Alarie et al.
pointed out, "As recent literature attests, there is also an obvious lack of
knowledge  about the correlation between subtle microscopic alterations in the
lung and concomitant changes  in this  physiological parameter (lung function)."
Further, the transient nature of the  pulmonary function effects observed
during  short-term  exposures would be  difficult to detect morphologically
unless  the lungs were fixed during the time of exposure.  Even then, if the
cause of the increased pulmonary resistance were a simple alteration of smooth
muscle  tone as has been hypothesized,  it  might be morphologically
undetectable.
                                    12-29

-------
     Most of the studies in which the lungs of S02-exposed animals have been
examined center around tracheitis, bronchitis, ulceration, and mucosal hyper-
plasia (Table 12.4).   The lowest concentrations at which these alterations
have been reported have been in the rat at 131 to 134 mg/m  (50 to 51 ppm)  for
30 to 113 days.  At higher concentrations (1,048 mg/m  or 400 ppm S02 for 3
hr/day, 5 days/wk for 3 wk), recovery to normal morphology did not occur after
5 wk post-exposure.  The possibility of recovery from lower concentrations  and
                                           82 83
shorter durations of exposure is not known.   '    The studies of Alarie et
al 88,90-92  are  unfortunately flawed by the questionable health of the exposed
animals and  the  accidental exposure to high concentrations.
12.2.5  Alterations  in  Pulmonary Function
      Changes in  pulmonary  function have been  among the most sensitive and
 fruitful  areas of  research in $02 toxicity.   They have likewise been  useful  in
 studying  the effects  of aerosols alone or  in  combination with S02 (Sections
 12.3.3.1  and 12.4.1.1).  A variety of methods  have been used, some of which
 have been applied  to  human exposures.  A method for measuring increases  in
                                                           94 95
 flow resistance  in guinea  pigs  has been developed by Amdur.   '    Animals are
 not  anesthetized and  breathe spontaneously, which allows  sensitive measure-
ments  of  pulmonary function.  (A complete  description of  this method  appears
 in Appendix  I,  section  7.2.1.)
     The  respiratory  rate  of mice has been used as an indication  of  pulmonary
                           pc
irritation by Alarie et al.     Mice were exposed for 10 min to  0, 44.-5,  83.8,
162, 233, 322, 519, or  781 mg/m3 (0, 17, 32,  62, 89, 123,  198,  or 298 ppm)
S02-  About  a 12 percent decrease was observed at 44.5 mg/m3  (17  ppm).   The
respiratory  rate decreased inversely to the  logarithm of  the  concentration  of
inspired  SO,,.  The decrease in  respiratory rate, however,  was  transient,
                                    12-30

-------
returning to nearly control levels within 10 min even at continued exposure to
781 mg/m  (298 ppm) S02-  Complete recovery to control values occurred within
30 min following all exposures to S02.  The time for maximum response was
inversely related to the logarithm of the concentration of S02, being shortest
at highest concentrations.   Mice exposed to 262 mg/m3 (100 ppm) S02 for 10 min
were allowed to recover in clean air prior to a subsequent 10 min exposure to
the same concentration.  As the length of the recovery period was decreased
(from 12 min to 3 min), the effect of the subsequent S02 exposure on
respiratory rate was lessened.  "Desensitization" thus appeared to occur
during the course of exposures.  When another irritant, aerosols of
chlorobenzilidene malononitrile (CBM), was used during the refractory period
following S02 exposure, the respiratory rate decreased at a rate comparable to
that following exposure to CBM alone.  Thus, the refractory period associated
with S02 exposures  appeared specific to S02 and not to CBM.  When 262 to 328
mg/m  (100 to 125 ppm)  S02 was provided repeatedly for durations of 90 sec,
with each exposure  separated  by a 60 sec recovery period, the refractory
period was cumulative.  Ten such exposures eventually abolished all
respiratory rate responses to S02.  Breathing clean air for 60 min resulted in
a return of the response to initial levels.  When mice were exposed to S02 by
means of a trachea! cannula,  no changes in the respiratory rate were observed,
indicating that the decrease  in respiratory rate was mediated by a reflex arc.
This hypothesis has been developed in considerable detail  in an extensive
                or
review by Alarie    who  suggests that  stimulation and desensitization occur via
                                                                          85
cholinergic nerve endings of  the afferent trigeminal nerve.  Alarie et al.
also suggest that SCL  is hydrated to  bisulfite and sulfite which react with a
receptor protein to form an S-thiosulfate and a thiol, cleaving an existing
                                    12-31

-------
disulfide bond.   The receptor protein slowly regenerates to its original
disulfide configuration by the oxidation of S-thiosulfide and free thiol
moieties of the receptor protein to disulfide.   No direct evidence for this
hypothesis has been presented.
     Other investigators87'98"100'251 found that bronchoconstriction resulted
from both head-only and lung-only exposures in cats and dogs.  When corrected
for the  amount of S02 hypothesized to reach the lung, Amdur's study   with
guinea pigs has shown that S02 is highly effective in producing
bronchoconstriction through direct exposure of the lung.  Two sets of
receptors are involved  in the response of animals to 502-  At high concen-
trations of S02 or  following  long durations of exposure, the nasopharyngeal
receptors fatigue or become unresponsive, whereas the bronchial receptors do
                  87 251
not.   Nadel et al.   '    demonstrated the existence of  a reflex arc by  "cold
blocking" the vagus  nerve.  Chilling the vagus nerve prevents conduction of
nervous  impulses and abolishes the bronchoconstriction  produced by inhaled
S02>   Intravenous injection of atropine, which blocks some vagal  responses,
also  prevents the SC^-induced effect.  Sulfur dioxide-induced broncho-
constriction probably  involves smooth muscle contraction.  By acting on the
same  smooth muscles, acetylcholine (which is the neurotransmitter of the
vagus) aerosols evoke bronchoconstrictive responses similar  to those of
    102
S02-      Since the bronchoconstriction is dependent upon smooth muscle, which
is not likely to sustain constriction for long times, chronic exposures are
not likely to evoke sustained bronchoconstriction.  Hypersecretion of  mucus
and alteration of airway caliber are more likely chronic effects.
     Exposure to S02 evokes an increase in  resistance in guinea pigs which
persists for several hr and exhibits none of the tachyphylaxis found with
                                   12-32

-------
_*.            98 99
other species.  '    However, different techniques were used for these
 *•                       93
different species.  Amdur,   in a review of her data, reported that for a 1 hr
                             3                                        o
exposure, a mean of 0.68 mg/m  or 0.26 ppm (range of 0.08 to 1.57 mg/m  or
0.03 to 0.6 ppm) was the lowest concentration of S02 that increased flow
resistance in guinea pigs.  The response, a 12.8 percent increase (p < .001)
        93
at these   low levels of S02, was the average of 71 guinea pigs; the individual
data points were reported in other publications.  ''     For a 1 hr
exposure, the lowest concentration these researchers tested which caused an
increase (p <0.01) in resistance was 0.42 mg/m  (0.16 ppm) S02-     In a more
                          130
recent study, Amdur et al.     showed that a 1 hr exposure of guinea pigs to
0.84 mg/m  (0.32 ppm) S02 caused a 12 percent increase in resistance (p <0.02)
and a non-statistically  significant decrease in compliance.  At
concentrations of S02 below 2.62 mg/m  (1 ppm), the response of individual
animals varied considerably.  '    '     Of 1,028 guinea pigs, 135 were
"sensitive",  responding to low concentrations of S0« with greater changes in
resistance than the predicted mean.  Amdur cites comparative data for other
species, including man, to suggest that a certain fraction of all subjects may
exhibit this  phenomenon.93'170'274  On the other hand, Amdur et al.171 also
point out that some batches of animals may by chance not have a "sensitive"
individual.   In this study, 3 groups of 10 animals  each or a total of 30
guinea pigs exposed to 0.52, 1.05, or 2.1 mg/m  (0.2, 0.4, or 0.8 ppm) S02 had
no significant increase in airway  resistance above  the control  values.  Based
                          qc
on data from  earlier work,   she concluded that 10  to 13 percent of the guinea
                                                    170          98          99
pig population is more responsive  than the average.     In  cats   and dogs,
on
the other hand, few were found to be sensitive to short-term (< 1 hr)
exposure to 52.4 mg/m3  (20 ppm) S02  (cats) or 18.3 mg/m   (7 ppm)  S02  (dogs).
                                    12-33

-------
Even with the relatively small  sample sizes used, some cats and dogs responded
and others did not.
     Some of the problem of "sensitive" vs. "insensitive" members of the
experimental population can be understood by considering a simple hypothesis.
If one assumes that the response to a given toxicant, such as S02,  is the
result of a number of different genes within the population and not just a
single gene, then a single individual could have a number of recessive or
dominant  genes which could contribute to either the "sensitivity" or
"insensitivity" of that individual.  Since experimental animals and human
subjects  are drawn on as random a basis as is possible (in most experimental
designs), there will be a maximum chance of getting some "sensitive"
responders  in each experiment.  The total  number of "sensitive" responders
will  be  small and variable because of the  low incidence of "sensitive"
responders  in the general animal population.  A small, but variable, number of
"sensitive"  responders will tend to shift  the dose- or concentration-response
curve toward  lower concentrations and to decrease the slope of the  curve
(e.g., when  the data are expressed as the  log-probit transformation).  Such
phenomena have been studied in detail for  "resistant" insects which have
different genomes responsible for increased detoxification mechanisms.   In the
case  of  SC^, the matter is further complicated by comparisons between batches
of  animals and between different strains or species.  Even with guinea pigs,
the total number of animals examined to date (about 1,000 to 2,000) is too
small to  give more than a crude estimate of those animals having  a  "sensitive"
genome.  The incidence of "sensitivity" in the guinea pigs (about 13 percent)
is too low to have been detected clearly in the 100 or so cats and  dogs  used
in S0? experiments.   Here only 1 or 2 "sensitive" animals would have been
                                   12-34

-------
encountered.  Further, the small number of animals has been studied in
different laboratories and at different times, and the animals have come from
different genetic stocks.  It is fortuitous that Amdur's laboratory has
persisted in these studies with the same animal; the guinea pig, using the
same general methodology so this low incidence of "sensitivity" could be
detected.  While the mechanism(s) responsible for "sensitivity" is not known,
the question of "sensitivity" is an important aspect deserving of further
study.  A similar incidence of some 10 percent "sensitive" individuals in man
would have serious health policy implications.
                       79
     Using Strandberg's   data from the rabbit to correct for the
concentration of SCL hypothesized to reach the lung, Amdur   was able to
normalize the concentration-response curve for S0?-induced bronchoconstriction
in the guinea pig resulting from nose-only exposures (Figure 12-5).  A break
occurs in the concentration-response curve at about 52.4 mg/m  (20 ppm) S02,
perhaps due to the poorer extraction of gaseous SO^ by the upper airways at
low concentrations.  However, it should be recognized that SO- extraction data
for rabbits   and dogs   '    '    are in some conflict and that the data for
rabbits are not clear with respect to the site of S02 removal.  Thus, use of
the rabbit data for guinea pig studies can be done only hypothetically.
Sulfur dioxide introduced directly into the lung by a tracheal cannula was
much more effective in producing bronchial constriction.  Amdur    suggests
that at concentrations of 1.05 to 1.31 mg/m   (0.4 to 0.5 ppm)  very little
removal of SO^ occurs in the  upper airways.   These data contrast with the
radiotracer studies in dogs.   '    '     Others  have required  concentrations
greater than 18.3 mg/m3  (7 ppm) to evoke  increases  in flow resistance  in
anesthetized cats98 and  dogs.9   Differences  in the sensitivity of the  two
                                    12-35

-------
               • NORMAL    X.NORMAL  CONVERTED
               ACANNULA    TO "LUNG* CONCENTRATION
1'
u  _
UJ
2
Uj
IT
u Ol
u
<005
  ooi
^tr^r
OOI002 0-05 Ol O-2   0-5  I   2
                   S02  RPM

            Figure 12-5. Dose-response curves.
                                            50oo 20  so) ooo
                            12-36

-------
models may lie in the use of anesthesia, in the use of different species, or
in a different incidence of "sensitive" individuals.
     Using anesthetized, intubated, spontaneously breathing dogs exposed to
2.62, 5.24, 13.1, or 26.2 mg/m3 (1, 2, 5, or 10 ppm) S02 for 1 hr, Islam et
   102
al.    found an increased bronchial reactivity to aerosols of acetylcholine, a
potent bronchoconstrictive agent.  Acetylcholine is also the endogenous neuro-
muscular transmitter which can cause bronchoconstriction.  Bronchoconstriction
was determined by esophageal pressure concomitant with tidal volume.   Greatest
response occurred at 5.24 mg/m  (2 ppm), although 2.62 mg/m  (1 ppm)  also
caused an effect.  The effect of 26.2 mg/m  (10 ppm) was less than that at
2.62, 5.24, and 13.1 mg/m3 (1, 2, and 5 ppm).  These results suggest that S02
may modify bronchial reactivity and that bronchial  reactivity is susceptible
to other physiological modifications.
     Lee and Danner    reported that exposure to SO* concentrations above 50
mg/m  (19 ppm) for 1 hr caused an increase in tidal volume and a decrease in
respiratory rate in guinea pigs.  When guinea pigs  were exposed to 18 to 45
mg/m  (7 to 17 ppm) S02, a general decrease in tidal volume and an increase in
respiratory rate were observed.  The variability of these experiments was
extreme.  The hemoglobin concentration in the blood rose as much as 40 percent
during the exposure, suggesting some extreme hemoconcentration phenomenon.
Inorganic sulfate concentrations also increased by  as much as 100 percent
above pre-exposure values, but they were not corrected for hemoconcentration.
     Animals chronically exposed to S02  have also been examined for
alterations in pulmonary function.  Guinea pigs exposed  continuously to  0.34,
2.64, or 15 mg/m3 (0.13, 1.01, or 5.72 ppm) S02 for up to 1 yr showed no
changes in pulmonary function, however,  spontaneous pulmonary disease was
                                    12-37

-------
present in all animals (including controls) except those exposed to the
                      ftft                                         ^
highest concentration.    Dogs exposed for 21 hr/day to 13.4 mg/m  (5.1 ppm)
S02 for 225, but not 620, days demonstrated increased pulmonary flow
                                         89
resistance and decreased lung compliance,   after 620 days mean nitrogen
                                               90*92
washouts were increased.  Alarie and co-workers      exposed cynomologus
monkeys continuously to 0.37, 1.7, 3.4, or 13.4 mg/m3 (0.14, 0.64, 1.28, or
5.12 ppm)  SOp.  The latter concentration was used in an 18 mo study, whereas
the others were used  for 78 wk exposures.  Pulmonary function was  unchanged in
all of these  groups.  After 30 wk of exposure to 12.3 mg/m   (4.69  ppm)  S02,
monkeys were  inadvertently exposed to concentrations between 524 and 2,620
mg/m3  (200 and  1000 ppm) for  1 hr.  This treatment resulted  in pulmonary
 function  alterations  which persisted for the remaining 48 wk of the study
 during which  the  animals were exposed to clean air.  Morphological alterations
were  also seen  in this  group  (see Section  12.2.4).
      In summary,  there  are at least two  sets of receptors responsible  for
 changes in respiratory  function  in animals acutely exposed to S0?.  Decreases
 in respiratory  rate or  increased resistance to flow are reliable end points.
 Increased resistance  to flow  results from  SO^ concentrations as  low  as 0.42
 mg/m   (0.16 ppm)  using  guinea pigs.  Of  the animals so  far examined, guinea
pigs  are  the  most sensitive to S02-  The reason for this  is  not  known;
potential  factors include species, strains, and experimental technique used.
Within the laboratory population, some  individual  animals are  found  to be  more
sensitive  than  the average, but  the mechanism for  their sensitivity  is not
known.  While pulmonary function measurements in guinea pigs appear  to be
highly sensitive  to acute S02 exposures, chronic S02  exposure  has  not  been
proven to  have  a  similar effect, although  chronic  studies with  guinea  pigs are
                                    12-38

-------
Unclear because of disease in the control group.  In other chronic studies,
pulmonary function of monkeys was unchanged at S02 concentrations up to 13.4
mg/m  (5.12 ppm), but dogs were affected by 225, but not 620, days of exposure
to 13.4 mg/m  (5.1 ppm).  High levels of SCL likely to initiate airway
narrowing and hypersecretion of mucus do alter several parameters of pulmonary
function.  These results are not contradictory in view of the physiology of
Sl^-initiated bronchoconstriction.  Sulfur dioxide appears to cause
bronchoconstriction through action on the smooth muscles surrounding the
airways.  Since smooth muscles fatigue or become adjusted to altered tone over
time, chronic exposure to SOp is not likely to cause a permanent alteration in
bronchial tone.  Unfortunately, investigations of the reactivity of the
airways after chronic exposure to S0« have not appeared.  We do not know if
chronic exposure to SOp causes an alteration in response to SG^ itself, since
only direct measurements of pulmonary function were made on the animals after
chronic exposure.  It would be very informative to learn if chronically
exposed monkeys, for example, were more  or less sensitive to SO^. (Table 12-5)
12.2.6  Effects on Host Defenses
     Because alterations in particle removal could lead to increased suscepti-
bility to airborne microorganisms or increased  residence times of other
non-viable particles, the effects of SOp on particle removal and engulfment,
as well as on integrated defenses against respiratory infection, have been
studied.  The function  of the cilia does not appear to be affected by
exposure.  No changes were observed in the cilia beat frequency  or the
relative number of alveolar macrophages  laden with particles in  rats exposed
to 2.62 or 7.86 mg/m3 (1 or 3 ppm) S02 and graphite dust (mean diameter  1.5
urn, 1 mg/m3) for up to  119 consecutive days.105  Donkeys256 were exposed by
                                    12-39

-------
                                          TABLE 12-5.  EFFECTS OF SULFUR DIOXIDE OH PULMONARY FUNCTION
Concentration
0.37, 1.7, 3.4. or 13.4 mg/m3
(0.14. 0.64, 1.28. or 5.12 pp»)
SO,
0.42 or 0.84 mg/m3 (0.16 or
0.32 ppn) SO,
0.52. 1.04. or 2.1 mg/m3 (0.2.
0.4, or 0.8 pp«i) S02
2.62, 5.24, 13.1. or 26.2 mg/m3
(1, 2, 5, or 10 ppM) SO,
13.4 mg/m3 (5.1 ppm) SO,
V 18 to 45 mg/m3 (7 to 17 ppa)
g SO,
0, 44.5, 83.8. 162. 233, 322,
Duration
72-78 wk, continuous
1 hr
1 hr
1 hr
21 hr/day. 225 and
620 days
1 hr
10 «1n
Species
CynoMologus
monkey
Guinea pig
Guinea pig
Dog
Dog
Guinea pig
Mouse
Results
No change
Increase in resistance
No significant Increase In airway resistance.
Increased bronchial reactivity to aerosols of
acetylchollne, a potent bronchoconstrictlve agent
Increased pulmnary flow resistance and decreased
lung compliance at 225 days; Increased nitrogen
washout at 620 days
General decrease In tidal volume and an Increase In
respiratory rate
Respiratory rate decreased proportionally to the log
Reference
Al.rie et al.90'92
A^uret.l.124'130
Awdur et al.171
Isl-etal.102
Lewis et al.89
Lee and Danner
Alarle et al.85
 519. or 781 mg/m3 (0, 17. 32,
 62, 89. 123, 198, or 298 ppm)
 SO,
>50 mg/m3 (>19 pp«) SO,
1 hr
Guinea pig
 of the concentration; complete recovery within 30
 Mln following all exposures.   The tine for maximum
 response was Inversely related to the log of the con-
 centration, being shortest at highest concentrations

Increase In tidal volute and a decrease in respiratory Lee and Danner
 rate
                                                                                                                                            103

-------
nasal catheters to 68.1 to 1,868 mg/m3 (26 to 713 ppm) S02 for 30 min.   Below
786 mg/m  (300 ppm) clearance was not affected, but at high concentrations
(786 to 1,868 mg/m  or 376 to 713 ppm) clearance was depressed.  Increased
mucus flow and nasal irritation have been observed with as little as 26.2
mg/m  (10 ppm) SO^ for 24 hr.
     Ferin and Leach110 exposed rats to 0.26, 2.62, and 52.4 mg/m3 (0.1, 1, or
20 ppm) S02 for 7 hr/day, 5 days/wk, for a total of 10 to 15 days and then
measured the clearance of an aerosol of titanium oxide (Ti02).  The aerosol
was generated at about 15 mg/m  (1.5 urn MMAD, a  3.3).  These investigators
took the amount of Ti02 retained at 10 to 25 days as a measure of the
"integrated alveolar clearance".  Low concentrations of S02 (0.26 mg/m3 or 0.1
ppm) accelerated clearance after 10 and 23 days, as did 2.62 mg/m  (1 ppm) at
10 days but not afterwards until 25 days when clearance was decreased.   Hirsch
et al.    found that the tracheal mucous flow was reduced in beagles exposed
for 1 yr to 2.62 mg/m  (1 ppm) S02 for 1.5 hr/day, 5 days/wk.  The dogs were
examined by a broncho-fibroscope at the end of the exposures.  No differences
in pulmonary function were reported.  Confirmation of this study and
determination of the persistence of the decreased mucous flow at this low
level of S0? would be important to confirm in light of other data available.
     It appears that S02 may have more of an effect on anti-viral than on
anti-bacterial defense mechanisms.  Bacterial clearance was not depressed or
altered in guinea pigs exposed to 13.1 or 26.2 mg/m   (5 or 10 ppm) S02 for 6
hr/day for 20 days.107'     Using the infectivity model (see Section
12.3.4.3), Ehrlich178 found that short (3 hr/day for  1 to 15 days) or long (24
hr/day for 1 to 3 mo) exposures to 13.1 mg/m  (5 ppm) S02 did  not increase
mortality subsequent to a pulmonary streptococcal infection.   Virus
                                   12-41

-------
infections, however,  are augmented by simultaneous or subsequent S02 exposure.
Mice were exposed to  concentrations varying from 0 to 52.4 mg/m  (0 to 20 ppm)
S02 continuously for  7 days.108  Mice breathing 18.3 to 26.2 mg/m3 (7 to 10
ppm) S0? began to experience an increase in pneumonia.   The increase in lung
consolidation was significant at 65.5 mg/m3 (25 ppm), but not at 26.2 or 39.3
mg/m3 (10 or 15 ppm).  The rate of growth of the virus within the lung was
                                                                109
unaffected by S02 exposure.  When these results were reanalyzed,    S02 and
virus exposure produced weight loss at concentrations as low as 9.43 mg/m
(3.6 ppm).  Exposure to S02, whether alone or in combination with a viral
agent,  had more of an effect on weight reduction than on pneumonia.  Since
                     80
Giddens and Fairchild   showed that mice with apparent respiratory infection
were more  susceptible to the morphological effects of S02 (Section 12.2.4), a
rebound effect may be possible in which S02 and microbes each potentiate the
effect  of  the other.
     Several studies of the effects of S02 on alveolar macrophages have been
conducted, since  these cells participate in clearance of viable and non-viable
particles  in the  gaseous exchange regions of the lung.  Alveolar macrophages
from rats  exposed for 24 hr to 2.62, 13.1, 26.2, and 52.4 mg/m3 (1, 5, 10, and
20 ppm) S02 were  investigated by Katz and Laskin.195  Exposure to the 2
highest concentrations increased j_n vitro phagocytosis of latex spheres for up
to 4 days  in culture.  At  13.1 mg/m  (5 ppm) S02, phagocytosis was increased
after 3 or 4 days in culture, but not after 1 or 2 days.  Histochemical
studies of pulmonary macrophages from rats exposed to 786 mg/m3 S02 (300 ppm)
for 6 hr/day on 10 consecutive days showed no changes in the lysosomal
enzymes, p-glucuronidase,  p-galactosidase, and N-acetyl-p-glucosaminidase.112
Acid phosphatase  activity  was markedly increased.  This is  in  agreement with
                                   12-42

-------
Rylander's observation107 which suggests that SCL exposure (26.2 mg/m3 SO-, 10
ppm, for 6 hr/day, 5 days/wk for 4 wk) does not affect the bactericidal
activity of the lung. (Table 12.6)
12.3  EFFECTS OF PARTICIPATE MATTER
     Sulfur dioxide is oxidized to sulfuric acid in the atmosphere.  Sulfuric
acid can react with atmospheric ammonia to produce ammonium sulfate and
bisulfate.  Similar reactions can also occur in the animal exposure chamber
and confound the cause-effect relationships investigated.  Sulfur dioxide is
often present in polluted atmospheres with complex mixtures of other compounds
including heavy metals, which may be present as oxides or as sulfate or
nitrate salts.  In addition, organic compounds present in the atmosphere in
the gaseous phase can be associated with the particulate fraction or become
adsorbed on particles either i_n situ or during collection.  The diversity of
these organic compounds simply precludes any rational discussion of their
toxicity at this time, since little or no inhalation data is available.  The
details of the composition of atmospheric aerosols are dealt with elsewhere
(Chapter 5).  The deposition and transport of particles are also discussed
elsewhere (Chapter 11).
     Since very few  studies have appeared on the toxicity of complex
atmospheric particles themselves, this section will deal primarily with the
toxicity of the components of these particles and the toxicology of those
compounds which have been identified as constituents of atmospheric particles.
Therefore, these discussions, no matter how sophisticated for a single
component, are inherently simplistic.  The toxicities of the single components
are likely to be less than the combination which exists  in the atmosphere,
although antagonistic interactions can also occur.  For particles  other  than
                                    12-43

-------
                                                 TABLE  12-6.  EFFECTS OF SULFUR DIOXIDE ON HOST DEFENSES
        Concentration  S02
                                         Duration
                          Species
                                  Results
                                                                                                                                     Reference
0.26.  2.62.  or  52.4 mg/m3
  (0.1,  1,  or 20 ppm)
2.62. 13.1, 26.2. and 52.4 mg/m3
 (1. 5, 10, and 20 ppm)
2.62 mg/m3 (1 ppm)

2.62 or 7.86 mg/m3 (1 or 3 ppm)
 S02 + graphite dust (mean
 diameter 1.5 pm, 1 mg/m3)

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

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

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

26.2 mg/m3 (10 ppm)

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

3 hr/day. 1-15 days
 and 24 hr/day. 1-3 mo

7 days, continuous
6 hr/day for 20 days

30 min
6 hr/day, 10 days
 continuous
                         Rat
 1.5  hr/day, 5 day/wk    Dog

 Up to  119 days          Rat



 7 days continuous       House
Guinea pig

Mouse


House


Rat

Donkey



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

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

             Tracheal mucous flow was reduced.

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

             Exposure to S02 and a virus produced weight loss.
Bacterial clearance was not altered.

Did not increase mortality subsequent to a pulmonary
 streptococcal infection.

Increase in viral pneumonia at 18.3 to 26.2 mg/m3
 (7 to 10 ppm).  Rate of growth of virus unaffected.
Below 786 mg/m3 (300 ppm) clearance was not affected,
 but at high concentrations (786 to 1868 mg/m3 or 376
 to 713 ppm) clearance was depressed.

No changes in selected lysosomal enzymes.
                                                        Ferrin and Leach
                                                                                                             110
                                                        Kati and Laskin
                                                                                                            195
                                                                                                          111
                                                                     106
Hirsch et al.

Fraser et al.



Lebowitz and
 Fairchlld10*

Rylander107-192

Ehrlich178


Fairchild et al.

        107
                                                                                                                                                 108
Did not affect the bactericidal activity of the lung.   Rylander
Spiegelman et al.
                                                                         256
Barry et al.
                                                                                                                                             112

-------
^2^4' (NH.)?SO., anc' NH^HSO., no attempt will be made to be as inclusive as
documents for some of the individual components.  Rather, an attempt will be
made in this section to integrate this information in the perspective of the
potential biological effects of atmospheric particles.
     As will be apparent from the discussion of the toxicity of sulfate
aerosols in this section, the chemical composition of the atmospheric
particulates will determine the toxicity of the aerosol.  Atmospheric
particles are likely to have direct toxic effects in themselves, indirect
toxic effects through interactions with other pollutants, and chronic effects
through cell transformation or chronic alteration in cell function.  Direct
toxic effects are best substantiated by studies of cytotoxicity.  Those
reviewed here are for some specific compounds which are known to occur in the
particulate fraction.  The studies cited are by no means complete and could be
expanded by including a number of other investigations carried out i_n vitro or
by exposures other than inhalation.  The review was purposefully restricted to
those most applicable to the inhalation route of exposure.  Most of the
indirect effects through interaction with other pollutants have previously
been discussed  for SOp.  Some additional data implicating interactions between
S0? and particulate material, between S02 and ozone, and between ^SO. and
ozone are included here.  One should recall that a large fraction of the mass
of atmospheric  particles is composed of sulfate and nitrate compounds.
12.3.1  Mortality
     The susceptibility of laboratory animals to sulfuric acid  aerosols  varies
considerably.   Amdur    has reviewed the toxicity of  sulfuric acid aerosols
and pointed out that, of the commonly used  experimental  animals, guinea  pigs
are the most sensitive and most  similar to  man  in their  bronchoconstrictive
                                    12-45

-------
response to sulfuric acid.   The lethal  concentration (LC) of sulfuric acid
depends upon the age of the animal  (18 mg/m  for 1 to 2 mo-old versus 50 mg/m
for 18 mo-old animals), the particle size (those near 2 |jm being more toxic),
                                                                           252
and the temperature (extreme cold increasing toxicity).  In a recent study,
the LC50 (the concentration at which 50 percent of the animals die) in guinea
pigs for an 0.8 urn (MMAD) aerosol was 30 mg/m , whereas for a 0.4 um (MMAD)
aerosol, the LC50 was above 109 mg/m .   In determining acute toxicity, the
concentration of the aerosol appears to be more important than the length of
exposure.     The animals which died did so within 4 hr.  Chronic studies have
only  recently been undertaken, and they support this conclusion that mortality
rarely occurs at moderate concentrations of sulfuric acid.
      Sulfuric acid aerosol appears to have two actions.  Laryngeal and/or
bronchial  spasm are the predominant causes of death at high concentrations.
When  lower concentrations are  used, bronchostenosis and laryngeal spasm can
still  occur.  Pathological  lesions in the  latter case  include capillary
engorgement and hemorrhage.  Such findings are in accord with anoxia as the
prime  cause of death.
12.3.2  Morphological Alterations
                  197
      Alarie et al.     investigated the effects of chronic H2S04 exposure.
Guinea pigs were exposed continuously for 52 wk to 0.1 mg/m3 H2SO. (2.78 um,
HMD)  or to  0.08 mg/m  H2S04 (0.84 um, MMD).  Monkeys were exposed continuously
for 78 wk  to 4.79 mg/m3 (0.73 um, MMD), 2.43 mg/m3 (3.6 um, MMD), 0.48 mg/m3
(0.54  Mm, MMD). or 0.38 mg/m3  (1.15 um, MMD).  Sulfuric acid had  no
significant hematological effects in either species.   No microscopic  lung
                                   12-46

-------
alterations resulting from H^SO. exposure were observed in guinea pigs after
                                      197                     Q?
12 or 52 wk of exposure in this study     or in a later study.
Morphological changes were evident in the lungs of monkeys.   At the two
highest concentrations, there were changes (more prevalent in the 4.79 mg/m
H2$04 group) regardless of the particle size.  Major findings included
bronchiolar epithelial hyperplasia and thickening of the walls of the
respiratory bronchioles.  Alveolar walls were thickened in monkeys exposed to
         3                      3
2.43 mg/m  , but not to 4.79 mg/m  HUSCL.  However, particle size had an impact
at lower h^SO^ concentrations.  No significant alterations were seen after
exposure to 0.48 mg/m  of the smaller particle size (0.54 urn).   However,
bronchiolar epithelial hyperplasia and thickening of the walls of the
respiratory bronchioles were seen after exposure to the larger size (1.15 urn,
and lower  concentration (0.38 mg/m ).  Pulmonary function changes followed a
slightly different pattern (See Section 12.3.4.2).  In these studies, the
cynomolgus monkey was much more sensitive than the guinea pig.   Dogs also
appear to  be relatively insensitive to morphological effects of HpSO. alone.
            104
Lewis et al.    found no morphological changes after the dogs had been exposed
                                       3
for 21 hr/day for 620 days to 0.89 mg/m  H2S04 (90 percent <0.5 urn in
diameter).
     Recently, Cockrell et al.118 and Ketels et al.120 studied the
morphological changes resulting from sulfuric acid aerosols.  Cockrell et
al.118 examined the effects of 25 mg/m3 (1 urn, MMD, a  1.6) for 6 hr/day for 2
days in guinea pigs.  Segmented alveolar hemorrhage, type 1 pneumocyte hyper-
plasia, and proliferation of pulmonary macrophages were reported.  Ketels et
al.120 examined the response of mice to 100  mg/m  sulfuric acid; these
exposures  produced injury to the top and middle of the trachea, but  none to
                                    12-47

-------
the lower trachea and distal airways.   In an attempt to investigate the
dose-response relationship for sulfuric acid, mice received either 5 daily 3
hr exposures to 200 mg/m3, 10 daily exposures to 100 mg/m3, 20 daily exposures
to 50 mg/m3, or any one of these doses combined with 5 mg/m  carbon particles.
The damage was judged to be proportional to the concentration (C), but not to
the product of concentration and time (T) of exposure or to the time of
exposure.   (All of the exposures had the same C x T and therefore their
equivalence might have been hypothesized.)
      A  number of other studies of the morphological effects of H,,$04 when
combined  with other pollutants have been conducted.  (See  Section 12.4.1.2.
and Table 12-7)
12.3.3  Alterations in Pulmonary Function
12.3.3.1   Acute  Exposure  Effects—Generally, for short-term studies,
respiratory mechanics have  been much more sensitive to H^SO. and some other
compounds than other parameters tested.  Amdur has cautioned    that her
                               94 95
method  for measuring resistance  '   should not be used as an indication of
chronic toxicity and should be considered only for very short-term toxicity.
As pointed out above, the Mead-Amdur method uses unanesthetized guinea pigs  in
which a transpleural catheter has been  implanted.  Amdur suggests    that, if
anything, this procedure  increases rather than decreases the sensitivity of
the guinea pigs to inhaled  irritants.
      Using this method, Amdur and co-workers96'97'121"125'130'171'172  have
studied the effects of aerosols alone (see Table 12-8) or  in combination with
S02-  The combination studies are described in Section 12.4.1.1.   In all of
their studies, exposures were for 1 hr.  The method records  resistance to  air
flow  in and out of the lungs and airways, compliance (a measure of lung
                                   12-48

-------
                                             TABLE 12-7.   EFFECTS OF PARTICIPATE MATTER ON LUNG MORPHOLOGY
       Concentration
                                           Duration
 Species
                     Results
    Reference
0.08 «Kj/n3 H,SO« (0.84 u*. MHO),
 or 0.1 «g/m5 H2SO« (2.78 pit,
 MMD1
0.38 mg/m3 (1.15 urn, HMD).
 0.48 mg/m* (0.54 um. HMO),
 2.43 nig/m3 (3.6 M™. HMO), or
 4.79 mg/m3 (0.73 um.
   0.89 mg/ms (90X <0.5 um  in
    diameter) H2S04 aerosol
»-•

i. 25 mg/m3 (1 pm. MMO. o   1.6)
*°  H2SO, aerosol        9
50 mg/m3 H2SO«, or
 100 mg/m3 H2SO«. or
 200 mg/m3 H2S04. or any of
 of these doses combined with
 5 mg/m3 carbon particles
 (at all three duration schedules)
                                       52 wk, continuous
                                       78 wk, continuous
Guinea pig
Monkey
                                    21 hr/day, 620 days     Dog
                                    6 hr/day, 2 days        Guinea pig
                                       3 hr/day, 20 days; or   Mouse
                                        3 hr/day, 10 days; or
                                        3 hr/day, 5 days
No significant hematological effect.  No Microscopic
 lung alterations after 12 or 52 weeks exposure.
No significant heaatological effect.  Morphological
 changes in the lungs.  At the two highest concentra-
 tions there were changes, regardless of the particle
 size.  Major findings included bronchiolar epithelia
 hyperplasia and thickening of the respiratory bron-
 chioles.  Alveolar walls were thickened with 2.43
 mg/m3. but not 4.79 mg/m3.  No alterations with
 0.48 ing/in3 (0.54 p"), but with larger size (1.15 UM,
 0.38 mg/m3) hyperptasla and bronchiole thickening.

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

             Damage was proportional to the concentration.
Alarie et al.92-197
                                                                                                                                    Alarie et al
                                                                                                                                              197
                                                                                                                                 Lewis et al
                                                                                                                                             104
                                                                                                                                 Cockrell et al.
                                                                                                                                                118
                                                                                                                                 Ketels et al
                                                                                                                                              120

-------
                              TABLE  12-8.   RESPIRATORY  RESPONSE  OF GUINEA  PIGS  EXPOSED  FOR 1 HR TO PARTICLES

                                                         IN  THE AMDUR  et  al.  STUDIES
ro
i
in
o
Concentration
Compound mg/m3
H2S04 o.lO
0.51
1.00
1.90
5.30
15.40
26.1
42.00
0.11
0.40
0.69
0.85
2.30
8.90
15.40
43.60
30.50
(NH4)?S04 0.50
* 2.14
1.02
9.54
NH4HS04 0.93
2.60
10.98
Particle
size, pm, MMD
0.3
0.3
0.3
0.8
0.8
0.8
0.8
0.8
1.0
1.0
1.0
1.0
2.5
2.5
2.5
2.5
7.0
0.13
0.20
0.30
0.81
0.13
0.52
0.77
Resistance
cm H20/ml/sec
% difference
from control
+41*
+60*
+78*
+51*
+54*
+69*
+89*
+120*
+14*
+30*
+47*
+60*
+39*
+61*
+96*
+317*
+42*
+23*
-4
+29*
0
+15*
+28*
+23*
Compliance
ml/cm H20
% difference
from control
-27*
-33*
-40*
-35*
-40*
-24*
-38*
-26*
-13
-8
-25*
-28*
-16
-26*
-43*
-76*
-17
-27*
-13*
-23*
-12*
-15*
-30*
-19*
Reference
172,173
172
172
64,125
125
125
125
125
172
172
172
172
125
125
125
125
125
130
130
123,130,170
130
130
130
130

-------
                                                  TABLE 12-8  (continued).
ro
i
in

Compound
Na2S04
ZnS04
ZnS04-
(NH4)2S04







CuS04


NaV04
FeS04
Fe203 (2hr)

MnCl2
Mn02
MnS04
Concentration
mg/m3
0.90
0.91
0.25
0.50
1.10
1.80
1.50
2.48
1.40
1.10
3.60
0.43
2.05
2.41
0.70
1.00
11.70
21.00
1.00
9.70
4.00
Particle
size, pm, HMD**
0.11
1.4
0.29
0.29
0.29
0.29
0.51
0.51
0.74
1.4
1.4
0.11
0.13
0.33


0.076 (GMD)
0.076 (GMD)



Resistance
cm H20/ml/sec
% difference
from control
+2
+41*
+22*
+40*
+81*
+129*
+43*
+68*
+29*
+6
+32*
+9
+25*
+14*
+7a
+2a
-^
oa
+4a
-6a
-la
Compliance
ml/cm H20
% difference
from control Reference
-7 130
123,170
123,173
123
123,170
64,123
123,173
123
64,123,173
123,173
123
-11* 130
-15* 130
-11* 130
96
96
96,124
96,124
96
96
170

-------
                                                   TABLE 12-1.   POTENTIAL MUTAGENIC  EFFECTS OF  S02/BISULFITE
Concentration SO.



4

1310 mg/m3
(500 ppm)
Bisulfite
0.9 M HSO"
pH 5.0 J
3 M HSO"
pH 5-6 J
1 M HSO"
pH 5.2 J
5 x 10"3 M HSOl
pH 3.6 J
0.04 or 0.08 M
/
Organisn
Phage T4-R11 Systen
Phage T4-R11
Systen
E. coll K12 & //
K15 //
S. cerevtslae
D. nelanogaster
Hela cells
(Hunan)
End Point ^^
GC-»AT or /
deani natl on'of
cysocine'''
deami nation of
X cytocine
GC+AT or
deani nation of cytocine
Point Mutation
Point Mutation
Cytotoxiclty
^
Response Connents Reference
Sunne56o.nd
201
± Poor dose Hayatsu and.Miura
response I Ida et al.
+ Mukai et al.203
-»• * Doranga.and
Dupuy204
May not be Valencia et al.205
bioavallable
+ Thomson and Pace
13.1 - 105 ng/mj
(5 - 40 ppm n 3 nin)
Mouse flbroblasts &
Peritoneal nacrophages
Nulsen et al.
                                                                                                                                                208

-------
                                                TABLE 12-8 (continued).
    Compound
                Concentration
                    mg/ma
                 Particle
                size, pm, HMD
 Resistance
cm H20/ml/sec
% difference
from control
Compliance
ml/cm H20
% difference
from control
                                                                                             Reference
ro
    Na2S04

    ZnS04

    ZnS04-
    (NH4)2S04
CuS04



NaV04

FeS04

Fe203 (2hr)
MnCl2

   2
    Mn0
0.90

0.91

0.25
0.50
1.10
1.80
1.50
2.48
1.40
1.10
3.60

0.43
2.05
2.41

0.70

 1.00

11.70
21.00

 1.00

 9.70

 4.00
                                                             +9
                                                            +25*
                                                            +14*
   -io
     0

    +4

    -6

    -I
                                                                             -11*
                                                                             -15*
                                                                             -11*
                   123,173
                   123
                   123,170
                  64,123
                   123,173
                   123
                   64,123,173
                   123,173
                   123

                   130
                   130
                   130

                   96

                   70,96

                   96
                   124

                   96

                   96

                   170

-------
                                           TABLE 12-8 (continued)
Resistance CompH
^
anc*^
cm H20/ml/sec nl/c^H^O
Concentration Particle % difference $xTffference
Compound mg/m3 S1-ze> pn)j mo from controi ^-'from control Reference
Open hearth 0.16 +lla ^/
dust 7.00 +6*''
Activated 8.70 / -3a
carbon
Spectographic 2.00 // +7a
carbon 8.00 / +i7a
/
»2 *p < 0.05 /
• /
tn /
a*». *. • . . . . x
96,124
96,124
96
96
96


Statistics not done

-------
Compound
                                                  TABLE  12-9  (continued)
Concentration
    mg/m3
  Particle
size, urn, MMD
 Resistance
cm H20/ml/sec
% difference
from control
Compliance
ml/cm H20
% difference
from control
                                                                                                   Reference
Open hearth
dust
Activated
carbon
Spectographic
carbon
0.16
7.00
8.70

2.00
8.00
0.037 (GMD) +lla
0.037 (GMD) +6a
-3a

+7a
+17a
0 96,124
-16 96,124
96

96
96

ro
i
en
ro
*p < 0.05


aStati sties not done
      **Diameters are provided as  mass  median diameter (MMD)  unless  specified as geometric
        median diameter by count (GMD).

-------
 Additional References Recommended for Considerati^fKui  Chapter 12

Costa, D. L. and M. 0. Amdur.  Effect of oil jrrfsts  on  the  im'tancy of sulfur
     dioxides.  II.  Motor Oil.  Am. Ind-^Hyg. Assoc.  J. 40:809-815,  1979.

Costa, D. L., and M. 0. Amdur.  Effect of oil mists on the  irritancy of sulfur
     dioxide.  I.  Mineral Oils arid Light Lubricating  Oil.  Am.  Indust.  Hyg.
     Assoc. J. 40(8):680-685,/I979.

Costa, D. L., and M. O.^Afndur.   Respiratory responses of guinea pigs to oil
     mists.  Am.  Indusi.  Hyg. Assoc. J.  40(8):673-679, 1979.

Schneider and Ca-Tkins.  Sulfur dioxide induced lymphocyte defects in  peripheral
     blood cuKures.  Environ. Res. 3:473-482, 1970.

-------
distensibility), tidal volume (the volume of air moved during normal
breathing), respiratory frequency, and minute volume.  While increased flow
resistance is often the most striking feature of the response to aerosols,
calculations of the elastic, resistive, and total work of breathing can also
be made.  The method  is, therefore, nearly as elaborate and inclusive an
evaluation of pulmonary mechanics as could be made in small laboratory animals
until very recently.  (See Appendix I for a more detailed discussion of
methodology.)
     The importance of particle size on the site of pulmonary deposition is
described in Chapter  11.  The health effects impact of these factors is clear
                    125
from an early study.     Sulfuric acid aerosols of concentrations ranging from
1.9 to 43.6 mg/m  were generated in three particle sizes:  0.8 urn (a ,
1.32 urn), 2.5 urn (a   1.38 urn), or 7 urn (a   2.03 urn) MMD.  Particles of the
                   y                      y
largest size (7 pm, at 30 mg/m  ) produced a significant increase in flow
resistance but no other detectable changes in respiration.  At the  lowest
concentration tested, 1.9 mg/m  , the 0.8 urn particles produced an increase in
resistance to flow and in elastic, resistive, and total work of breathing; but
they produced a decrease in compliance.  The 2.5 urn particles also  increased
the resistance to flow at concentrations from 2.3 to 43.6 mg/m .  The relative
efficacy of the 0.8 and 2.5 urn  particles differed.  At concentrations of 2
mg/m , the 0.8 urn particles were more effective than the  2.5 urn particles.
The time course of the response also varied with the particle size, since the
2.5 urn particles did  not evoke  their major effects until  the last 15 to 20 min
of the 1 hr exposure.  These differences in response were probably  associated
with the degree and site of obstruction within the bronchi.  The 2.5 urn
particles affected the larger bronchi producing obstruction, whereas  the
                                    12-53

-------
0.8 pm particles caused narrowing of the smaller bronchi.  While the results
of the experiments are reported in a straightforward concentration-response
curve, the physiological response producing the measurable effects is
obviously highly complex.   Detailed understanding is lacking.
                                                 172
     In a more recent investigation, Amdur et al.    exposed guinea pigs for 1
hr to either 0.3 or 1 urn (MMD) H2S04 in concentrations ranging from 0.1 to 1
mg/m  .  The concentration-response for percent change in resistance was linear
for both particle sizes.  However, the smaller particle caused a greater
response, particularly at 0.1 mg/m  where a 26 percent increase in airway
resistance was observed.  Except for exposure to 0.11 mg/m  ^SO^ (1 pm), all
increases in resistance were significant.  The smaller particle size also
decreased compliance  at all concentrations tested.  However, for the 1 urn
particle the lowest effective concentration tested was 0.69 mg/m . For
equivalent concentrations, the 0.3 urn particle decreased compliance more than
the 1 urn particle.  Animals were also examined for 30 min after exposure
ceased.  At this  time, after exposure to 0.1 mg/m  HpSO. (0.3 urn) resistance
was still elevated above control in guinea pigs; but for the 1 urn particle,
recovery had occurred.  These exposures caused no alterations of tidal volume,
respiratory frequency, or minute volume.  In comparing these results to
                      155
earlier work with S02,    Amdur et al. describe  how the same amount of sulfur
when  given as H2$04 produces 6 to 8 times the response observed when given as
so2.
                    253
      Silbaugh et  al.    exposed Hartley guinea pigs for  1 hr to 1 urn (MMAD)
sulfuric acid aerosols at concentrations and relative humidities  of 0 mg/m3
(control group) (40 or 80 percent RH), 1.2 mg/m3  (40 percent RH). 1.3 mg/m3
(80 percent RH), 14.6 mg/m3 (80 percent RH), 24.3 mg/m3  (80  percent RH), and
                                   12-54

-------
48.3 mg/m   (80 percent RH).  Ten animals were exposed at each concentration
except for  the 24.3 and 48.3 mg/m  groups, which consisted of 9 and 8 animals,
respectively.  Measurements of  tidal volume, breathing frequency, minute
volume, peak  inspiratory and expiratory flow, tidal transpulmonary pressure
excursions, total pulmonary resistance and dynamic  lung compliance were
obtained every 15 min during (1) a 30 min baseline  period, (2) the 60 min
exposure period, and (3) a 30 min recovery period.  Pulmonary function changes
in sulfuric acid-exposed animals did not differ from controls, except for 1
animal exposed to 14.6 mg/m  , 3 animals exposed to  24.3 mg/m  , and 4 animals
exposed to  48.3  mg/m .  Pulmonary function changes  in these 8 responsive
animals included marked increases in total pulmonary resistance and marked
decreases in  dynamic compliance.  Four of these 8 animals died during
exposure.   The proportion of responsive to non-responsive animals increased
with exposure concentration, but the magnitude of pulmonary function change
was similar for  all responsive  animals.  Compared to non-responders,
responsive  animals tended to have higher pre-exposure values  of total
pulmonary resistance and  lower  pre-exposure  values  of dynamic compliance.
These results suggest that the  guinea pig reacts to acute sulfuric acid
exposure with an essentially all-or-^ine airway constrictive  response.   The
finding that  resistance and compliance changes are  important  components  of the
guinea pig's  airway response to sulfuric acid aerosols  is consistent with
                                 172
results published by Amdur et al.     The presence  of high pre-exposure
pulmonary resistance values  in  responsive animals  is similar  to  the  finding  by
Amdur^54 that guinea pigs with  high pre-exposure  resistance values were  those
most severely affected during irritant aerosol exposure.  However, the  lack  of
effects at  lower concentrations and the  essentially all-or-none  airway
                                    12-55

-------
constrictive response observed in these studies differs markedly from the
                                        125 172
graded response observed by Amdur et al.   '    during similar exposures.  The
reasons for these differences are unclear, but may be at least partially
related to differences in animal strains used in these studies and the studies
of Amdur and co-workers.  These results indicate an absence of respiratory
function responses to environmental concentrations of sulfuric acid, but
suggest that sensitive subpopulations might exist.
      Sackner et al.    evaluated pulmonary function in anesthetized dogs
 exposed  either to  approximately 18 mg/m  HUSO^ for 7.5 min or to 4 mg/m  ^SO^
 for 4 hr immediately  after exposure or 2 hr later.  The MMAD was < 0.2 urn.
 There were no significant changes in respiratory resistance, specific
 respiratory conductance, specific lung compliance, or functional residual
 capacity.   At the  higher concentration, cardiovascular parameters (e.g., blood
 pressure,  cardiac  output, heart rate, and stroke volume) and arterial blood
 gas tensions were  also studied, but no significant changes were observed.  The
 pulmonary function (pulmonary  resistance and dynamic compliance) of donkeys
 was not  affected by H2S04 exposure (1.51 mg/m3, 0.3 to 0.6 MMAD, 1 hr).222
      Studies of the irritant potential of sulfate salts have shown that  these
 aerosols are not innocuous and evoke increased flow resistance  similar to
 sulfuric acid aerosols.  The influence of particle size on the  effects of zinc
 ammonium sulfate has  also been investigated by Amdur and Corn.     They
 showed,  in guinea  pigs exposed for 1 hr, that zinc sulfate had  about  half the
 potency  of zinc ammonium sulfate, with ammonium sulfate being one-third  to
 one-fourth as potent  as zinc ammonium sulfate.  Zinc ammonium sulfate was
 chosen for study because it had been reported as a major component of the
                                            1 A/L
 aerosol  from the Donora, PA episode of 1948.     Zinc ammonium  sulfate is  not
                                   12-56

-------
 a common species found in urban air.   Four sizes of aerosols were
TT
'administered:   0.29, 0.51, 0.74, and 1.4 urn (particle mean size by weight).

'When the aerosol concentration was held constant at 1 mg/m , the smaller


 particles produced greater increased resistance to flow.   This response was


 thought to be the result of the number of particles rather than of


 differential sites of deposition.   The dose-response curve also became steeper


 with decreasing particle size.  These data should be carefully compared with


 those from similar human exposures (Chapter 13, pp. 37-42) where no response

 occurred.


      Amdur et al.130 recently compared the effects of (NH4)2$04, NH4HS04,

 CuS04> and Na2S04-  Although particle sizes and concentrations were not

 precisely matched throughout the study, statistical analyses for ranking were


 not applied, and the degree of response increased with decreased size (size

 range, 0.1 to 0.8 urn, MMD), the authors suggest that the order of irritant

 potency was (NH4)2$04 > NH4HS04 > CuS04-  Sodium sulfate (0.11 mg/m3, 0.11

 MMD) caused no significant effects on either resistance or compliance.  At the

 lowest concentrations used, (NH4)2$04 (0.5 mg/m3, 0.13 urn MMD), NH4HS04 (9.93

     o                                    o
 mg/m , 0.13 urn MMD), and CuS04 (0.43 mg/m , 0.11 urn MMD) decreased compliance.

 These concentrations of (NH4)2S04 and NH4HS04 also increased resistance.  For


 CuS04, the lowest concentration tested which caused an increase in resistance


 was 2.05 mg/m  (0.13 urn MMD).  All of these compounds are less potent than


 H2S04 in the Amdur studies.

      Comparisons between sulfuric acid and sulfate salt aerosols are  difficult


 to make because of the marked dependence of the efficacy on the aerosol size.


 If the particles are of identical size, sulfuric acid is more efficacious than


 zinc ammonium sulfate; but if the zinc ammonium sulfate were present  as a
                                    12-57

-------
submicron aerosol  and the sulfuric acid as a large aerosol,  then zinc ammonium
sulfate would be more efficacious at the same concentration.      Regardless of
the particle size, the equivalent amount of sulfur present as SC^ is much less
efficacious than if it were present as a sulfate salt or sulfuric acid.  When
present as SCL, 2.62 mg/m3 (1 ppm) S02 is equivalent to 1.3 mg/m  S and
produces a 15 percent increase in flow resistance.  If this amount of sulfur
were present as 0.7 urn aerosol of sulfuric acid, it would evoke a 60 percent
increase in flow  resistance or be about 4 times more efficacious.  If the
sulfur were present as zinc ammonium sulfate as a 0.3 urn aerosol, the increase
in  flow  resistance would be about 300 percent or a 20-fold increase in
efficacy.   Some sulfate salt aerosols are not irritating.  For example, though
ferrous  sulfate and manganous sulfate do not cause an increase in flow
resistance,  ferric sulfate does  cause this response.  A summary or irritant
potency  is  presented  below.
               Relative  Irritant Potency of Sulfates In Guinea Pigs
                            Exposed          for         One          Hour.  '

                     Sulfuric acid                      100
                     Zinc  ammonium sulfate               33
                     Ferric  sulfate                      26
                     Zinc  sulfate                        19
                     Ammonium sulfate                    10
                     Ammonium bisulfate                    3
                     Cupric  sulfate                        2
                     Ferrous sulfate                    0.7
                     Sodium  sulfate (at 0.1 urn)         0.7
                     Manganous  sulfate                 -0.9

      Data  are  for 0.3 urn  (MMD) particles.   Increases  in airway  resistance were
      related  to sulfuric  acid (0.41% increase  in  resistance per ug of sulfate
      as  sulfuric acid)  which was assigned a  value  of  100.
                                    12-58

-------
                  126
      Nadel  et al.     found that zinc ammonium sulfate (no concentration  given)
*bnd histamine aerosols produced similar increases in resistance to flow  and
^decreases in pulmonary compliance in the cat.   Histamine was more potent than
 zinc ammonium sulfate.   The increase in flow resistance could not be blocked
 by intravenous administration of atropine sulfate,  but was blocked by either
 intravenous or inhaled isoproterenol.   The increased flow resistance was
 suggested to be due to an increase in bronchial smooth muscle tone.   Histamine
 appears to be a likely mediator of the bronchoconstriction following
                                                         1 0-7
 inhalation of sulfate salt aerosols.  Charles and Menzel    investigated the
 release of histamine from guinea pig lung fragments incubated with varying
 concentrations of sulfate salts.  Almost complete release of tissue histamine
 occurred with 100 mM ammonium sulfate.  Intratracheal injection of ammonium
 sulfate also released all of the histamine from perfused and ventilated  rat
       128
 lungs.      The potency ranking of different sulfate salts in the release of
                              127 128
 histamine from lung fragments    '    was equivalent to that for increased
 resistance to flow.     Bronchoconstriction of the perfused lung occurred on
                                                       128
 intratracheal injection of sulfate salts or histamine.     About 80 percent of
 the constriction could be blocked by prior treatment of the isolated lungs  .
 with an H-l antihistamine.  These experiments as well as the original
 observations of Nadel et al.      and Amdur,    support the concept that an
 intermediary release of histamine or some other vasoactive hormone is involved
 in the irritant response of sulfate aerosols.  An ammonium sulfate particle is
 calculated to reach a concentration of about 275 mM at equilibration with the
                                                         129
 99.5 percent relative humidity of the respiratory tract.     Thus, the
 concentration of the hydrated particle on striking the mucosa would be within
 the range found to cause release of histamine  in guinea pig and  rat  lung
                                    12-59

-------
          197 128
fragments.    '      A recently published estimate of the dose of inhaled
                                                                     129
ammonium sulfate needed to release histamine in the lung is in error.
Complete release of histamine (100 percent) occurred with 1 umole of ammonium
                                                       128
sulfate/lung and not 1 uM solution for the entire lung.     Further, total
release of all histamine stores of a tissue rarely, if ever, occurs  under
physiological conditions.  Only about 10 percent of the total histamine  is
released during degranulation reactions uj vivo, producing anaphylactic  shock.
Therefore, even if the calculations were correct, only a small fraction  of  the
ammonium sulfate dose would be required to produce the far less violent
increases  in flow resistance reported by Amdur et al.    for ammonium
bisulfate  and ammonium sulfate.  Assuming the calculation of ammonium  sulfate
to be correct,  a 4 hr, not a 2 day, inhalation would produce a marked  increase
 in resistance to flow.   Additionally, Charles et al.    found the  rate of
            35   -2
 removal  of   SO.   from  the rat lung both i_n vivo and  i_n vitro to  be a
 function  of  the cation associated with the salt and to follow the  same order
 of potency as reported by Amdur and co-workers    in the guinea pig  irritancy
 test.  Especially noteworthy is the fact that manganous sulfate was  removed at
 essentially  the same  rate as sodium sulfate, both of which did not produce
 increased  resistance  to  flow in the guinea pig.
             196
      Hackney    has presented a preliminary summary of the effects of  aerosols
of H2S04 and  nitrate  and sulfate salts on squirrel monkeys (Sairniri  sciurens).
Monkeys were exposed  (head-only) to aerosols at 2.5 mg/m3 of  the  respective
salts or sulfuric acid,  40 or 85 percent RH at 25°C.   The exposure system was
designed to reduce stress on the unanesthetized monkey.  A non-invasive  method
of pulmonary function measurement was used in which total respiratory
resistance was measured  by the forced pressure oscillation technique at  sine
                                   12-60

-------
wave frequencies of either 10 or 20 Hz.  The measurement of pulmonary
resistance included the resistance of the chest wall which was assumed to be
irrelevant to pollutant response and to be constant throughout the
experiments.   To correct for stress, control values were taken as those for a
given monkey exposed on the previous day to an aerosol of distilled water (for
aerosol experiments).
            196
     Hackney    reports that the measurement of resistance was frequency
dependent with changes in resistance appearing greater in the 10 Hz than the
20 Hz measurements.  The exposure period in the experiments was either 1 or 2
hr.  Some aerosols were studied at only 40 percent RH.  No attempt was made at
a dose-response curve for aerosols and all exposures were at or near 2.5
mg/m .   At low relative humidity (40 percent RH; MMAD 0.3 urn, o  2.0), there
were no differences between (NH.^SO.-exposed and control values, while at
high relative humidity (85 percent RH, MMAD 0.6 urn, a  2.3), 3 of 5 monkeys
had increased airway resistance by 1 hr.  Zinc ammonium sulfate aerosols
produced increased resistance at low humidity (40 percent RH; MMAD 0.3 urn, o
2.5) but no consistent increases over control values at high humidity (85
percent RH; MMAD 0.6 urn, o  1.6).  Ammonium bisulfate (40 percent RH; MMAD 0.4
urn, a  1.8) also produced an effect at 2.7 mg/m .
     3
         1 Qfi
     Data    from exposures to sulfuric acid and NH4NO, aerosols were analyzed
by computer and differed quantitatively from the data reported above for those
exposures which were reduced by hand.  Differences were probably due to a
systematic error in the hand reduced data which required a judgement in
selection of raw data points.  The biological interpretation does not appear
to be altered by these two approaches, but it does point out the experimental
difficulties in interpretation of pulmonary function data from experimental
                                   12-61

-------
animals.   While H2$04 aerosols (40 percent RH; MMAD 0.4 urn, o  2.0) caused no
statistically significant increases, there was a trend toward increased
resistance after 60 min which then tended to decline.  Ammonium  nitrate
exposures produced no changes.
                                                 196
     Multiple contrast analysis of the above data    showed that no
significant differences between baseline or control values could be found  for
any  exposure using data collected at 20 Hz.  At 10 Hz, the data  was more
variable, but  significant differences indicative of increased airway
resistance  could be  found for animals exposed to ZnSO^,  (NH4)2$04 and  H2$04  at
40 percent  relative  humidity.  Several procedural aspects  should be
 recognized.  First,  data were analyzed on a group mean basis, even though
 large differences  between individual monkeys existed in  both variability and
 absolute magnitude.   Second,  the  time course of exposure to the  aerosols
 illustrated a  trend  indicative of a  transient response on  the part of  monkeys
 to sulfate, nitrate, or  sulfuric  acid aerosols.  The use of group means  tended
 to reduce the  magnitude  of  the response and flatten the  response-time  curve.
 This is  certainly  true  for  the S02  exposures.  Third,  there were major
 differences in the response measured at either 10 or 20  Hz.   Fourth,  the
 response estimated by both  manual and computer reduction differed by  as  much
 as 40 percent.   However, compared to the  data reported for guinea pigs,  these
experiments support  the  general trends originally proposed from the  guinea pig
data.
      Sackner and co-workers  "     have noted a  failure  of ammonium sulfate
aerosols to alter  cardiovascular  and pulmonary function  in dogs or trachea!
mucus  velocity in  sheep.  Some of these reports  are  at variance with the
previously  cited published  reports,  and no  detail  is  presently available to
                                    12-62

-------
evaluate this new evidence.  No significant alterations in pulmonary
resistance and dynamic compliance were observed in donkeys exposed to 0.4 to
2.1 mg/m3 (NH4)2$04 (0.3 to 0.6 urn MMAD) for 1 hr.222
                          132
     Larson and co-workers    have proposed that breath ammonia is important
in neutralizing inhaled sulfuric acid.  Ammonia is released in the breath from
blood ammonia and bacterial decay products in the buccal cavity.   Ammonia in
the breath could react with sulfuric acid to produce ammonium bisulfate or
ammonium sulfate, depending upon the amount of ammonia and sulfuric acid
present in the aerosol droplet.  Complete neutralization of sulfuric acid
would produce ammonium sulfate.  This theory has been discussed at some
       129
length.     Much of the data has not yet been published, so a critical review
of the model given for the neutralization of sulfuric acid aerosol droplets by
gaseous ammonia is not available.  Calculation of the relation between inhaled
sulfuric acid aerosol and  neutralization by breath ammonia is not simple, and
the model needs to be validated.
     The biological effects of  sulfuric acid aerosols could be due to a
combination of several factors.  First, the pH of the particle could be very
                         132
important.  Larson et al.    have calculated the neutralization capacity of
the breath ammonia.  Once  the neutralization capacity of the ammonia present
in the breath is exceeded, the  pH of  the aerosol reaching the lung may fall
rapidly.  Under low pH, the physical  properties of the mucous layer  lining the
                            219
upper airways may be altered    or the permeability of the lung may  be
increased.134 Second, the  chemical composition of the sulfate aerosol, if
other than sulfuric acid,  may also alter the permeability of the  lung to
sulfate.131'134'135  Third, the cation associated with the sulfate compound
may have pharmacological properties  in itself.  The permeability  of  the  lung
                                    12-63

-------
to sulfate ion presented as various sulfate salts    is in the same relative
order as the irritant potential found for aerosols of the same sulfate
sans.130
     It is likely that ammonia functions within pulmonary tissue as a source
of protons to increase the flux of sulfate to the site of action.  Ammonia can
diffuse readily across cell membranes as unionized ammonia to react with
protons forming ammonium ion.  Transport of sulfate would result in the
accumulation of protons to preserve electrochemical neutrality.   At
physiological pH values, a significant fraction of ammonium salts is present
as ammonia.  Ammonium salts could augment the local ammonia concentration and
thus increase the uptake of sulfate ions and result in release of histamine.
Ammonia increased the uptake of sulfate by the lung,   '    possibly by this
mechanism.
     In relation to  sulfuric acid, ammonium sulfate and bisulfate are less
irritating to the lung because of their higher pH values once dissolved in the
milieu of the lung.  Thus, neutralization of sulfuric acid aerosols by breath
ammonia could be an  important detoxification step.  The concept  of breath
ammonia does not negate the histamine release hypothesis since ammonium
                                                                          1 ?7
sulfate is active in the release of histamine in guinea pig lung fragments
                 128
and  in rat lungs.
     An important problem  is the relation of these observations  to human
effects.  Unfortunately, histamine release by non-immune mediate reactions
such as the apparent ion exchange process due to sulfate interaction with mast
cell granules    is  poorly understood.  Metabolism of histamine  by man and
rodents could have important differences.  Also, not all of the
pharmacological action of ammonium sulfate instilled intratracheally  in the
                                   12-64

-------
                                                            128
 perfused  rat lung could  be  blocked  by  an  H-l  antihistamine.     A  number  of
 other  inflammatory hormones,  aside  from histamine,  mediate  bronchial  tone in
t
 man.   Slow reacting substance of  anaphylaxis  (SRS-A),  prostaglandins,  and
 kinins would not  be blocked by an H-l  antihistamine.   Thus,  species
 differences are not unanticipated,  but should be  clarified  so the  potential
 applicability of  these data to man  is  understood.
     One  fact is  clear from all of  the studies so far  reported.  The
 biological  effect of sulfate compounds is highly  dependent  upon the chemical
 composition of the compound.   For example,  for pulmonary  function  sulfuric
 acid is much more potent than any sulfate salt, but the sulfate salts  also are
 of differing potency.  The  cationic species associated with  the sulfate ion
 may promote the transport of the  sulfate  ion  and,  thereby,  increase the
 biological  response.  The cation  has biological effects by  itself  as  discussed
 here.   It is not  possible,  then,  to predict the potential toxicity of  a
 sulfate aerosol based solely on the sulfate content.   Clearly, the acidity of
 the aerosol also  plays an important role  in the toxicity.
     An important experimental problem is raised  by the ammonia neutralization
 of sulfuric acid.   Ammonia  is produced in all animal  experimental  exposure
 systems through the accumulation  of urine and feces.   This  is particularly so
 in whole-body chronic exposures.  Few  exposure systems provide a  rapid
 turnover  of the chamber  air, e.g.,  1 chamber  volume/min,  and given the
 technological problems  in monitoring NH,, even this rate  of air flow  may  be
 insufficient. The usual turnover rate is 10  to 15 chamber  volumes of air/hr
 or less.   Under these conditions, animals exposed to sulfuric acid aerosols
 may, in fact, be  inhaling ammonium  sulfate and ammonium  bisulfate aerosols as
 well.   The high concentrations of sulfuric acid aerosols  needed to produce
                                    12-65

-------
significant pathological  effects on chronic exposure may be due to these
chemical conversions.   Since human exposure chambers would not be expected to
have comparably high levels of ammonia, there could be difficulty in comparing
results of human and animal studies of H-SO..  The level of ammonia in the
breath of animals is also unknown and is sure to vary with the diet of the
animals.  Some commercial animal diets are low in protein, while others are
high.  The blood ammonia will depend, in part, on the total amount of protein
and  quality of the protein as well as on the kidney function of the animal.
What effects, if any, the buccal flora have on the exhalation of ammonia in
animals is totally unknown.  Certainly, the propensity of SO^- and sulfuric
acid-exposed animals to develop nasal infections raises disturbing questions.
The  buccal flora of animals may be very different from that of man in its
ability to produce ammonia.  This technical problem of ammonia in the exposure
atmosphere should be addressed and solved before further reliance can be
placed  on these data for sulfuric acid. (Table 12-9)
12.3.3.2  Chronic Exposure Effects—The influence of chronic exposure to H^SO.
                                                       92 197
on pulmonary function was  investigated by Alarie et al.  '     Guinea pigs
exposed continuously to either 0.9 mg/m  (0.49 urn, HMD),   0.1 mg/m3 (2.78 urn,
     197             3               1Q7
HMD),    or 0.08 mg/m  (0.84 urn, MMD)    for 52 wk had no significant changes
of pulmonary mechanics (including measurements of flow resistance, respiratory
rate, some lung volumes, and work of breathing) that could be attributed to
^SO^.  However, cynomolgus monkeys exposed  continuously and tested
periodically during 78 wk were affected by some treatment regimens.197
Monkeys exposed to 0.48 mg/m  (0.54 urn, MMD) experienced an altered
distribution of ventilation (increased N2 washout) early in the  exposure
period, but recovery occurred during exposure.  Animals exposed  to a similar
                                   12-66

-------
                                    TABLE 12-9.  EFFECTS OF ACUTE EXPOSURE TO PARTICULATE MATTER ON PULMONARY FUNCTION*
          Concentration
                                           Duration
 Species
Results
Reference
   0 mg/ma (40 or 60% RH) 1.2 mg/m3    1 hr
    (40% RH), 1.3 mg/m3 (80% RH).
    14.6 mg/m3 (80% RH), 24.3 mg/m3
    (80% RH). and 48.3 mg/m3 (80% RH)
    1 M» (MMAD) HtS04 aerosol

   0.8 - 1.51 mg/m* H2S04              1 hr
    (0.3 - 0.6 \tm, MMAD) or
    0.4 - 2.1 mg/m3 (NH4)2S04
    (0.3 - 0.6 M*. MMAD)

   2.5 mg/m* (NH4)2S04>                1 hr
    ZnS04,(NH4)2S04, H2S04,
    and NH4N03; 2.7 mg/m3
    NH4HS04
Guinea pig   Pulmonary function changes observed In one animal       Sllbaugh et al.
              (out of 10) exposed to 14.6 mq/m3, three animals
              (out of 9) exposed to 24.3 mg/m3, and four animals
              (out of 8) exposed to 48.3 mg/m3
                                                                                                                                                   253
Donkey       No significant alterations In pulmonary resistance
              and dynamic compliance
                                   Schleslnger et al.
                                                                                       222
Monkey       Increased airway resistance at high relative hiMldlty   Hackney
              for (NH4)2SO<, and low relative hualdity for
              ZnS04 (NH4)2S04.   NH4HS04 also increased resistance.
              No significant effects with H2S04 or NH4NO,
                                                                            196

-------
concentration (0.38 mg/m ) but a larger particle size (2.15 urn, HMD) had no
change in this parameter.  Higher concentrations altered distribution of
ventilation, with the lesser concentration (2.43 mg/m ) and larger particle
size (3.6 urn, HMD) causing an onset sooner at 17 wk compared to 49 wk in
monkeys exposed to 4.79 mg/m3 H2$04 (0.73 urn, HMD).  Beginning at approximatey
8 to 12 wk of exposure, 0.38 mg/m3 (2.15 urn, HMD), 2.43 mg/m   (3.6 urn, HMD)
and 4.79 mg/m3 (0.73 urn, HMD) H2S04 increased respiratory rate.  The only
alteration  in arterial partial pressure of Q~ was a decrease observed in
monkeys exposed to 2.43 mg/m .  Except for respiratory rate as described
above, mechanical properties (including resistance, compliance, tidal volume,
minute volume, and work of breathing) were not significantly altered by the
chronic H?SO. exposures.  Morphological studies of these animals are described
 in  Section  12.3.2.
      Chronic studies of  dogs were performed by Lewis et al.   '     The animals
were  exposed for  21  hr/day for 225 or 620 days to 0.89 mg/m3 H2S04 (90 percent
<  0.5 urn  in diameter)  alone and in combination with S02 (see Section 12.4.1.2
                                         89
 for expanded discusion).  After 225 days,   dogs receiving H2S04 had a
 significantly lower  diffusing capacity for CO than animals that did not
                                           10.4.
 receive  H2S04-  After  620 days of exposure,    CO diffusiong capacity was
still decreased (p < 0.05).   In addition, residual volume and  net  lung volume
 (inflated)  were decreased (p < 0.05), and total expiratory resistance was
increased  (p < 0.05).  Total  lung capacity, inspiratory capacity,  and
functional  residual  capacity were also decreased (p =  0.1).  Other pulmonary
function measurements  were not significantly affected,  (see  Table  12-10)
                                    12-68

-------
                                    TABLE 12-10.   EFFECTS OF  CHRONIC EXPOSURE  TO PARTICULATE  MATTER  ON PULMONARY  FUNCTION
          Concentration
                                           Duration
                               Species
                                  Results
                                                            Reference
   0.08 mg/m3 H,SO« (0.84 \m, HMO)
    or 0.1 *g/MS H,SO« (2.78 M", H
HMD)
   0.38 mg/m3 (1.15 \tm, HHO)
    0.48 mg/m3 (0.54 MM, HMD)
    2.43 mg/m3 (3.6 u". HMD)
    4.79 mg/m3 (0.73 M«, MHO)
    H.SO,
   0.89 mg/m3 H,SO« (SOX
    <0.5 p» In diameter)
      52 wk, continuous
      78 wk, continuous
Guinea pig   No effects on pulmonary function.
                                                        Alarie et al.92'197
Monkey
      21 hr/day, 225 or
       620 days
Dog
Exposure to 0.48 mg/m3 altered distribution of
 ventilation early in the exposure period, but
 not later.  Exposure to 2.43 or 4.79 mg/m3 altered
 distribution of ventilation.  Exposure to 0.38,
 2.43, or 4.79 mg/m3 Increased respiratory rate.
 Other pulmonary function parameters were not affected.

After 225 days lower CO diffusing capacity.   After
 620 days capacity-was still decreased, residual
 volume and net lung volume were decreased,  and
 total expiratory resistance was increased;  total
 lung capacity, insplratory capacity, and functional
 residual capacity were also decreased.  Other
 pulmonary function parameters were not affected.
Alarie et al.
                                                                                                                                                 197
                                                                     Lewi, et al.89'104
ex
•o

-------
12.3.4  Alteration in Host Defenses
     To protect itself against inhaled viable or non-viable particles, the
host has several mechanisms of defense.  Particles which reach the gaseous
exchange regions of the lung can be phagocytized and killed (in the case of
microbes) by alveolar macrophages.  Later these cells can be moved up to the
ciliated airways where they are cleared from the lung, along with other
particles that  impact on the airways, by the mucociliary escalator.  This very
brief  description of clearance is expanded in Chapter 11.
                                                 218
12.3.4.1  Hucociliary Clearance—FairchiId et al.    showed that 4 hr
exposures to 15 mg/m  H2$04 (3.2 urn, CMD) after exposure to a nonviable radio-
 labeled streptococcal aerosol reduced the rate of ciliary clearance of the
bacteria  from  the lungs and noses of mice.  When mice received a 90 min
                    3
 exposure  to 15 mg/m H2SCL (3.2 urn, CMD) 4 days prior to the bacterial
 aerosol,  clearance  of nonviable bacteria was reduced in the nose but  not  in
 the lungs.   Neither regimen affected clearance of viable streptococci.  No
 significant effects were  seen at concentrations of 1.5 mg/m  (0.6 urn, CMD).
                       222
      Schlesinger  et al.    demonstrated that 1 hr exposures to 0.3 to 0.6 urn
 H2S04 mist  at  concentrations  in the range of 0.19 to 1.36 mg/m  produced
 transient slowings  of bronchial mucociliary particle clearance in 3 of 4
 donkeys tested.   In addition, 2 of the 4 animals developed persistently  slowed
clearance after about 6 exposures.  Similar exposures had no effects  on
 regional  particle deposition  or respiratory mechanics, and corresponding
                                   •i
exposures  to (NH4)2S04 up to  2 mg/m  had no measurable effects.   In  subsequent
             223
experiments,    the 2 animals showing  only transient responses and  2
previously  unexposed animals  were given daily 1  hr exposures,  5  days/wk,  to
H2S04  at  0.1 mg/m .  Within the first  few wk of  exposure, all  4  animals
                                    12-70

-------
developed erratic clearance rates, i.e., rates which, on specific test days,
were either significantly slower than or significantly faster than those in
their pre-exposure period.  However, the degree and the direction of change in
rate differed to some extent in the different animals.  The 2 previously
unexposed animals developed persistently slowed bronchial clearance during the
second 3 mo of exposure and during 4 mo of follow-up clearance measurements,
while the 2 previously exposed animals adapted to the exposures in the sense
that their clearance times consistently fell within the normal range after the
first few wk of exposure.  The sustained, progressive slowing of clearance
observed in 2 initially healthy and previously unexposed animals is a
significant observation,  since any persistent alteration of normal mucociliary
                                                           279
clearance can have important implications.  Lippmann et al.    have conducted
similar experiments in human subjects which are reviewed in Chapter 13.
     Trachea! mucociliary transport rates have been measured in several other
                               221
animal studies.  Sackner  et al.    failed to find significant changes in
tracheal mucus velocity following short-term exposures to 14 mg/m  (0.12 urn)
                                              222
HpSO. in sheep.  Similarly, Schlesinger et al.    saw no effect on tracheal
transport in donkeys after 1 hr exposures to concentrations up to 1.4 mg/m
                                                            774
(0.3 to 0.6 urn MMAD) H2$04.  On the other hand, Wolff et al.    reported a
depression in tracheal transport  rate  in anesthesized dogs exposed for 1 hr to
1.0 mg/m3 (0.9 urn, MMAD,  a  1.4)  which  persisted at  1 wk postexposure.
Recovery had occurred when the animals  were examined  again at 5 wk post
exposure.  Following a 1  hr exposure to 0.5 mg/m  H2S04, there were  slight
increases (p >0.05) in tracheal mucous  velocities immediately and  1  day after
exposure.  However, 1 wk  after exposure, clearance was  significantly
decreased.  The  latter results are  quite  similar to  those  observed  in  the
                                    12-71

-------
bronchi of individual humans in the Lippmann et al.    study (see Chapter 13),



although they recorded no significant change in the mean tracheal mucociliary



transport rates.



     Clearly, the results of the donkey studies support the human experiments



(Chapter 13) which indicate that H2S04 aerosol affects mucociliary  clearance



in the distal conductive airways.  Mucociliary clearance is dependent  upon



both the physicochemical properties of the mucus and the coordinated beat of



the underlying  cilia.  Mucus is excreted  into the  airway lumen  in an alkaline


                                    219
form which  is then acidified by C02-      In vitro  studies  have  shown that


                                                                          217
mucus  is a  sol  in high pH solutions, while at lower pH it  becomes viscous.



The H   supplied by the H2SO. may stiffen  the mucus and increase  the efficiency



of  removal.  This is  consistent with the  increase  in bronchial  clearance rate
                                          A   ML. 7^, 3
                                          (J* f s73$$s f*sffl               -I Q"I  TOO

observed  in humans following exposure to  400 (gg/m-.  Other studies    '    have



shown  that  exposures  to  0.9 to 1.1 mg/m   HLSO. can cause a depression  of



tracheal  ciliary beat frequency  in hamsters which  may  lead to a  depression  in



overall  bronchial clearance.  See Sections 12.4.1.1 and 12.4.2  for  more


                               181 182
details on  these latter  studies    '    which were  conducted with pollutant



mixtures.



     Based  on the results summarized above,  it is  possible that chronic  H?SO.



exposures at concentrations of about 0.1  mg/m  could produce persistent



changes  in  mucociliary clearance and exacerbate preexisting  respiratory



disease,  (see Table  12-11)



     Cadmium and nickel  chlorides also disrupt the activity  of  the  ciliated



epithelium.    '      Tracheal rings have been  isolated  from hamsters and  the



beat frequency  and morphology of the ciliated epithelium  have  been  observed.



Concentrations  of CdCl2  as  low as 6 uM i_n vitro resulted  in  decreased beat
                                    12-72

-------
                                            TABLE 12-11.   EFFECTS OF SULFURIC ACID ON MUCOCILIARY CLEARANCE
       Concentration
    Duration
                                                             Species
                                  Results
Reference
0.1 mg/m* H2S04
0.19 to 1.4 mg/m3 H2S04 (0.3
 tc 0.6 UM. MMAO)

0.5 mg/m3 H,S04
1 hr/day, 5 day wk,
 several MO
                                    1 hr


                                    1 hr
1.0 mg/ma H2S04 (0.9 u". MMAD,      1 hr


1.4 mg/m3 H2S04 (0.3 to 0.6 urn,     1 hr
 MMAO)

1.5 mg/m3 H2S04 (0.6 UM, CMO)       90 Min

14 mg/m3 H2S04 (0.12 MI* MMAD)       Short-ten*


15 mg/m3 H2S04 (3.2 u«, CMO)        4 hr



15 mg/m3 H2S04 (3.2 \m, CMO)        90 Min
Donkey       Within the first few wk, all 4 aniMls developed
              erratic bronchial Mucoclllary clearance rates,
              either slower than or faster than those before
              exposure.  Those aninals never pre-exposed before
              the 0.1 mg/m3 H2S04 had slowed clearance during
              the second 3 MO of exposure.

Donkey       Bronchial Mucoclllary clearance was slowed.
Dog          Slight Increases In tracheal •ucoclllary transport
              velocities Immediately and 1 day after exposure.
              One wk later clearance was significantly decreased.

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

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

                        Sheep        No significant changes in tracheal  •ucoclllary
                                      transport rate

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

                        Mouse        Exposure to H2S04 4 days prior to bacterial aerosol.
                                      Clearance of nonviable bacteria reduced in nose,
                                      but not lungs.
                                                                                                                                 Schleslnger  et al.
                                                                                                                                                   223
                                                                                             Schleslnger et al.


                                                                                             Wolff et al.224



                                                                                             Wolff et al.224
                                                                                                                                                   222
                                                                                                                                 Schleslnger et al.

                                                                                                                                                 71A
                                                                                                                                 Falrchild et al.  °

                                                                                                                                 Sackner et al.221

                                                                                                                                                 218
                                                                                                                                                   222
                                                                                                                                 Falrchild et al.'
                                                                                                                                 Falrchild et al.
                                                                                                                                                 218

-------
frequency and degradation of the ciliated epithelium architecture.     A prior
2-hr exposure i_n vivo to 2 urn aerosols of CdCl^ at 0.05 to 1.42 mg/m  caused a
significant decrease in cilia beat frequency proportional to the aerosol
concentration.  When hamsters were exposed to 1.33 mg/m  Cd for 2 hr/day for 2
days, the beat frequency did not return to control values until 6 wk after
exposure.  Nickel chloride aerosols or solutions had similar, but less marked,
effects.      The beat frequency decreased by 60 beats/min on exposure to 0.1
mg/m  Ni for  2 hr.  The decrement in beat frequency was proportional to the
concentration of Ni aerosol or solution.  A single 2 hr exposure to 0.1 mg/m
Ni  depressed  cilia  beat  frequency 24 hr after exposure, but the frequency
returned to  near normal values after 72 hr.  After exposure to 0.1 mg/m  , Cd
was about  20  percent more effective than Ni in slowing cilia beat. (Table
12-12)
12.3.4.2  Alveolar  Macrophages—Cytotoxicity of components of atmospheric
aerosols has  been studied with alveolar macrophages (AM).  The physiological
 role of AM in the prevention of infection and in the defense of the  lung
                                                                  148
 through removal  of  inhaled particles has been amply demonstrated.
                        005
      Allison and Morgan    have summarized the evidence that AM ingest  both
toxic and  non-toxic particles in the same manner.  In the case of fibers,
                                                              ??fi
ingestion  appears more  dependent upon the  length of the fiber.     Short
fibers  of  >5  urn are almost always ingested, while fibers >30 urn are  seldom
ingested completely and  remain in contact with the plasma as well as with the
lysosomal  surface.  Intermediate sized  particles  (5 to  20 urn)  are sometimes
completely ingested and  sometimes not.  Once  ingested,  particles  have  two
effects.   An  immediate  cytotoxicity appears which is  apparently  due  to the
interaction  of the  particle with the plasma membrane.225  This  interaction  is
                                    12-74

-------
similar to the hemolytic effects described for silica particles.  The second
effect results in delayed cytotoxicity and occurs after the particle has been
ingested into a primary phagocytic vacuole which then combines with a primary
                                                               J>pC
lysosome to yield a secondary lysosome containing the particle.     Here toxic
particles exert an effect upon the permeability of the lysosomal membrane,
resulting in the release of lysosomal enzymes into the cell and into the
external medium.   These proteolytic enzymes have the potential of causing
tissue damage.
     Hatch et al.    examined the influence of HI vitro exposure to a variety
of particles on AM oxidant production (02~ and H^) and found the response to
be chemical specific.  All the particles studied stimulated the
chemiluminescence, with amphibole asbestos being the most active.   Silica,
chrysotile asbestos, and metal oxide (Pb, Ni, Mn)-coated fly ash had
intermediate activity.  Fugitive dusts and fly ash had the lowest activity.
                  149
     Waters et al.    found that AM cultured with particulate forms of
vanadium had decreased cell viability, indicating a direct cytotoxicity.
Alveolar macrophages were cultured in medium containing vanadium pentoxide
(VpOr), vanadium trixoide (VJD.,), or vanadium dioxide (VCL).  Cytotoxicity was
directly proportional to the solubility of the vanadium compound:   V^ > V,,03
> V02.  The concentration of V required to produce a 50 percent decrease in
viability after 20 hr of culture was found to be:  13 ug V/ml as V205, 21 ug
V/ml as V203, and 33 ug V/ml as VCL.  When V205 was dissolved in the medium
prior to incubation with the AM, only about 9 ug V/ml were required to reduce
viability by 50 percent, thus indicating that the soluble V was responsible
for toxicity.  Phagocytosis, an essential function for the defense of the
lung, was decreased by 50 percent  with 6 ug V/ml as dissolved  V205.  Acid
                                    12-75

-------
phosphatase, a lysosomal degradation enzyme necessary for digestion of phago-
cytized bacteria, was inhibited by 1 pg V/ml as VpOc, while the lysosomal
enzymes, lysozyme and p-glucuronidase, were not inhibited by concentrations as
high as 50 pg V/ml.
     Alveolar macrophages exposed jm vitro for 20 hr to metallic salts were
also studied by Graham et al.    using a technique to determine phagocytosis
of viable cells only.  The chlorides of Cd (2.2 x 10~5M), Cr (3.1 x 10~3M), Mn
(1.8 x  10"3M), and Ni (5.1 x 10~4M) significantly inhibited phagocytosis.
Ammonium vanadate  (6.9 x 10  M) had no effect on phagocytosis, but did lyse
and  kill cells.  Nickel, which caused the greatest reduction in phagocytosis,
had  very little effect on viability or cell lysis.  Antibody-mediated rosette
formation of AM was  also inhibited in vitro by low concentrations of CdC^
 (2.2 x  10"5M)  or NiCl2  (10"4M).163  Inhibition was proportional to the Hi"1"*" or
   ^ jr
Cd   concentration and  reached its maximum within 20 min.  These studies
 showed  that the  antibody dependent recognition system of AM was inhibited by
                          ++       4>^*
 trace concentrations of Ni   and Cd   almost immediately after contact with
the  metal.   Such an  effect  implies that these metals may affect receptors for
phagocytosis of  the  opsonized bacteria.  Depression of AM viability,
phagocytosis,  and  receptors  for phagocytosis may  be a mechanism by which  these
heavy metal  salts  increase  the susceptibility to  airborne infections  as
discussed  later  (Section 12.3.4.3).
      Aranyi  et al.    reported cytotoxic effects  to AM with  fly  ash  particles
coated  with  PbO, NiO, or Mn02>  The percentage of metal  adsorbed  on  the  fly
ash  was fairly similar  across particle  size  for a given  metal.   The  fly  ash
particles were of  three size ranges:  <2,  2  to 5, or  5  to 8  urn in diameter.
All  of  the  particles, regardless of the coating or  particle  size,  decreased
                                    12-76

-------
cell viability and were phagocytized by the AM.   Within a given chemical
series of coated particles, the effects were both concentration and size
related, with smaller particles and greater concentrations producing greater
effects.  The greater surface area of the smaller particles was suggested as
being responsible for the greater toxicity of the small particles.  Total
cellular protein and lactic acid dehydrogenase also decreased after treatment,
probably as a non-specific result of the death of the cultured AM.  For each
particle size, Pb-coated particles were most toxic, NiO- and MnCL-coated
particles had intermediate effects, and the untreated fly ash was least toxic.
The toxicity did not appear related to the solubility of the metal oxide
coating, since no soluble metal could be found using the AM themselves as a
bioassay.  The toxicity appeared to be associated with the uptake of the
intact particle.  No changes were observed in the total lysosomal enzyme
content, but the latency or intactness of the lysosomal membrane was not
examined.  Toxicity could have resulted from the disruption of the intra-
cellular lysosomal membrane, which in turn could have released intracellular
lysosomal enzymes.  Lysosomal enzyme release has been proposed as one
potential mechanism for the toxicity of asbestos and silica particles.
These results support the concept that the surface activity of particles
                                        225
determines the toxicity of the particle.
     Bingham and co-workers    '    have examined the effects of  Pb and  Ni
inhalation on the number and type of AM present in the  lungs of  rats.   In  a
                                  152
preliminary report, Bingham et al.    showed that a 3 mo exposure to  0.01  or
0.15 mg/m3 Pb203 (0.18 urn, MMAD) decreased the number of AM/lung.  The
specificity of this response was investigated in a subsequent  study     using
                                    12-77

-------
soluble PbCl2 (0.1 mg/m3, 0.17 urn HMD) and NiCl2 (0.11 mg/m3, 0.32 urn HMD)
and insoluble Pb203 (0.15 mg/m ,  0.15 urn MMD) and NiO (0.12 mg/m3, 0.25 urn
HMD) aerosols.   Rats were exposed for 12 hr/day, 6 days/wk for 2 mo.  The only
exceptions were those exposed to Pb203 continuously.  Exposure to Pb203, but
not PbCl2, aerosols resulted in a depression of the number of AM which
persisted throughout the experiment (Figure 12-6).  The number of AM was
depressed on inhalation of 0.15 mg/m  Pb203 for up to 3 mo,  but returned to
control levels within 3 days after discontinuation of the exposure.  The
solubility of the Ni compound also had marked effects on the biological
response.  Nickel oxide produced a marked elevation in the number of AM/lung,
while  NiCl2  did not.  The most significant effects in NiCU-exposed rats were
marked increases  in mucus secretion and bronchial hyperplasia.  No
morphological alterations were observed in those rats exposed to PbCl2  or
PbpO.,.   Isolated  AM also varied in diameter with the exposure, but  the
biological significance  of this size  variation  is not known  at present.
 Perhaps different cell populations were recruited into the lung with the
 differing exposure  conditions.
      Cadmium chloride aerosols also altered the number and kind of  cells
 recoverable  by  lavage following exposure.    '     The total  number  of AM
 isolated  from exposed rats decreased  following  exposure to 1.5 mg/m Cd (99
percent <3 urn  in  diameter) but returned to normal values within 24  hr.  The
viability of the  isolated cells decreased by 11.2 percent  immediately after
exposure  and was  still depressed 24 hr  later.   There was an  influx  of
polymorphonuclear leukocytes, especially 24 hr  post-exposure, but  no  increase
in lymphocytes.
                                    12-78

-------

i;
•vj
£
f»
^
"c
i.
^
*
10
9
NiO T
/ ,-\
6 r

y f
7 -

/
c /
b ~ .-x
5
4
3
2
1
n
I-''
T /I Contro/
- ! T , y / T
XV J*- " '
"M * ^
- V / ^^j
I^^I ^ T
/[ 1 1 1 I I t i 1 !
          0   2   4   6   8   10  12  14  16  16
                   Doys  of  Exposure
Figure 12-6. Mean number and standard error of alveolar
cells washed from Jungs of rats after inhalation of oxides
of lead and nickel.
               12-79

-------
These effects were not observed at 0.5 mg/m3 Cd, indicating that the minimum
effective dose may lie somewhere between these two concentrations.
     Nickel chloride aerosols   '    produced neither an effect on the number
of AM isolated by lavage of rats the day following a 2 hr exposure to 0.65
mg/m3 Ni nor an influx of polymorphonuclear leukocytes.  The phagocytic
capacity of the isolated AM was, however, depressed.  A 2 hr exposure of mice
to 0.9 mg/m3 Mn,0. reduced the number of AM which could be  recovered by
                                                            188
lavage, but did not result in an influx of other cell types.     The AM had a
reduced concentration of ATP and total protein and acid phosphatase activity.
Viability  and  phagocytic activity of AM were normal.
      The  number,  function and kind of cells isolated from the  lung by lavage
are  influenced by the prior exposure to heavy metal aerosols.  Not all metals
produced  the  same effect but Cd, Ni, and Mn also enhanced the  susceptibility
of mice  to subsequent airborne infections.     The observations of two
 independent laboratories    '    '    on NiCK aerosols are essentially in
 agreement.   (Table 12-12)
 12.3.4.3   Interaction with  Infectious Agents—Gardner    and Ehrlich    have
 reviewed  their groups'  studies and presented new data on the effects of
 aerosols  on host  defense mechanisms against infectious pulmonary  disease  in
mice.   In  all  of  the Gardner studies, 94 to 99 percent of the  aerosols was
 less than  1.4  urn  in diameter.    '     Animals were placed in a head-only
exposure  system for 2 hr and were given graded concentrations  ranging  from
0.075 to  1.94  mg/m3 Cd,154  from 0.1 to 0.67 mg/m3 Ni,155 or from  0.5  to  5
     3    189
mg/m  Mn.   J   In mice, these exposures to Cd and Ni chlorides and  Mn.,0.
resulted  in the deposition  of 0.002 to 0.026 mg Cd,154 0.001 to 0.012  mg
Ni,    or  0.005 to 0.042 mg Mn190 per g dry weight  of  lung  respectively.
                                    12-80

-------
 Nickel clearance    from the lungs of mice had a half-life of 3.4 days; while
   190
 Mn    clearance was rapid, with a half-life of only 4.6 hr.   None of the
'exposures appeared to be edematogenic as judged by the ratio of dry weight to
 wet weight of the lung.   After metal exposure, mice were challenged with an
 aerosol of Streptococcus pyogenes (S. pyogenes).  The aerosols of CdClp,
 NiC^,    or MnCU    increased the mortality from the subsequent standard
 airborne infection.  Cadmium was more toxic than Ni, which was more toxic than
 Mn.  Exposure to Cd and Mn resulted in a significant linear concentration
 response.  The lowest concentration tested at which a significant increase in
                                    3               3
 mortality was detected was 0.1 mg/m  Cd or 0.5 mg/m  Ni.  Manganese, as
       189
 Mn20.,    was statistically estimated to produce a 10 percent increase in
                       3                176
 mortality at 1.55 mg/m  Mn, while MnClp    required a higher concentration to
 produce  a measurable increase in mortality.  Using a different infectivity
       191                                               3
 model,    3 or 4 days (3 hr/day) of exposure to 109 mg/m  Mn02 (0.70 urn, mean
 diameter) were required to increase mortality consequent to Klebsiella
 pneumoniae infection when the mice received the bacterial aerosol immediately
 after exposure.
      The toxicity of NiCl/, was complex.     Nickel exposure had no effect on
 the S. pyogenes  infection if the bacteria was given immediately after Ni
 aerosol  exposure.  When the bacterial exposure was delayed by 24 hr, Ni
 aerosols increased the mortality in a concentration-related fashion.  In
 contrast, effects of CdCl2    and Mn    were observed when the bacterial
 challenge immediately followed exposure.  The concentration-response curve of
 Ni was very steep compared to Cd and Mn exposures.      No explanation has been
 offered  for the  delay in effect of Ni.  Perhaps the delayed effects represent
 either redistribution of Ni to the site of action  or some major  change  in the
                                    12-81

-------
lung such as death of a specific cell type.  The delayed toxicity does raise
the possibility of carry-over of effects from a single exposure to a second.
     The influence of a variety of sulfate species on host defense mechanisms
                                                                       178
against infectious respiratory disease has been investigated by Ehrlich     and
              17Q
Ehrlich et al.    using the infectivity model with S. pyogenes.  Mice were
exposed for 3 hr.  The estimated concentrations of the compounds which caused
a  20 percent enhancement of bacterial-induced mortality over controls were  0.2
mg/m3 CdS04, 0.6 mg/m3 CuS04, 1.5 mg/m3 ZnS04, 2.2 mg/m3 A12(S04)3, 2.5 mg/m3
A1(NH4)2(S04)2, and 3.6 mg/m3 MgS04-  Ammonium sulfate at 5.3 mg/m  S04,
NH4HS04  at  6.7 mg/m3 S04, Na2$04 at 4 mg/m3 S04, Fe2(S04)3 at 2.9 mg/m3 S04,
                           o
and Fe(NH4)2S04  at 2.5 mg/m  S04 did not cause significant alterations.  The
nitrates of Pb,  Ca, Na, K, and NH4 did not cause an  effect at concentrations
of 2 mg/m  or  higher.  However, ZnNO., caused effects similar to ZnS04>  From
this body of work, it appears that the NH4 ion rendered the compound  less
toxic,  and  that  the toxicity is primarily  due to the cation.  With the
 infectivity model, ZnS04 and Zn(NH4)2(S04)2 ranked differently than with
airway  resistance experiments.     This is not unexpected as airway resistance
primarily detects alterations of the medium to large conducting airways, while
                     180
the infectivity  model    is hypothesized to reflect  alveolar level changes.
      The increased mortality of the  infectivity model does  seem to be a
measure  of  toxicity.  When mice were exposed for 2 hr to 5.0 mg/m3 carbon
                 3
black or 2.5 mg/m  iron oxide, no significant increases  in  mortality  resulted
on subsequent  exposure to airborne infection.
      Death  from  S.  pyogenes  exposure  in  this  infectivity model  is due to
            154                                                       ^
 septiceima.      Septicemia occurs when the  bacteria  have grown  to 10
 organisms per lung.   Removal  and killing of the  inhaled organisms will reduce
                                    12-82

-------
the growth of the bacteria within the host and prevent the occurrence of
septicemia.  For these reasons, the infectivity model is an integrative
assessment of toxicity for host defense systems against infectious pulmonary
disease.  As reported above, the number, kind, function and viability of the
cells isolated by lavage from the lungs of animals exposed to heavy metal
aerosols are different from control animals.   Studies of tracheal rings
isolated from aerosol-exposed hamsters also indicate depression of mucociliary
clearance.  Both mucocilary and AM clearance of bacteria are depressed by
aerosols of these heavy metals.     (Table 12-12)
12.3.4.4   Immune Suppression—Antibodies play a significant role in the
ability of macrophages to recognize and engulf pathogenic bacteria.   The
functioning of the immune system interlocks with the macrophage system in
other ways also.  In mice, intramuscular injections of NiClp depressed the
                                                 159
number of antibody-producing cells in the spleen.     Using the Jerne plaque
assay, a negative linear dose-response curve was found with injections ranging
from 9.26 to 12.34 ug Ni/g body weight.  No effect was observed with a dose of
3.09 ug Ni/g body weight.  The inhalation of NiClp aerosols (99 percent less
than 3 urn in diameter) was more effective in suppressing the primary immune
response.  Graham et al.    calculated that exposure to an aerosol of 0.25
mg/m  Ni for 2  hr would result in a maximum deposition of 0.98 ug Ni , assuming
complete retention and a minute volume of 1.45 ml/g body weight.  This
concentration was found to be the lowest tested which produced a significant
depression in the immune response.  The lowest dose found to produce a similar
                                        159
effect by injection was 208 ug Ni /mouse.     The inhalation dose was,
therefore, approximately 200 times more potent.  Ni was found to follow first
order removal kinetics from the lung, but measurable elevations remained  in
                                    12-83

-------
the lung up to 4 days after exposure.  Similar kinetics of removal have been
                                                           230
found using the isolated, ventilated, and perfused rat lung    and human, rat,
                                       231
and cat type II pneumocytes in culture.
     Inhaled Cd also depresses the number of antibody producing cells and is
more potent than intramuscularly injected Cd.  The highest intramuscular dose
of CdCl2 examined by Graham et al.    was 11.81 ug Cd/g body weight (about 266
ug Cd/mouse), and it produced no immunosuppression.  When mice were exposed to
0.19 mg/m  Cd for 2 hr, a significant suppression was observed.   In both cases
the  Cd  was administered as CdCl2, a  highly soluble salt.  The  inhalation dose
can  be  calculated on the same basis  as that given above for Ni to be at a
maximum at 0.74 ug Cd/mouse.  The inhaled dose was, therefore, at least
350-fold more potent.  Inhalation also appeared to be more potent than
ingestion  or  interperitoneal injection.   '     Keller et al.     found that
150  ug  Cd  given orally was required  to produce imrnunosuppression.
      For comparative purposes, the lowest inhalation exposure  of  CdCK found
                                     3          3
to be  immunosuppressive was 0.19 mg/m  ; 0.2 mg/m  was the 1971 Threshold Limit
Value  (TLV).  The current TLV is 0.05 mg/m .  The human intake from air has
 been estimated to  be  7.4  ug/day  and  from water to be 160 ug/day.     NiCl- was
 found to be immunosuppressive  at an  inhalation exposure of 0.25 mg/m  while
 its TLV is 1 mg/m  .   The  human exposure is estimated to be 2.36 ug/day  from
                                         229
 inhalation and 600 ug/day from ingestion.     Should the effectiveness  of
 inhaled aerosols be equivalent in mice and men, then the inhaled  doses  are
 biologically almost equivalent to those ingested.
      Inhaled Cd or Ni  aerosols impair the bacterial defenses  of the  lung
 through direct cytotoxicity  to AM, depression of antibody production, and
                                    12-84

-------
inhibition of antibody dependent aggregation reactions.  All of these
mechanisms can help to explain the increased susceptibility of mice to
airborne pathogens following inhalation of Ni or Cd aerosols.  The rapidity of
clearance of Ni and Cd from the lung may allow rapid recovery,  (see Table
12-12)
                                    12-85

-------
                                      TABLE  12-12.  EFFECTS OF METALS AND OTHER PARTICLES ON HOST DEFENSE MECHANISMS
         Concentration
                                          Duration
                                                               Species
                                                          Results
                                                                                                 Reference
  0.01 or 0.15 mg/m3 Pb,03
   (0.18 urn, MMAD)

  0.01 mg/m3 (0.17 pm. MMAD) PbCl2
   or 0.11 mg/m* (0.32 urn. MHAO)
   NiC12 or 0.15 mg/m3 (0.15 Mm.
   MMAD) Pb203 or 0.12 mg/m3 (0.17
   Mm, MMAO) NiO
  0.05 to 1.42 mg/m* CdCl,

  0.1 mg/» N1C12
!-•
ro
^Graded concentrations:
<* 0.075 to 1.94 mg/m3 CdCl2
   0.1 to 0.67 mq/m3 N1C1,.  or
   0.5 to 5 mg/m3 Mn30«;
   all aerosols (94-99*)  <1.4 urn
   in dia*eter

  109 mg/m3 Mn02 (0.70 \tm, mean
   diameter)
  0.2 mg/m3  CdSO«, 0.6 mg/m3 CuS04,
   1.5 mg/m3 ZnSO«, 2.2 mg/m3
   A12(S04)3,  or  3.6 mg/m3 MgS04

  Ammonium sulfate at 5.3 mg/m3
   S0«,  NH«HSO«,  at-6.7 mg/ni  S04.
   N02SO«  at 4 mg/m* S0«, Fe2(SO«)2
   at 2.9  mg/m3  S0«, or
   Fe(NH4)2S04 at 2.5 mg/m3 S0«
 3 mo
 12 hr/day.  6 day/wk.
  2 MO with  PbC)2,
  NiCl2,  or  NiO;  con-
  tinuously  for 2 mo
  with Pb203
 2  hr

 2  hr

 2  hr
 Rat


 Rat
Hamster

Hamster

Mouse
3 hr/day
Mouse
3 hr
3 hr
Mouse
Mouse
Decreased the number of alveolar macrophages/lung.      Bingham et al.


Exposure to Pb20,, but not PbCl,, resulted in a         Bingham et al.
 depression of the number of alveolar macrophages
 (AM) for up to 3 mo but returned to control levels
 within 3 days after discontinuation.  NiO produced
 a marked AM elevation, while NiCl2 did not.  NiCl2
 resulted in marked increases in mucus secretion and
 bronchial hyperplasia.  No morphological alterations
 with PbC)2 or Pb203.

Decreased ciliary beating frequency in trachea.         Ada1 is et al.

Decreased ciliary beating frequency in trachea.         Adalis et al.

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

Estimated concentrations which caused a 20X enhance-    Ehrlich et al.
 ment of bacterial-induced mortality over controls.


No significant alterations of host defense              Ehrlich et al.
 mechanisms.
                                                                                                                                                 152
                                                                                                           153
                                                                                                                                                157
156
 154
 155,189
                                                                                                                                                178,179
                                                                                                           178,179

-------
                                                                 TABLE 12-12.  (Continued)
         Concentration
                                        Duration
 Species
                                                                                                Results
                                                                         Reference
5,0 mg/m* carbon black or 2.5       2 hr
 •g/ir iron oxide

0.19 mg/m3 CdCl,                    2 hr
0.25 mg/m' NIC12
Mouse        No significant increases In Mortality resulted on       Gardner
             subsequent exposure to airborne infection.

Mouse        Decreased number of antibody-producing spleen cells     Graham et al.
                                                                                                                                                160
I
TO

-------
12.4  INTERACTION OF SULFUR DIOXIDE AND OTHER POLLUTANTS
12.4.1  Sulfur Dioxide and Particulate Matter
     Although man breathes a multitide of chemicals in various mixtures at
various dose-rates, most animal toxicological and controlled human exposures
are conducted with single chemicals.  This simplifies the research and permits
an improved estimate of cause-effect relationships, but it prohibits
evaluation of the effects of pollutant mixtures which may be additive,
synergistic, or antagonistic with respect to the individual pollutants.
      However, some interaction studies which elucidate the complexity of
toxicological interrelationships have been conducted.  Some of this work
utilized  pollutant combinations that would favor the conversion of the primary
pollutant to a secondary pollutant  (i.e., S02 altered to H-SO^, etc.).  Other
research  was directed  at evaluating the influence of several pollutants when
delivered in combination or  in sequence.
12.4.1.1   Acute  Exposure Effects—The question of the possible effect of
aerosols  on  the  response to  S02 is  a critical problem in air pollution
toxicology.      The  phenomenon has  been investigated in simple model  systems
of S02 alone or  in combination with an aerosol of a single chemical.  The
typical bioassay  system has  been the comparison of the increase in pulmonary
flow resistance  in guinea pigs produced by a given concentration  of S02 alone
with that produced in  the presence  of the aerosol.  The aerosols  used  in many
of these  studies  were  "inert"  in the sense that they did not produce  an
alteration in flow resistance when  they were given alone.
      The  initial  simple prototype aerosol used was sodium  chloride  (NaCl)at
concentrations of 10 mg/m  and 4 mg/m .    These experiments with guinea pigs
indicated that the response  to a given concentration of S02 was potentiated  by

-------
       3                                                            3
10 mg/m  sodium chloride.  For example, a concentration of 5.24 mg/m  (2 ppm)
S02 alone produced an increase of 20 percent in pulmonary flow resistance;
when the sodium chloride was present, the increase was 55 percent.  The
potentiation did not occur until the latter part of a 1 hr exposure.  When the
concentration of sodium chloride was reduced to 4 mg/m , the potentiation was
greatly reduced.  Examination of post-exposure data indicated that the
response to the combination resembled the response to a more irritant aerosol.
The length of recovery was related to the concentration of SOp, and the
presence of the aerosol delayed recovery to control values.  The chamber
relative humidities were below 70 percent, but on entering the high humidity
of the respiratory tract, the sodium chloride would absorb water to become a
droplet capable of dissolving S0« thus favoring the production of I^SO..
Sodium chloride does not catalyze the oxidation of S02 to sulfuric acid.
                                   141
     Experiments by McJilton et al.    indicate the importance of ambient
relative humidity and the solubility of SO- in the sodium chloride droplet.
They examined the effect of 1 mg/m  NaCl on the response to 2.62 mg/m   (1 ppm)
S02 at low (<40 percent) and high (>80 percent) relative humidity.  An
increase in pulmonary flow resistance in guinea pigs was the criterion  of
response.  As would have been predicted from the earlier work, no increase was
observed with this sodium chloride concentration at low relative  humidity.  At
high relative humidity, the potentiation was marked and was evident during
both the early and late parts of the 1 hr exposure.  The rapid onset  indicates
the formation of an irritant aerosol in the exposure chamber under  conditions
of high humidity.  As would have been predicted, no conversion to sulfate  was
found, but the droplets were acid with an estimated pH  of  4.   Presumably,  this
was sulfurous acid.  (See the discussion of the effect  of  relative  humidity  on
                                    12-89

-------
sulfate and nitrate aerosols above and on human exposure experiments in
Chapter 13).
     Amdur and Underhill   studied the effect of aerosols of soluble salts of
metals shown to convert S02 to sulfuric acid.  Manganous chloride, ferrous
sulfate, and sodium orthovanadate caused a threefold increase in the response
to S02 concentrations of 2.62 mg/m3 (1 ppm).  The potentiation was evident
during the first 10 min as well as during the remainder of the 1 hr exposure.
Chamber relative humidity was 50 percent, indicating that high humidity was
not  necessary  for the formation of an irritant aerosol in the chamber when the
catalyzing metals were  present.  Analysis of the collected aerosol indicated
                                                     93
the  presence of  sulfate, presumably as sulfuric acid.    These analyses
 indicated that at an S02 concentration of 0.52 mg/m  (0.2 ppm) about 0.08 mg
 sulfuric  acid  was formed.  When this amount of sulfuric acid was administered
with 0.52 mg/m  (0.2 ppm) S02, the increase  in flow resistance duplicated the
 increase  observed with  the  iron and vanadium aerosols.     This suggests that
 sulfuric  acid  formation is  the most likely mechanism of potentiation for the
 aerosols  of  these metals.   Amdur et al.    have reported that a 1  hr exposure
 to 0.4 mg/m   copper sulfate  also potentiated the response to 0.94  mg/m   (0.36
 ppm) S02.  At  the moment,  it is not certain whether this is mediated through
 the  formation  of sulfuric  acid or through the formation of a sulfite complex.
The  response  to  0.79 to 0.84 mg/m  (0.3  to 0.32 ppm) SO- with ammonium  sulfate
 (0.9 mg/m ),  ammonium bisulfate (0.9 mg/m ), or sodium  sulfate  (0.9 mg/m  ) was
purely additive.   It should  be pointed out that these salts  have  not been
 tested under conditions  of  high  relative  humidity.
                         96
      Amdur and Underhill    also  examined  the  effec
 aerosols  (carbon,  iron oxide,  manganese dioxide,  and fly ash) which do not
                   96
Amdur and Underhill   also examined the effect of a variety of solid
                                    12-90

-------
catalyze the conversion of SCL to H-SO..  None of these potentiated the
response to S02.  (Table 12-13)
12.4.1.2  Chronic Exposure Effects
     Animals were exposed continuously to various combinations of S02,
sulfuric acid (0.5 to 3.4 urn, HMD), and fly ash (3.5 to 5.9 urn, MMD) which
were collected downstream from electrostatic precipitators of coal-burning
                            92
electric generating plants).    Monkeys were exposed for 18 mo and guinea pigs
for 12 mo.  For monkeys, exposures were to S02, H2S04 + fly ash, S02 + H2$04,
or S02 + H2S04 + fly ash.  Guinea pigs received either 0.9 mg/m3 HpS04 (0.49
pm MMD) or 0.08 mg/m3 H2$04 (0.54 or 2.23 urn HMD) + 0.45 mg/m3 fly ash
(3.5 or 5.31 urn HMD).  In monkeys, a battery of hematological and pulmonary
function (tidal volume, respiratory rate, minute volume, dynamic compliance,
pulmonary flow  resistance, work of breathing, distribution of ventilation, CO
diffusing capacity, and arterial blood gases) tests were applied at various
times during exposure, but no  significant effects were attributed to the
exposures.  Similar methods (except for distribution of ventilation and CO
diffusing capacity) were used  with guinea pigs, but no significant effects
                                                       3
were observed.  At the end of  the exposure to 2.59 mg/m  (0.99 ppm) SO,, + 0.93
mg/m  H2$04 (0.5 urn MMD, a  1.5 to 3.8), the lungs of monkeys had
morphological alterations in the bronchial mucosa (focal goblet cell
hypertrophy and occasional hyperplasia and focal squamous metaplasia).
Monkeys exposed to 2.65 mg/m3  (1.01 ppm) S02 + 0.88 mg/m3 H2S04 (0.54 urn MMD,
o  1.5 to 3.8) + 0.41 mg/m  fly ash (4.1 urn MMD, a  1.8 to 2.8) had similar
alterations,."Thus, fly ash did not enhance the effect.  Monkeys which received
0.99 mg/m3 H2S04 (0.64 urn MMD, a  1.5 to 3.0) + 0.55 mg/m3 fly  ash  (5.34 urn
MMD, a  1.8 to  2.2) had slight alterations in the mucosa of  the bronchi and
                                    12-91

-------
                              TABLE 12-13.  EFFECTS OF ACUTE EXPOSURE TO SULFUR DIOXIDE IN COMBINATION WITH ("ARTICULATE HATTER
Concentration Duration
5.24 ug/m* (2 ppa) SO,. 10 Mg/M3 I hr
and 4 Kg/*3 NaCl
Species
Guinea pig
Results
5.24 Mg/M» (2 PPM) SO, alone
of 20X in pulMonary flow rei

produced an Increase
dstance; with NaCl at
Reference
A-dur97
ho
i
   2.62 Mg/ar* (1 ppM) SO,, 1
    NaCl at low (40 X) and high (80X)
    relative huMidity (RH)

   2.62 efl/K3 (1 ppn) SO,, an
    aerosol of soluble salts
    (•anganous chloride, ferrous
    sulfate, and sodiDM orthovana-
    date) 50% RH
   0.94 wg/M3 (0.36 ppn) SO,,
    0.4 ng/M3 copper sulfate

   0.79 to 0.84 Mg/M3 (0.3 to
    0.32 ppM) SO, and 0.9 Mg/M3
         iuM blsulfate,  or 0.9
          sodluM sulfate
1 hr
1 hr
1 hr
1 hr
              10 ng/Ma the increase was 55X and the potentialion
              did not occur until the latter part of the exposure.
              At 4 Mg/M3 NaCl, the potent(ation was greatly
              reduced.

Guinea pig   No increase In pulMonary flow resistance at low RH.     McJIlton et al.
              At high RH, the potentiation was Marked and evident
              during both early and late parts of the exposure.

Guinea pig   Presence of soluble salt Increased pulannary flow       AMdur and «g
              resistance about 3-fold.  The potentiation was          Underbill
              evident early in the exposure.
                                                                                                            141
Guinea pig   Potentiated pulMonary flow resistance.                  AMdur et al


Guinea pig   The effect on pulMonary flow resistance was             AMdur et al
              additive.
                                                                                                                                                130
                                                                                                         130

-------
respiratory bronchioles.  Focal areas of erosion and epithelial hypertrophy
and hyperplasia were observed.  The other groups of monkeys had no remarkable
morphological changes.  All monkeys exposed to fly ash displayed no
morphological alterations, although presence of the fly ash was easily
observed.  Guinea pigs experienced no morphological effects which could be
attributed to pollutant exposure.
                                       199
     In a previous study, Alarie et al.    found no effects on pulmonary
function, hematology, or morphology of monkeys or guinea pigs exposed to
approximately 0.56 mg/m  fly  ash in combination with 3 concentrations of S02
(0.28, 2.62, or 13.1 mg/m  ; 0.11, 1, or 5 ppm).  Monkeys were exposed
continuously for 78 wk and guinea pigs for 52 wk.
                 89 104
     Lewis et al.   '    investigated the effects of S02 and H2S04 in normal
dogs and in dogs which had been previously exposed for 191 days to 48.9 mg/m
(26 ppm) N02.  Dogs identically treated with N02 had morphological changes in
the lung, and one of the animals had striking bullous emphysema.  Sulfur oxide
exposures were for  21 hr/day for a maximum of 620 days to 13.4 mg/m  (5.1 ppm)
S02, to 0.89 mg/m   H2SO. (90 percent < 0.5 urn in diameter); or to a combination
of the two.  These  concentrations were averaged over time,and when the animals
were examined at 225 days, the concentration of HpSO. was lower (0.76 mg/m
H2S04 in the H2$04  group and 0.84 mg/m  H2S04 in the H2S04 + S02 group).
                           89
After 225 days of exposure,   dogs receiving HUSO, had a significantly lower
diffusing capacity  for CO than those that did not receive H2SO..  In the
S02-exposed animals, pulmonary compliance was reduced (p < 0.05), and
pulmonary resistance was increased (p < 0.05) compared to animals that did  not
receive S0?.  Dogs  not pre-exposed to N02 which  received S02 +  H2SO. had  a
smaller residual volume (p < 0.01) than all other dogs.
                                    12-93

-------
     These dogs were also examined after 620 days of exposure.104  At 3, 7, 19
or 20.5 mo of exposure, sulfur oxides did not markedly affect hematological
indices (number of erythrocytes and leukocytes, hemoglobin concentration,
hematocrit, mean corpuscular hemoglobulin value, mean corpuscular volume,  and
mean corpuscular hemoglobin concentration).   There were no morphological
changes that could be clearly identified as resulting from sulfur oxide
exposure.  However, pulmonary function was altered.  Generally, the animals
pre-exposed  to N0? were more resistant to the sulfur oxides.  Sulfur dioxide
did not produce any significant effects except for an increase in mean
nitrogen  washouts.  Sulfuric acid caused a significant (p < 0.05) decrease in
diffusing capacity  for CO, residual volume, and net lung volume (inflated)
with an  increase  in total expiratory resistance.  There was also a significant
 (p = 0.1) decrease  in  total lung capacity, inspiratory capacity, and
 functional  residual capacity.  Total lung weight and heart weight were  also
 decreased.   Other measurements (other  lung volumes, dynamic and static
 compliance,  and N2  washout) were not significantly affected.  These
 alterations  of diffusing  capacity for  CO and lung volumes are interpreted  as a
 loss of  functional  parenchyma, and, along with the increase in total pulmonary
 resistance,  are in  the direction expected for animals that develop obstructive
pulmonary effects.  Although the standard histological techniques used  did not
detect morphological effects, it is conceivable that the pulmonary function
effects preceeded measurable structural alterations.
      Beagle  dogs  were  exposed 16 hr/day for 68 mo to raw or photochemically
reacted auto exhaust,  oxides of sulfur or nitrogen, or their  combinations.  A
description  of the exposure groups is  given in Table 12-14.   They were
examined  after 18,186  36,104 and 61105 mo of exposure and 32  to  36 mo185'187
after the 68 mo exposure  ceased.
                                   12-94

-------
                                TABLE 12-14.  POLLUTANT CONCENTRATIONS FOR CHRONIC EXPOSURE OF DOGS
                                                                                                   185
          Atmosphere
                                              Pollutant Concentration,  mg/m
                                 CO
                                          HC
                                        (as CH)      N0
                                      NO
                                   OX
                                  (as 0)     S0
     Control Air (CA)'
      Non irradiated auto
      exhaust  (R)
                           112.1
              18.0
            0.09
           1.78
r\>
vo
tn
Irradiated auto
exhaust (I)
108.6
15.6
1.77
0.23
0.39
      S02  +  H2S04(SOy)
                                                                                      1.10
                                                                      0.09
      Nonirradiated  auto
      exhaust  +  S0_  +
      HS0   (R + S6)
                           113.1
              17.9
            0.09
           1.86
                      1.27
                      0.09
      Irradiated auto
      exhaust  +  SO,  +  H.SO.
      (I  +  S0x)    Z     i
                           109.0
              15.6
            1.68
           0.23
           0.39
           1.10
0.11
      Nitrogen  oxides,  1
      (N02  high)
                                                     1.21
                                     0.31
      Nitrogen  oxides,  2
      (NO  high)
                                                     0.27
                                     2.05
      Abbreviations  in parentheses
      3>90% of H?SO.  particles  were  <  0.5 urn in  diameter  (optical sizing)

-------
     After 18    or 36 mo    of exposure, no significant changes in pulmonary
function were observed.  A variety of alterations were found using analysis of
variance after 61 mo    of exposure, but only those significant results
related to sulfur oxides will be discussed in detail here.  Residual volumes
were increased in dogs receiving R + SOX (see Table 12-14 for abbreviations)
compared to those receiving I + SO   SO  , and CA.  Residual volumes of the SO
                                  A    A                                     "
                                                    2
group were lower than those of the CA group.  When x  analyses were applied to
the  data of the number of dogs/group having alterations as judged by clinical
criteria, additional significant differences were found.  More dogs of the I +
SO   group had  higher total expiratory resistance than their controls (CA  and
SO  ).   The ratio of residual volume to total lung capacity was higher in
animals exposed to R + SO  , compared to  those receiving air (CA).  This change
was  interpreted as pulmonary hyperinflation.  Although other lung volumes,
compliance,  resistance,  diffusing capacity for CO, ^ washout, peak expiratory
flow,  and maximum breathing capacity were also measured, sulfur oxides had no
effects.
                         18*5
      Thirty-two to 36  mo   after exposure ceased, the lungs of the beagles
were examined  using morphologic (light,  scanning electron and transmission
electron microscopy) and morphometric techniques.  Only the results for sulfur
oxide  combinations will  be described in  detail.  In the SO  group,  lung
weight, total  lung capacity and the displaced volume of the processed right
lung were significantly  increased over the controls (CA).   In the most
severely affected S0x  dogs, the air spaces enlarged and the number  and  size of
interalveolar  pores increased.  Only the N02 high dogs had  a greater  degree of
air  space enlargement.   The SOX animals  had a loss of cilia in  the  conducting
airways without squamous cell metaplasia, nonciliated bronchiolar cell  hyper-
                                    12-96

-------
plasia, and loss of interalveolar septa in alveolar ducts.  When SO  was
combined with R, cilia were also lost, but squamous cell metaplasia occurred.
Exposure to R + SO  and I + SOX produced nonciliated bronchiolar cell
hyperplasia and an increase in interalveolar pores and alveolar air space
enlargement.  The enlargement of the distal air spaces was centered on
respiratory bronchioles and alveolar ducts and was associated with an apparent
loss of interalveolar septa in all animals receiving S0~ and H^SO..  The
authors consider these changes to be analogous to an incipient stage of human
proximal acinar (centrilobular) emphysema.
     Biochemical analyses were also performed on the lungs of these dogs at
                                                         187
the time of sacrifice, 2.5 to 3 yr after exposure ceased.     Hydroxyproline
concentration (used as an index of collagen content) and prolyl hydroxylase
activity (the rate-limiting enzyme in collagen synthesis) were measured.  No
significant changes in hydroxyproline were found.  The SO  and I + SO  groups
had significantly elevated prolyl hydroxylase activity compared to the R, R +
SO  , and CA groups.
  ^
     Zarkower    reported mixed effects on the immune system of mice exposed
            o                          3
to 5.24 mg/m  (2 ppm) S02 and 0.56 mg/m  carbon (1.8 to 2.2 urn, MMD), alone
and in combination for 100 hr/wk for up to 192 days.  Animals were immunized
with aerosols of bacteria (Escherichia coli) at various times during exposure.
After 102 days of exposure, there were no  statistically significant changes.
Sulfur dioxide caused an increase (p < 0.05) in serum antibody titer at 135
days and a decrease (p < 0.01) at 192 days.  Carbon and carbon + S02 produced
an equivalent decrease (p < 0.01) in antibody titer at  192 days (but not at
135 days) which appeared to be a greater decrease than  that found  in the
S0?-exposed mice.  In the spleen, S02 caused an  increase  (p <  0.01)  in  the
                                    12-97

-------
number of antibody-producing cells at 135 days and a decrease (p < 0.01) in
number at 192 days.   In the mediastinal lymph nodes (which drain the lung),
SOp caused no such changes.  Carbon + SO-, but not carbon alone, caused an
increase (p < 0.01) in the number of antibody-producing cells in the
mediastinal lymph nodes and a decrease (p >0.05) in the spleen at 135 days.
After 192 days of exposure to carbon or carbon + S02, the number of antibody
producing spleen cells decreased (p <0.01).  The immunosuppression in these 2
groups was roughly equivalent and appeared to be more severe than that  in  the
SOp  alone group.  In the mediastinal lymph nodes, only carbon + S02 caused
 immunoenhancement (p < 0.05).  Thus, for the pulmonary immune system, only
 exposure to  the  combination of S02 and carbon caused significant effects.
 After 192 days,  the  systemic  immune system was affected in all 3 exposure
 groups.   It  appeared that  carbon and carbon + S02 caused equivalent effects
 and that both fag-i-mes  were  more  effective than S02-
                    183
      Renters et al.     showed  that  exposure  for 3  hr/day, 5 days/wk  for  up  to
 20 wk to a mixture of  1.4 mg/m  HpSO^  plus 1.5 mg/m  carbon (0.4  urn,  mean
 particle diameter) or  to 1.5 mg/m   carbon only (0.3 urn, mean particle
 diameter) also altered the  immune system of  mice.  Some classes of serum
 immunoglobulins (Ig) decreased,  with the exception of  IgM which was  increased
 after 1 wk of exposure to either carbon or H2SO. + carbon.  After 1  wk,  some
 Ig classes decreased in both exposure  groups, but  after 4 or 12 wk of
 exposure, alterations  were  observed only in  the H^SO.  + carbon group.   Results
 for Ig were mixed at 20 wk.  In  the carbon group,  the  number of  specific
 antibody-producing spleen cells  was increased at 4 wk, unchanged  at  12 wk,  and
 decreased at 20 wk.  A similar trend was observed  in the HUSO. +  carbon group,
 but only the immunosuppression at 20 wk was  significant.   In examining other
                                    12-98

-------
*host defense systems, no alterations of alveolar macrophage viability or cell
^numbers were observed.  After 4 and 12 wk of exposure, pulmonary bactericidal
* activity was increased in both exposure groups.  By 20 wk of exposure, values
 were not significantly different from controls.  Using the infectivity model
 with influenza A2/Taiwan virus, a 20-, but not a 4-, wk exposure to H2SO. +
 carbon increased mortality.
                                                       183
      Morphological changes were observed in these mice    using scanning
 electron microscopy after 12 wk of carbon exposure.  In the external nares,
 there was excess sloughing of squamous cells.  In the trachea, the number of
 mucous cells appeared to increase; dying cells were present, and microvilli
 were lost.  No alterations of the bronchi were seen.  The alveoli had some
 areas of congestion with thickening, loss of interalveolar septa, and enlarged
 pores.  After^20 wk of exposure, damage was similar, but to a lesser degree.
 Mice exposed to the mixture of H2SO. and carbon showed equivalent effects, but
 the damage was somewhat more severe than that seen in the carbon only group.
      The influence of H2SO. and carbon on the trachea of hamsters was
                              182                                           3
 investigated by Schiff et al.     Animals were exposed for 3 hr to 1.1 mg/m
 H2SO. (0.12 urn, mean  size) and/or 1.5 mg/m  carbon (0.3 urn, mean size) and
 were examined either  immediately, or 24, 48, or 72 hr later.  Carbon caused no
 change in ciliary beat frequency.  Sulfuric acid exposure, However, caused
 depression in this frequency at all time periods.  The combination of HUSO^
 and carbon produced similar effects, but recovery  had occurred by 48 hr
 post-exposure.  Using light microscopy, the percentage of normal tracheal
 epithelium was determined.  Up to 48 hr after  exposure, the combination of
 H?SO. and carbon resulted in more tissue destruction  than either pollutant
 alone, although the single pollutants did cause some  damage.  Morphological
                                     12-99

-------
alterations of all pollutant exposure groups were observed using light and
scanning electron microscopy,  (see Table 12-15)
12.4.2  Interaction with Ozone
     Cavender et al.    exposed rats and guinea pigs to sulfuric acid aerosols
(10 rog/m3, 1 urn MMD), 3.9 mg/m  (2 ppm) ozone, or a combination of the two  for
6 hr/day for 2 or 7 days; they then measured the ratio of  lung to body weight
and examined the  lungs historically.  No synergism was observed between the
ozone  and  sulfuric  acid treatments.  The histological lesions were those
                                         119
ascribed to ozone alone.  This same group    exposed rats  and guinea pigs to
sulfuric acid aerosols (10 mg/m , 50 percent equivalent aerodynamic diameter,
0.83 urn, a = 1.66),  1.02 mg/m  (0.52 ppm) ozone, or a combination of the two
for 6  hr/day, 5  days/wk for  6 mo.  The histological alterations were those  due
to ozone alone.
                    144
      Last  and Cross   found synergistic effects of a continuous exposure of
 sulfuric  acid aerosol  (1 mg/m ) and ozone (0.78 to 0.98 mg/m  or 0.4 to 0.5
 ppm)  when  administered simultaneously to rats  for 3 days.  Glycoprotein
 synthesis  was stimulated in  trachea!  ring explants measured ex vivo.  Ozone
 alone  caused  a  decreased glycoprotein secretion; sulfuric  acid was relatively
 inactive,  requiring concentrations in excess of 100 mg/m   to produce changes
 in glycoprotein  secretion.   The lung  DMA, RNA, and protein content increased
 in the group exposed  to ozone and sulfuric acid aerosols,  while the ozone-
exposed group had only a small increase and the sulfuric acid group had none.
                  181
     Grose et al.     investigated the interaction of H-SO. and 0, on ciliary
beat frequency  in the trachea of hamsters.  A  2 hr exposure to 0.88 mg/m3
H2S04  (0.23 urn,  VMD)  significantly depressed ciliary beat  frequency.   By  72 hr
after  exposure,  recovery had occurred.  Hamsters exposed to 0.196 mg/m3  (0.1
                                    12-100

-------
                                      TABLE  12-15.   EFFECTS OF CHROMIC EXPOSURE TO  SULFUR OXIDES AND PARTICULATE MATTER
Concentration
Various combinations of S02l
H2SO« (0.5 to 3.4 \m. HMD),
and fly ash (3.5 to 5.9 MM,
HMO): SO,, H2SO« + fly ash.
SO, * H2SO«. S02 + H2SO« +
fly ash
0.9 mg/m3 H2SO« (0.49 \im,
HMO); 0.08 mg/m3 H2S04
Duration
18 mo,
continuous
12 MO.
continuous
Species Results
Monkey No significant effects on heiutology or pulmonary
function tests during exposure. At end of exposure
to 0.99 pp» S02 + 0.93 mg/m3 H2S04 (O.S u». MMO)
lungs had Morphological alterations In the bronchial
Mucosa. Exposure to 1.01 DDM S02 + 0.88 mg/m3 H.SO.
(0.54 M«. MHO) + 0.41 Mg/m3 fly ash (4,1 MM, MMD) hid
similar alterations, thus fly ash did not enhance
effect. Exposure to 0.99 Mg/MJ H SO. (0.64 MM, MMO)
+ 0.55 mg/m fly as (5.34 M", MMO) hid slight
alterations.
Guinea pig No significant effects on hematology, pulMonary
function, or Morphology.
Reference
Alarie et al.92
Alarle et al.92
    (0.54 or 2.23 p«.  MMD)  +
    0.45 mg/m3  fly ash (3.5
    or 5.31 M<*.  HMO)
   Approximately 0.56  mg/m3 fly
,_  ash In combination with S02  at
7*  0.28, 2.62,  or 13.1 mg/m3  (0.11,
S  1.  or 5 ppm).
i—
   Approximately 0.56  mg/m3 fly  ash
    in combination with S02 at
    0.28, 2.62,  or 13.1 mg/m3
    (0.11, 1. or 5 ppm)
   13.4 mg/m3 (5.1 ppm) S02. or
    0.89 mg/m3  H2SO«  (90X <0.5
    MM in diameter),  or to a
    combination  of the two
78 wk.                  Monkey
continuous
             No effects on pulmonary function,  hematology,
              or morphology.
                                                                                             Alarle et al
                                                                                                          199
52 wk,
continuous
Guinea pig   No effects on pulmonary function,  hematology,
              or morphology.
                                                                                             Alarle et al.
                                                                                                          199
21 hr/day, 620 days     Dog
             After 225 days, dogs receiving H2S04 had a lower
              diffusing capacity for CO than those that did not
              receive H2SO«.  In the S02-exposed group, pulmonary
              compliance was reduced and pulmonary resistance was
              Increased compared to dogs that did not receive S02.
              Dogs not pre-exposed to N02 who received SO, + H2S04
              had a smaller residual volume than all other dogs.
              After 620 days, pulmonary function was altered fro*
              sulfur oxide exposure but no hematological or
              morphological changes occurred.   S02 did not produce
              any effects except for an increase in mean nitrogen
              washout.  H2S04 decreased diffusing capacity
              for CO, residual volume, and net lung volume and
              increase in total expiratory resistance.
              Total lung capacity, inspiratory capacity functional
              residual capacity were decreased.  Total lung weight
              and heart rate were also decreased.
                                                                                             Lewis et al.89'104

-------
                                                               TABLE 12-15 (continued).
       Concentration
                                         Duration
                                                             Species
                                                          Results
                                                                                                 Reference
(see Table 12-»)
                                    16 hr/day, 68 mo
                        Dog
5.24 *g/m3 (2 ppm) SO,, or 0.56
 mg/m3 carbon (1.8 to 2.2 urn,
 HMO), or In combination
1.4 mg/m3 H2SO, plus 1.5
 mg/m3 carbon (0.4 pm,  mean
 particle diameter), or 1.5
 mg/m3 carbon only (0.3 urn,
 •can particle diameter)

1.1 mg/m3 H2SO« (0.12 urn.  mean
 size), or 1.5 mg/m3 carbon (0.3
 pa. mean size), or in  combination
100 hr/wk, 192 days     Mouse
3 hr/day,
 20 wk
3 hr
5 day/wk,
Mouse
                        Hamster
After 18 or 36 mo exposure no changes In pulmonary
 function.  Residual volumes Increased In dogs
 receiving R + SO  compared to I + SO , SO ,  and CA.
 Residual volumes of the SO  group Mere lower than of
 the CA group.  More dogs or the 1 + S0x had higher
 total expiratory resistance than their controls
 (CA and SO ).  The ratio of residual volume to total
 lung capacfty was higher in R + SO  than CA.  32 to 36
 mo after exposure ceased, the SO  group had lung
 weight, total lung capacity. andxdisplaced
 volume of the processed right lung increased over
 controls (CA).  SO  dogs had loss of cilia in the
 conducting airways.  SO  * R had loss of cilia
 and squamous metaplasia.  Exposure to R + SO
 and I + SO  produced none 1 Hated bronchlolar
 cell hyperplasla and an increase In interalveolar
 pores and alveolar air space enlargement.

For the pulmonary Immune system, only exposure to
 the combination caused significant effects.   After
 192 days, the systemic Immune system was affected
 in all 3 exposure groups; carbon and carbon + S0t
 were more effective than S0t, although S02 did
 cause significant effects.

Altered the Immune system.  Morphological changes
 observed; more severe with carbon only exposure.
                           Carbon caused no change In ciliary beat frequency.
                            Ciliary beat frequency was depressed after
                            H,SO, exposure.  The combination produced similar
                            effects, but recovery had occurred by 48 hr post-
                            exposure.   Up to 48 hr after exposure H2SO, *
                            carbon resulted In more tissue destruction than
                            either pollutant alone.
                                                                                   Lewis et al.89'104
                                                                                   Zarkower
                                                                                                                                         115
Renters et al.
                                                                                                                                               183
                                                                     Schiff et al
                                                                                                          182

-------
ppm) 0., for 3 hr were not significantly affected.  However, when animals were
exposed in sequence, first to 0, and then to HUSO., ciliary beat frequency was
decreased significantly, but to a lesser extent than that caused by H2SO.
alone.  Analysis showed that antagonism (p < 0.05) occurred in this sequential
exposure.
                   145
     Gardner et al.    found that the sequence of exposure to sulfuric acid
aerosols and ozone altered the response of mice to airborne infections.  Mice
were exposed alone or in sequence to 0.196 mg/m  (0.1 ppm) ozone for 3 hr and
to 0.9 mg/m  sulfuric acid aerosol (VMC 0.23 urn ± 2.4 SD, geometric) for 2 hr.
When given alone, neither pollutant caused a statistically significant
increase in the mortality to a subsequent infection with Streptococcus
pyogenes.  When the pollutants were given sequentially, a significant increase
in mortality occurred only when ozone was given immediately before exposure to
sulfuric acid, and the response was additive.  The reverse procedure had no
effect on mortality due to Streptococcus pyogenes infections.  Because photo-
chemical oxidants and sulfur oxides often co-exist in polluted air, these
studies are of very practical importance.  The question of the temporal
sequence has been poorly investigated.  Simple mechanisms to predict this
add'itive response sequence are not apparent.  Thus, the results are opposite
                         181
those of the Grose et al.    study described above with the trachea! model
which showed that sequential exposure to 03 and H2SO. had an antagonisitic
effect.  The reasons for this difference are not known.  However,  the
                                                               180
infectivity model is thought to reflect alveolar level effects,    whereas the
ciliary beat frequency model is a measure of effects at the  level  of the
trachea.  In addition different animal species were used. These findings  also
indicate the complexity of interaction effects and the need  to exercise  care
                                    12-103

-------
in extrapolating the effects of pollutants from one parameter to another, (see
Table 12-16)
12.5 CARCINOGENESIS AND MUTAGENESIS
     Attempts have been made for several decades to correlate various indices
of particulate air pollution with the development of cancer  in man.  In  many
cases a positive association has been found between increased community  air
pollution and cancer of the lungs and/or gastrointestinal tract.  This
knowledge has led to suspicions concerning the chemical nature of that portion
or portions  of airborne particulate matter which may be contributing to  an
excess  of human cancer.  At least three classes of potential etiologic agents
have been studied in this  regard:  organic matter (including polycyclic
hydrocarbons) which is adsorbed to suspended particles; sulfur oxides; and
trace metals.
      Test systems for the  bioassay of potential mutagens and carcinogens are
diverse,  ranging  from the  measurement of chemically-induced  reverse mutations
 in  bacteria to the  frank production of carcinomas by administration to
mammals.  However,  it is commonly believed that fundamental  similarities exist
between the molecular mechanisms of both mutagenesis and carcinogenesis.  This
assumption  is based on the theory that chemical interaction  with DNA and/or
other critical cellular macromolecules initiates a mutagenic or carcinogenic
transformation.
      Because of the strong formal relationship between molecular events
involved  in mutagenesis and carcinogenesis (Miller, 1978)323,  the
demonstration of mutagenic activity for a substance is generally taken  as
strong  presumptive  evidence for the existence of carcinogenic  activity.
Therefore,  it is believed  that an investigation of the mutagenicity of  a
                                    12-104

-------
                                               TABLE 12-16.  EFFECTS OF INTERACTION OF SULFUR OXIDES AND OZONE
          Concentration
                                           Duration
                                                             Species
                                                                                                 Results
                                                                                                                                     Reference
o
en
10 mg/m3 (1 u«, HMO) H2S04
 aerosol, or 3.9 mg/m3 (2 ppm)
 03, or combination of the two

10 mg/m3 (SOX equivalent aero-
 dynamic diameter, 0.83 urn, a  =
 1.66) H4S04 aerosol, or 1.029
 mg/m3 (0.52 ppm) 03, or com-
 bination of the two

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

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

0.196 mg/m3 (0.1 ppm) 03;
 0.88 mg/m3 M2S04 aerosol (0.23
 tim, VMO) exposed alone or In
 sequence
                                       6 hr/day, 2 or 7
                                        days
                                       6 hr/day, 5 day/wk,
                                        6 mo
                                        3 days,
                                        continuous
                                       3 hr. 03;
                                       2 hr, H2S04
                                        3  hr, 03;
                                        2  hr, H2S04
Rat and
Guinea pig
Rat and
Guinea pig
Rat
House
                                                               Hamster
No synerglsM In effect on ratio of lung to body         Calender et al.
 weight.   Hlstologlcal lesions were those ascribed
 to 03 alone.

Morphological  alterations due to 03 alone.               Cavender et al.
                                                                                                                                                   143
                                                                                                                                                   119
Synerglstlc effects.   Glycoprotein synthesis was        Last and Cross
 stimulated In tracheal ring explants; lung ONA,
 RNA, and protein content Increased.

In response to airborne Infections a significant        Gardner et al.
 increase in Mortality only when Os was given
 immediately before exposure to H2S04, and the
 response was additive.

H2S04 depressed ciliary beat frequency.                 Grose et al.
 By 72 hr after exposure, recovery had occurred.
 03 exposure had no effect.   Sequential 03 then
 H2S04 exposure decreased ciliary beaUwtg frequency
 significantly but to a lesser extent than that
 caused by H2S04 alone.
                                                                                                                                                  144
                                                                                                                                                  1*4-
                                                                                 181

-------
substance may be predictive of its carcinogenic potential, and may serve as an
early warning of a possible threat to human health in cases where positive
results are obtained.
12.5.1    Airborne Particulate Matter
12.5.1.1  In vitro studies—Organic material associated with airborne
particles has been investigated to a limited extent for mutagenic and
carcinogenic potential.  In these studies, particulate material  is
experimentally  limited to that which is retained by the filter medium  used
(glass  fiber, paper...etc.).  Organics associated with aqueous particles
cannot  effectively be trapped, and thus there is no information  on the
biological  effect or nature of these compounds.  The particles that  have
created most interest are those with a carbonaceous core.  These particles,
because of their large surface area, adsorb many organic  compounds some of
which are known to be mutagenic and carcinogenic, such as benzo(a)pyrene.
 Because of the  small size (0.2-0.3 urn mean diameter) of many of  the  particles,
 they can be effectively  drawn  into the deep compartments  of the  lung where  the
 adsorbed organic material can  desorb into the alveolar fluid and enter the
 associated tissue.   The  ability of soluble proteins to leach mutagens  off
 particulates has been demonstrated using horse  serum and  coal  fly ash  (Crisp
et al.  1978).29°
      A number of studies were  conducted with fractionated extracts of
particulate matter from  urban  air in order to obtain information on  the
chemical  nature of the mutagens present (Teranishi, 1978; Miller and Alfheim,
1980; Dehnen and Tomingas,  1977; Tokiwa et al., i980).346»354»296.355
Estimates have  been  made as to the relative mutagenicity  of each extract;
however,  due to the  possible interaction among  the many compounds present  in
                                    12-106

-------
any fraction of the extracts the only conclusion that can be drawn is that
both the polar and neutral fraction contain significant portions of the total
mutagenic activity.  These studies also have confirmed in two ways that
polycyclic aromatic hydrocarbon (PAH) compounds are not the sole mutagens
present in particulate matter.  First, the total mutagenic activity does not
co-fractionate with the PAH as evidenced by appreciable activity remaining in
the polar fraction.  Second, the presence of mutagenic activity in the absence
of metabolic activation implicates non-PAH compounds.  At present the identity
of compounds which are acting as direct mutagens is uncertain.
     In a similar manner as in studies with airborne particulate matter,
mutagens were extracted from particles emitted from a coal powered electric
plant (Crisp et al., 1978; Kubitshek and Venta, 1979),290>356 gasoline engines
(Wang et al., 1978),    and light-duty and heavy-duty  diesel engines
(Huisingh et al., 1978).     The extracts obtained from all sources were
mutagenic to bacteria susceptible to frame-shift mutation, and no obligatory
requirement for metabolic activation was shown.  Only in the heavy duty diesel
engine study was fractionation carried out on the crude extract. An extensive
review of diesel engine particulate matter is available (Santodonato et al.,
1978).332
     The Ames assay has been used in an attempt to define air quality by
measuring the mutagenic potential of airborne particulates.  Tokiwa et al.
(1977)    compared the number of revertants per ug of particulate matter
collected in the industrial area of Ohmata with that collected  in the
residential area of Fukuoka, Japan.  In a similar manner  Pitts  et al.
      loo
v!978)    compared eight urban samples in the California  South  Coast Basin
with one collected in a rural area of the San Bernadino mountains.   In  both
                                    12-107

-------
 cases  the mutagenic activity was less in the residential and rural areas



 compared to that observed in the urban areas.   Also, mutagenic potential was



 determined in a quantitative manner for a variety of air samples collected in


                                 294
 Chicago (Commoner et al., 1978).      In order to rank samples, the inverse of



 the  minimum quantity of particulate matter needed to obtain a significant Ames



 assay  result was calculated.   Wind direction was then correlated with



 mutagenic potential.



      Caution must be exercised when comparing  in a -quantitative manner results



 of Arnes assays on complex environmental  mixtures.   Indirect mutagenesis is



 extremely difficult to quantitate,  since the detoxifying action of the



 microsomal preparation makes the  response of direct- and indirect-acting



 mutagens non-additive.   For any valid comparison there  has  to be nearly


                                                                           294
 complete separation of these two  types of mutagens (Commoner et al.,  1978).



 Also,  the effects on mutagenesis  of synergism  and  antagonism among compounds



 in complex mixtures has not been  adequately  investigated.   In the case ot



 complex mixtures obtained from tar-sand,  the mutagenic  activity of the known



 mutagen, 2-aminoanthracene,  was greatly  inhibited  by interaction with  the



 mixture (Shahin and Fournier,  1978).      For the above  reasons  a quantitative



 assessment of air quality is  not  readily  obtainable  with the use of the  Ames



 Salmonella mutaqenicity assay.



     The data obtained  with  mammalian  cell transformation assays  support the



 conclusions  derived from the Ames Salmonella assays.  There  appears to be a



 variety  of biologically active  agents  present  in the  extracts of  airborne



 particulate matter, and these agents are of  both a polar and nonpolar  nature.



The identity  of  these compounds is unknown,  however  the activity present is



greater than  that which  could be accounted for by the polycyclic aromatic
                                   12-1OR

-------
hydrocarbons present in the samples.  Even though the cells transformed by
extracts of particulate matter formed tumors when injected into newborn mice,
it is presently unclear as to how the process of transformation in
virus-infected cells relates to the process of chemical carcinogenesis.
Hence, cell transformation assays should be considered in the same way as Ames
assays; that is, as only an indicator of the presence of biologically active
compounds.
                                                       oqq
     The dominant lethal assay of Epstein et al. (1972)    is the only short
term j_n vivo assay performed on airborne particulate extracts.   The water
soluble and benzene soluble fractions produced no fetal deaths  or
preimplantation losses beyond control limits.  On the other hand, the
oxygenated fraction showed significant fetal deaths and decreased total
implants.  Conclusions from these experiments are difficult to  draw due to the
limited validation and sensitivity of this assay system.
12.5.1.2. In vivo studies--It was realized as early as the 1930's that
increasing amounts of particulate matter in the air may correlate with the
increasing rate of human lung cancer.  Some of the earliest ui  vivo
experiments dealt with the repeated exposure of mice to clouds  of soot,
followed by autopsy examination for tumors at the end of their natural
lifespan.  A number of different kinds of soot have been chosen for these
studies due to their significant contribution to airborne particulate matter.
Upon bioassay of soot from chimneys (Campbell, 1939; Seelig and Benignus,
1938)288'335 motor exhaust (Campbell, 1939)288 and airborne particulate matter
collected in the vicinity of a factory and roadway (McDonald and Woodhouse,
      ooo
1942),    a slight increase over control in the number of lung tumors was
observed.  Only in the case where road dust from a freshly tarred road was
                                   12-109

-------
used were there significant increases, with 57 percent  of the experimental
                                                                       287
and 8 percent of the control group having lung tumors (Campbell, 1934).
However, when five years later dust from the same road, which had not been
retarred, was again tested only 8 percent of the experimental group and  1.4
                                                                     289
percent  of the control group developed lung tumors (Campbell, 1942).      In  a
recent study with lifetime exposure of rats to automotive exhaust, there were
no tumors detected in the lungs of the treated animals.  Although these
studies  have all attempted to demonstrate the potential of airborne
particulate matter to cause lung tumors, the results obtained are ambiguous
due  to  the  low  tumor incidence and the small size of the animal  groups.
     Among  the  various  compounds associated with airborne particles, PAH's
have received the greatest attention with regard to carcinogenic potential
                          331
 (Santodonato et al., 1979)    PAH's were the first compounds ever shown  to be
 associated  with carcinogenesis.  To this day, carcinogenic PAH's are still
 distinguished by several  unique features:   (a) several  compounds of this class
 are among the most  potent animal carcinogens known to exist, producing tumors
 by single exposures  to  microgram quantities; (b) they act both  at the  site of
 application and at  organs distant  to  the site of absorption; and (c) their
 effects have been demonstrated  in  nearly every tissue and species tested,
 regardless  of the route of  administration.  The most widely  studied PAH,
 benzo(a)pyrene, is  ubiquitous in the  environment and produces  tumors  in  ani-
mals which  closely  resemble human  carcinomas.
     The production  of  lung tumors with airborne particulates  has been
extremely difficult.  However,  organic extracts of airborne  particulates
readily cause tumors when injected subcutaneously  into  mice.   As early as  1942
sarcomas were produced  in mice  using  the benzene extracts  of particulate
                                    12-110

-------
matter collected from an urban area (Leiter and Shear, 1942; Leiter and
               iiq oor)
Shimkin, 1942).   '     In these initial studies the tumor incidence was low,
with only 8 percent of the mice developing tumors by the end of the study;
however, none of the control mice had sarcomas.  In one later study, the tumor
incidence was as high as 61 percent  when particulates were collected in the
                                                          330
vicinity of a petrochemical plant (Rigdon and Neal, 1971).      Even in this
case of high tumor production, no increase in the incidence of tumors over the
spontaneous rate was observed in any organ of the animal distant to the site
of injection.  Only when neonatal mice were injected subcutaneously with
particulate extracts did tumors appear distant from the injection site
(Epstein et al., 1966),    with a very high incidence of hepatomas (83
percent) and multiple pulmonary adenomas (67 percent).  Remote tumor formation
after subcutaneous injection of neonatal mice was confirmed with both the
crude extract  of particulates collected in New York City and subfractions of
                                                                          284
this extract;  the predominant tumors were again hepatomas (Asahina, 1972).
     The carcinogenic nature of extracts of particulate matter has also been
demonstrated by studies involving skin painting on the backs of mice.  With
repeated application (three times per week for the life of the animal) of the
benzene extract of particulates collected in the Los Angeles area, papillomas
were formed which subsequently progressed to carcinomas (Kotin et al.,
1954).     Papillomas first appeared after 465 days, and at the time the data
were presented 42 percent  of the mice had developed tumors.  Although
papillomas and carcinomas  of the skin were the most commonly observed tumors,
lung tumors have also been noted after  skin application (Clemo et al.,
      oqi
1955).     Among the different methods  of administering particulate  extracts
to the mouse for bioassay, skin painting yields the highest tumor incidence,
with greater than 90 percent of the surviving  animals  in some cases  developing
tumors.
                                   12-111

-------
     In subsequent studies, the phenomenon of two-stage tumorigenesis was used
to further characterize the biological activity in airborne particulates.  In
two-stage tumorigenesis an initiator is an agent (usually a carcinogen)
applied in a single dose to the skin of a mouse which does not produce tumors
at the applied concentration but predisposes the skin so that later repeated
application of a promoter (an agent that by itself will not produce tumors)
will cause the formation of tumors.  A complete carcinogen is one which, if
applied  in sufficient concentration, can produce tumors by itself.  Extracts
of airborne particulates from Detroit were fractionated, and the fractions
examined  for complete carcinogenicity and tumor initiating and promoting
                                                 04? -ico
activity (Stern, 1968; Wynder and  Hoffman, 1965).    '-"^  Only the whole
extract  and the aromatic fraction  proved to be a complete carcinogen, while
the  insoluble,  acidic, aliphatic and oxygenated fractions produced no tumors
 (there was  insufficient basic fraction to perform the assay).
      In  order  to examine the aromatic fraction for initiating activity,  this
 fraction was applied to the backs  of mice in a sub-tumorigenie dose followed
by  repeated application of the  known promoter croton oil.  Tumor initiating
activity corresponded  in a general way to the benzo(a)pyrene content of  the
fraction.   The  other fractions  of  the particulate extract were not tested  for
initiating  activity.   It should be noted that an initiator does not
necessarily have to be a complete  carcinogen, although most  if not all
complete  carcinogens will  initiate if applied at a low dose where their
complete  carcinogenic action is not apparent.  For this reason it  is possible
that some of the fractions could have initiating activity even though they did
not act as complete carcinogens when first tested.   However,  the  relevance of
two-stage carcinogenesis to environmentally-caused cancer is  not  known.
                                   12-112

-------
     Several contributing sources of airborne particulate matter, gasoline and
diesel engines and the soot from coal and oil burning furnaces, have been
examined individually and shown to produce tumors jji vivo.  Extracts of
particulates from gasoline engines show carcinogenic activity when painted on
the backs of mice (Brune, 1977; Wynder and Hoffman, 1962)286'353 and when
                                            329
injected subcutaneously (Pott et al., 1977).     Extracts from diesel engines
have shown tumorigenie activity in some studies but not in others; the same
holds true for extracts of chimney soot where activity was shown in some
                          288
instances (Campbell, 1939)    while not in others (Mittler and Nicholson,
      324
1957).     The discrepancies among these results could be due to qualitative
and/or quantitative differences in the nature of the organic compounds
adsorbed to the particulates.  These differences may be a reflection of the
operating parameters of the generating source, or variations in particulate
collection procedures.  With diesel engines the mode of operation (the load
under which the engine was run), the type of fuel and the temperature at which
the particles were collected all affect the biological activity of the sample.
(A complete review of diesel particulate matter is provided by Santodonato et
          332
al. 1978.)     With soot collected from chimneys, an important consideration
is the temperature at which the particulate matter is collected.  The organic
material on participates is generated in the gaseous phase and only after
cooling are they adsorbed onto the inert core.  Unless particulates are
collected under similar conditions, disparities will exist in their chemical
composition and biological activity.  Taken together it is nevertheless
apparent that all the major types of airborne particulate matter contain
adsorbed compounds which are carcinogenic to animals and may contribute  in
some degree to the incidence of human cancer associated with exposure  to  urban
particulate matter.
                                   12-113

-------
12.5.2    Sulfur Oxides
     Sulfur dioxide hydrates rapidly in the moist upper airways, to form
several ions.  One of these, a bisulfite ion, effects the conversion reactions
of nucleic acids.  In 1970 and 1974 Shapiro et al. (1970,1974)337'338 reported
that bisulfite ions mediated the conversion of one nucleic acid cycle to
another cycle.  Compared with optimal conditions, 1 M bisulfite solution  at  pH
5  to 6, Shapiro  (1977)337 noted that the same solution at the physiological  pH
of 7 was  only  1  percent as effective.  In living cells the reaction could
change the nucleotide sequence of DNA possibly resulting in mutations.
      Uncharacterized free radical reactions may also occur under physiological
conditions (Shapiro, 1977).     Since free radical reactions do not depend on
high  concentrations of bisulfite to obtain favorable equilibrium,  they  may be
of greater significance in biological systems.  The evidence that  bisulfite
 reacts with  model  compounds  (polycytidylic acid) and single- and possibly
double-stranded  DNA has lead to the  investigation of its genotoxic, mutagenic
 and carcinogenic effects.  This compound, however, has been considered
 innocuous, and has a GRAS  (generally recognized as safe) designation  as a food
 additive.
      Mammalian |n vitro and  i_n vivo  systems were used to determine the  ability
of bisulfite to  cause chromosomal aberrations.  Cultures of human  lymphocytes
treated by bubbling S02 gas  through  the media  (Schneider and Calkins,  1970)333
and  cultures of  human embryonic lung (Newell and Maxwell,  1974)325 and  mouse,
cow,  and  ewe oocytes treated with bisulfite  (Jagiello et al.,  1975)314  showed
extensive chromosomal clumping after treatment.   In  severe cases  of
chromosomal  damage, the cell will not survive  and  hence  a  mutagenic or
carcinogenic transformation  cannot occur.  However,  some  cells showed only
                                    12-114

-------
moderate  damage,  with inhibition  of  DNA  synthesis,  fragmentation of
chromosomes  and  inhibition  of mitosis  with  damage to cells  in anaphase.   The
possibility  exists  that sublethal  changes  in chromosomes  may produce adverse
effects on the cell  which,  particularly  in  the case of germ cells,  may be
transmitted  to future offspring.   Although  cells  in culture are sensitive to
low concentrations  of bisulfite,  it  has  not been  determined to what extent
bisulfite exists  in the intact animal. Also, the  ability  of the dominant
lethal  assay to  detect mutagens has  received only limited validation,  and
hence the sensitivity of this assay  is not  known.
     327                                -
                                      at
3 ' o_^ J&JT^' ^m^u^e^ry^ .Jrf  dz-r?~ t/3/a P
      Peacock and Spence (1967)    exposed LX strain mice^to an atmosphere of
-5QO .ppm 50^ -five-days per weak,  for two-yeaj&s-.   The LX mice have a high
 incidence of spontaneous tumors,  with 31  percent of the males and 17 percent
 of the females in the control  group developing tumors of the lung by the end
 of the experiment.   The SOp treated group had a greater number of tumors,  with
 54 percent  of the males and 43 percent  of the females developing adenomas
 and/or carcinomas.   Due to the high spontaneous tumor incidence in these mice,
 it was concluded that SOp elicited an inflammatory response, which accelerated
 the development of spontaneous tumors.
      A co-carcinogenic action has been ascribed to bisulfite because of the
 enhancement of the carcinogenic potential of benzo(a)pyrene.  Kuschner
 (1968)    allowed rats to inhale a mixture of S02 and benzo(a)pyrene for one
 hour followed by six hours of exposure to either air or an SO^ atmosphere.
 With this regimen,  18 percent  and 50 percent , respectively, of the animals
 developed tumors.   Control animals receiving air or SO* alone were tumor
                                                  303
 free.   In a similar experiment von Nieding (1978)    noted also that SCL
 appeared to function as a cocarcinogen.
                                    12-115

-------
     The lack of evidence for mutagem'city/carcinogenicity of bisulfite in
mammalian i_n vivo systems may be due to the ability of mammals to rapidly bind
bisulfite followed by enzymatic oxidation to sulfate.  In mammals bisulfite
can be regenerated by the reverse of the formation of S-sulfonates and the
resulting free bisulfite oxidized enzymatically to sulfate by sulfite oxidase.
Sulfite oxidase isolated from bovine liver has been extensively characterized
                            oqo
(Cohen and Fridovich, 1971).     Approximately 80 percent of the reaction
proceeds without the formation of free radicals.  However, a portion of the
reaction was inhibited by free radical scavengers, and the formation of the
free  radicals was shown to  be dependent on the enzyme and the bisulfite con-
centration. From what is known, mammals have a high capacity of detoxifying
bisulfite, but there is no  assurance that reactions with plasma constituents
and sulfite oxidase are sufficiently complete to prevent reactions with ONA
and possible mutations.  At present there has been no demonstration of genetic
damage  attributable to jm vivo exposure to SCK or bisulfite.  Sulfates have
not been  shown to be carcinogenic, but there is some evidence that they can
augment the carcinogenic action of other compounds.  Preliminary reports
indicate  an increased tumor incidence when sulfuric acid aerosols are
administered along with benzo(a)pyrene (Lee and Duffield, 1977; Sellakumar,
1977).    '  4  In a novel theory of carcinogenesis, Hadler and Cook (1979)304
showed  that Tris salts of sulfates induced transitory uncoupling of
mitochondria, with the speculated release of oncogenic mitochondrial genetic
material.  The cocarcinogenic action of sulfate was not fully confirmed in
these laboratory studies, and at present only the inflammatory response, with
its implications for carcinogenesis, has been demonstrated with ambient air.
                                   12-116

-------
     In summary, sulfur dioxide, its oxidation products and their salts have
been shown to react with DMA and other biological molecules, and in some
instances to induce mutations in lower organisms.  Although the potential for
similar mutagenic/carcinogenic interactions to occur in mammals cannot be
ruled out, it is apparent from the lack of genetic damage observed after
J£ vivo administration that the risk of direct carcinogenic action by these
compounds is small.  The cocarcinogenic action, particularly by the inflam-
matory induction of a proliferative response, may be of greater significance.
However, the work  in this area is in its infancy and hence only highly specu-
lative conclusions could be drawn.
12.5.3    Metals
     Among the  numerous trace metals found in the atmosphere, evidence of
carcinogenicity in experimental animals has been shown for at least nine
(beryllium, cadmium, cobalt, chromium, iron, nickel, lead, zinc, titanium).
Limited evidence also points to compounds of molybdenum and manganese as
possible tumorigens (Clemo and Miller, 1960; Cohen and Fridovich,
      OTJO 793
1971).*^^'      Moreover, three of these metals (cadmium, chromium, nickel), in
addition to arsenic, are implicated as human carcinogens.
     Although trace metals are ubiquitous in the environment, their levels are
generally so low that it is difficult to predict the magnitude of carcinogenic
risk in community  settings.  This problem is compounded by the fact that clear
dose-response relationships have  not been well-defined for most carcinogenic
metals.  For the present it is likely that the possible role of trace metals
in the production  of cancer due to particulate air pollution will be  limited
to qualitative  judgements.
                                    12-117

-------
     The topic of metal carcinogenesis has been extensively reviewed in recent
years from various perspectives (Furst, 1977; Furst and Haro, 1969; Sunderman,
1978; Sunderman, xgyg).301.302.344.345  These surveys generally conclude that
with certain compounds tumors can be induced via a mechanism which is
apparently distinct from the phenomenon of so-called solid-state or
foreign-body carcinogenesis.  However, it is still debatable in many cases
whether metal-induced  tumors which are associated with a particular route of
administration  (e.g.,  local sarcoma by subcutaneous implantation) are
indicative of of  true  chemical carcinogenesis.  While most carcinogenic metals
are active only in the form of organic and inorganic salts, for nickel and
cadmium it appears that both the pure elemental form as well as several of
their salts  are carcinogenic.
      One  of  the most widely recognized and well-studied carcinogenic metals is
 nickel  (IARC, 1973;  IARC,  1976).306'307  Sunderman (1978, 1979)344'345
 indicated that  nickel  subsulfide (Ni^S^) is probably the most potent
 carcinogenic metal studied to date.  Single intramuscular injections of 5 umol
 (1.2 mg)  or  10  umol  (2.5 mg) to Fischer rats produced rhabdomyosarcomas in 77
 percent and  93  percent of  the treated animals,  respectively.  Numerous
 investigators have confirmed that Ni3$2 produces  local sarcomas following
 injection, and  one group has indicated that chronic inhalation of  Ni3Sp in
 rats caused  lung  cancer (IARC, 1973; IARC, 1976).306'307  Several  other forms
of nickel have  shown both  positive and negative carcinogenic activity.  The
chronic  inhalation of  nickel carbonyl (Ni(CO)4) by rats at  levels  as  low  as
0.03 mg/1 has produced pulmonary carcinomas which were believed to be
treatment-related (IARC, 1976).307  In addition,  Lau et al.  (1972)317  induced
carcinomas and  sarcomas in various organs, including liver  and  kidney,  by
                                    12-118

-------
multiple intravenous injections of Ni(CO). to rats.   Inhalation of elemental
nickel powder has produced equivocal results in mice, rats, and guinea pigs,
and negative results in hamsters (IARC, 1976).      Single and repeated
intramuscular injections of nickel powder induced local tumors in rats and
hamsters, although intravenous injections were either marginally effective
                                                  007
(rat) or ineffective (mouse, rabbit) (IARC, 1976).     A single intrapleural
injection of nickel powder (0.02 ml of a 0.06 percent  suspension) did not
produce neoplasms in mice; multiple intrapleural injections at high doses in
rats were effective in the induction of local tumors (IARC, 1976).
     The toxicology and carcinogenic potential  of cadmium have been the
subject of extensive reviews in the past several years (IARC, 1976; USEPA,
1979; Towill et al., 1978).308>349.348  Cadmium is similar to nickel in that
both the elemental form and several salts are carcinogenic, and that oral
administration is ineffective  in producing tumors.  The ability of cadmium to
induce tumors by inhalation exposure has not been adequately studied.
However, single or repeated injections (intramuscular, subcutaneous) of
cadmium powder, cadmium chloride (CdC^), cadmium oxide (CdO), cadmium sulfate
(CdSO^), or cadmium sulfide (CdS)  to rodents frequently produces  local
sarcomas (Furst and Haro, 1969; IARC, 1976; Sunderman, 1979).302.308,344  A
unique feature of the action of cadmium is that single subcutaneous injections
of CdClp to rodents (3.7 - 5.5 mg/kg body weight) leads to a high incidence of
                                                                           •34-5
interstitial cell (Leydig cell) tumors of the testis.  Stoner et  al. (1976)J0
recently reported that cadmium acetate did not cause a significant  increase in
pulmonary tumor response in the strain A mouse bioassay system.
     Chromium in the hexavalent (but not trivalent)  state  has produced tumors
following inhalation, implantation, and injection (IARC, 1973; Towill,
                                   12-119

-------
      •SflQ "1AQ
1978).    '      The inhalation of mixed chromate dust failed to induce lung
tumors in mice, rats, and rabbits, although pulmonary adenomas developed in
                                                                          309
mice exposed by inhalation to calcium chromate (CaCr04) dust (IARC, 1973).
Local sarcomas in rats, mice, and rabbits have resulted from the
intramuscular, subcutaneous, intrapleural, intraosseous, and intraperitoneal
injection of chromium powder and hexavalent chromium compounds (IARC, 1973;
Sunderman, 1979).309'344  Several groups of investigators, however, have
failed to induce tumors by the paren teral administration of chromium
compounds.
     Although  arsenic  is recognized as a human carcinogen based upon epidemio-
logical  data,  there  is little evidence to indicate carcinogenic activity in
                                                             302 344
experimental  animals (Furst  and Haro, 1969; Sunderman, 1979).   '     In
particular,  the  chromic administration of arsenous trioxide (As^O,) in
drinking water (34 mg/1) to  rats failed to induce tumors (Furst and Haro,
       302
1969).     However,  others have reported that the subcutaneous injection of a
sodium arsenite  compound led to an increase in the incidence of lymphocytic
leukemias and  malignant lymphomas in pregnant Swiss mice and their offspring
(Sunderman,  1979).344
     Although  not generally  recognized as a human carcinogen,  lead compounds
have shown considerable carcinogenic activity in rodents (IARC, 1972;
Sunderman, 1979; USEPA, 1977).310'350  Several studies confirmed that renal
carcinomas result from the oral and parenteral administration  of lead
phosphate, lead  acetate, or  basic lead acetate to rats and mice, but not  to
hamsters.  In  addition, tumors of the testis (Leydig  cell),  adrenals, thyroid,
pituitary and  prostate have  been found among rats fed lead acetate  (3-4 mg/day
for  18 months) (USEPA, 1977).35°  In a recent study using the  strain A  mouse
                                   12-120

-------
pulmonary tumor bioassay system, Stoner et al. (1976)    reported that lead
subacetate caused a statistically significant increase in tumor formation.
However, a dose-response relationship could not be demonstrated.
     Beryllium salts have induced pulmonary cancers upon inhalation and osteo-
sarcomas upon intravenous injection in a variety of animal species (IARC,
1972).     Aerosols of beryllium sulfate (BeS04) induced pulmonary carcinomas
in all of a group of 43 rats (34 mg/m  for 56 weeks), and in two of ten Rhesus
monkeys inhaling the compound at 35 mg/m  for eight years (IARC,  1972).     In
addition, three of 20 monkeys developed pulmonary cancers after the intra-
bronchial and/or bronchomural implantation of pure beryllium oxide (5 percent
suspension in saline).  Numerous investigators found that the intravenous
injection of zinc beryllium silicate or beryllium oxide caused malignant bone
tumors (osteosarcoma) in rabbits (IARC, 1972; Sunderman, 1979).   '
     Evidence to support the carcinogenic potential of zinc and iron is
limited.  Zinc compounds (ZnCK, ZnSO., ZnNO^) are carcinogenic only by
                                                                  30? 344
intratesticular injection (Furst and Haro, 1969; Sunderman, 1979).   '
When evaluated in the strain A mouse pulmonary tumor bioassay system, zinc
                                                       343
acetate was found to be negative (Stoner et al., 1976).
Iron-polysaccharide complexes (e.g., iron-dextran) have commonly produced
local sarcomas upon injection in mice, rats,  and rabbits (Furst and Haro,
                  on? -3-1 y
1969; IARC, 1973). u*»d"  It is not clear whether this effect may have been
due to solid state carcinogenesis.  In contrast to the sarcomagenic properties
of iron-dextran, ferric oxide (FepOj, hematite) produced no tumors in  hamsters
(intratracheal instillation), guinea pigs (inhalation) or rats (subcutaneous
implantation).
                                   12-121

-------
     The carcinogenicity of titanium has not been fully investigated.  Chronic
studies with mice involving the ingestion of a titanium salt in the drinking
                                                   302
water gave negative results (Furst and Haro, 1969).     However, Furst and
Haro (1969)302 succeeded in producing local sarcomas and neoplasms in distant
organs by the intramuscular injection of titanocene to rats and mice.  In
addition, local fibrosarcomas developed in three out of 50 rats injected with
titanium dioxide.
      Several groups of  investigators have indicated that sarcomas can be
produced by the  subcutaneous, intramuscular, or intraosseous injection of
                                                     344
 cobalt powder, to  rabbits  and rats (Sunderman, 1979).     However, little
 additional  data  are available regarding the carcinogenic potential of cobalt.
 Stoner et  al.  (1976)343 recently  found that cobalt acetate had no effect on
 tumor incidence  in the  strain A mouse pulmonary tumor bioassay system.
      Although  selenium  is  not a metal, it has  recently received considerable
 attention  as  a potential carcinogen, and is found  in ambient air  (IARC,
 1975).     Oral  administration of sodium selenite  and sodium selenate to mice
 and rats  has  resulted in a wide range of neoplasmas  including  sarcomas,
 "lymphoma-leukemias," mammary carcinomas,  lung adenocarcinomas, and  hepatic
 tumors (IARC,  1975).     Because  selenium  is an essential trace element,  its
 role in the etiology  of environmentally-induced cancers  remains unclear.
      In an  attempt to understand  the fundamental biological activity of metals
 and its relationship  to carcinogenesis, numerous i_n  vitro experiments  have
 been conducted.  Many of these studies attempt to  exploit the  strong formal
 relationships  between molecular events involved in mutagenesis and carcino-
 genesis.   In particular, the interaction of xenobiotics  with  nucleic acids  is
believed to be a critical  event in mutagenesis and/or  cell  transformation.
                                    12-122

-------
Cultures of mammalian cells and bacteria, as well as cell-free systems have
been used to explore the potential mutagenicity/carcinogenicity of various
metals.
     Several biochemical studies have been completed which point to a possible
direct action on nucleic acids by metal cations as the basis for metal
                                         325
carcinogenesis.  Murray and Feisel (1976)    prepared mixtures of synthetic
polynucleotides and measured the changes in the mixing curves induced by the
addition of carcinogenic and non-carcinogenic metal salts at a 10  M
concentration.  Both cadmium chloride (CdCU) and manganese chloride (MnClp)
induced alterations in  spectrophotometric measurements which were indicative
of mispairing  of nucleotide bases.
     More extensive studies have been conducted on the ability of metal salts
to affect the  fidelity  of DNA synthesis in a cell-free system (Loeb et al.,
1977;  Si rover  and Loeb, 1976).    '     These investigators found a high
correlation between metals which were mutagenic/carcinogenic and the ability
to increase the error frequency of deoxynucleotide incorporation.  Nine metals
were scored as positive in this system at concentrations between 20 mM and
150 mM; silver, beryllium, copper, cadmium, cobalt, chromium, manganese,
nickel, and lead.  Negative results were obtained with barium, calcium,
aluminum, iron, potassium, magnesium, sodium, rubidium, strontium, and zinc.
The authors concluded that the fidelity of DNA synthesis may have potential
application as a screening technique for mutagenic/carcinogenic metals.
     The recent proliferation of  iji vitro cell transformation assays has
resulted in further confirmation  of the carcinogenic/mutagenic action of
several metals.  The most noteworthy cell transformation studies thus far with
metals have been those  employing  primary cultures of Syrian hamster embryo
                                    12-123

-------
                                                                            298
cells (Costa, 1979; DiPaolo and Casto, 1979; DiPaolo et al., 1978).    ''
Morphological transformation has been obtained with salts of nickel,  lead,
cadmium, chromium, beryllium, and arsenic.  Salts of iron, titanium,
tungstate, zinc, and aluminum displayed no transforming properties.
Unfortunately there has not yet been an extensive validation of  any  single
test system  for screening of potential metal carcinogens.  Moreover,
techniques are not yet available to elucidate the molecular mechanism of
metal-induced transformation, or to explain how the physicochemical  state of
the  metal affects  its carcinogenic potential.
12.6  CONCLUSIONS
12.6.1  Sulfur Dioxide
      Once inhaled,  S02 appears  to be converted to its  hydrated forms,
 sulfurous acid,  bisulfite,  and  sulfite.   The rate of absorption  and  removal of
 inhaled S02  varies  with  soecies, but >&• at least 80 percent of the inhaled
        to /ujfet4iu& 4s#u&-&01-* -^^ ^£K* sUtffz^&^'fi <2tei2£^
 amount/(see  Chapter ll for  an expandea discussion on absorption).
      The metabolism of S02  is predominantly to sulfate and  is mediated by the
 enzyme sulfite  oxidase.   Since  sulfite oxidase is a molybdenum containing
 enzyme, dietary  factors  could influence the function of the enzyme.   No
 conclusive evidence has yet been reported.  The reaction  of bisulfite with
 serum proteins to  form S-thiosulfates is  rapid.  The S-thiosulfates  are
remarkably long-lived, supplying a circulating pool of bisulfite which can
reach  all tissues.   Since some  circulating S-thiosulfates decompose  to SO-
which  is  exhaled, S-thiosulfates can donate their bisulfite content  to distal
tissues.  Sulfur dioxide and bisulfite are clearly mutagenic  in  microbial  test
systems  (Ames Salmonella and Yeast Systems).  The mechanism for  the
mutagenesis  could be the deamination of cytosine at high  concentrations.   Free
radical  reactions breaking  glycosidic bonds  in DNA may be responsible at low
                                   12-124

-------
concentrations.  The potency of bisulfite in these ^n vitro systems is
moderate to weak when compared to agents such as nitrosamines or polycyclic
aromatic compounds; but it is nonetheless positive.  To date, experiments
testing for mutagenicity or carcinogenicity by bisulfite in nanvnals have been
equivocal.  On the basis of present evidence, one can not decide whether or
not bisulfite, and hence SOp, is a mutagen in mammals.
     The influence of S02 on tumorogenesis has also been examined.   Rats
exposed (5 days/wk for 98 wk to a lifetime) to 26.2 mg/m  (10 ppm)  SOp for 6
hr/day in combination with 9.2 or 10.5 mg/m  (3.5 or 4 ppm) SOp plus 10 mg/m
benzo(a)pyrene had an increased incidence of lung squanous cell carcinoma.
Hamsters were not affected.  Statistical analyses were not performed,
preventing definite interpretation of the data.  However, from these studies,
the possibility exists that SOp mav De a co-carcinogen in rats.  The question
of carcinogenicity of SOp alone cannot be resolved at present.  For the rat
studies described above, a total of 15 rats were exposed to 26.2 mg/m  (10
ppm) SOp  for 6 hr/day, 5 days/wk for lifetimes, and none developed cancer.
However,  this sample size is small and would have a small probability of
detecting a low cancer incidence.  In a different study, mice were^xposed f-e-r—
                                                                        '
/dar-5-
-------
included lung morphology as an endpoint, but no lung tumors were reported.
This does not negate the positive studies since they showed a species
sensitivity to tumor development and were conducted either at very high
concentrations or in the presence of benzo(a)pyrene.  Without statistical
analyses of the cancer incidence data, the general conclusion to be drawn  from
these studies is that SCL has an unproven potential to act as a carcinogen or
a  co-carcinogen in some animal species.
      In  rats, histopathological effects of S02 alone are confined to the
bronchial  epithelium, with most of the effects occurring on the mucus
secreting  goblet cells.  Goblet cell hypertrophy occurs on chronic exposure of
rats,  leading some to suggest that SOp produces a chronic bronchitis similar
in many  respects to  that in man.  Repeated exposure to a critical
concentration of SO- (not  less than  131 mg/m  or 50 ppm) may be needed  to
produce  the chronic  bronchitis.  The nasal mucosa of mice (particularly those
with upper respiratory  pathogens) was  altered by 72 hr exposure to 26.2 mg/m
 (10 ppm) SOp.   Continous exposure to 0.37 to 3.35 mg/m  (0.14 to 1.28 ppm) S02
 for 78 wk did not cause any significant lung morphological alterations  in
monkeys.
      An  immediate effect of acute (£ 1 hr) S02 inhalation  is either  a decrease
in respiratory  rate  or  an  increase in  resistance to flow within the  lung.  The
decrease in respiratory rate  is mediated by a vagal reflex through receptors
in the nose and upper airways.  The  response is transient  in nature  and occurs
             2
at 44.5  mg/m  (17 ppm). Lower concentrations were  not  tested.  The  increased
resistance to flow is mediated through receptors  in the bronchial  tree  and
persists during continued  exposure.  With this physiological parameter, lower
concentrations of S02 have been observed to cause  reproducible  changes  in
                                    12-126

-------
respiration.  The guinea pig is the most sensitive animal, having significant
changes at concentrations as low as 0.42 mg/m  (0.16 ppm) SO^ for 1 hr.
Chronic exposures have produced alterations in pulmonary function in
cynomolgus monkeys, but only at concentrations greater than 13.1 mg/rn
                                   o
(5 ppm).  Dogs exposed to 13.4 mg/m  (5.1 ppm) S02 for 21 hr/day for 225 days
had increased pulmonary flow resistance and decreased compliance. Lower
concentrations were not examined.  It should be remembered that S02 appears to
cause its immediate bronchoconstrictive effect through action on airway smooth
muscles.  Since smooth muscles adapt or fatigue during long-term stimulation,
chronic exposure to SOp is not likely to evidence bronchoconstriction equiva-
lent to that occurring on short-term exposure.  Alterations in pulmonary
function after chronic exposure to S02 are likely to occur through other
mechanisms, such as morphological changes in the airways or hypersecretion of
mucus, which will  result in narrowing the airway.  Concentration, rather than
duration of exposure, seems to be the most important parameter in determining
responses to S02,  whether the response is measured as a histopathological
lesion  or as a permanent alteration in respiration.  There is no theoretical
hypothesis  available at present to integrate the short-term effects observed
with 1  hr exposures and the effects of long-term exposures of several mo.
     Some pulmonary host defense mechanisms are also affected by S02 exposure.
After 10 and 23 days of exposure (7 hr/day, 5 days/wk) to 0.26 mg/m  (0.1
ppm), clearance of particles from the lower respiratory tract was accelerated
in rats.  At a higher concentration (2.62 mg/m  , 1 ppm) there was an initial
acceleration (at 10 days), followed by a slowing at 25 days.  A  5 day  (1.5
hr/day) exposure to 2.62 mg/m  (1 ppm) reduced tracheal mucous flow in dogs,
but a longer exposure to this concentration caused no changes in ciliary beat
                                    12-127

-------
frequency of rats.   Antiviral defenses were altered by a 7 day continous
exposure to 18.3 to 26.2 mg/m  (7 to 10 ppm) S02 as evidenced by an increase
in viral pneumonia.  In this study, the combined exposure to S02 and virus
produced weight loss at concentrations as low as 9.43 mg/m  (3.6 ppm) S02-
Mice exposed to 13.1 mg/m3 (5 ppm) S02 for 3 hr/day for 1 to 15 days or for 24
hr/day  for 1 to 3 mo did not have increased susceptibility to bacterial lung
disease.  A variety of changes in the humoral immune response of mice exposed
for up  to 196 days to 5.24 mg/m  (2 ppm) have been reported.
12.6.2   Particulate Matter
     The dissolution of SO-  into liquid aerosols or the sorption onto solid
aerosols tends  to  increase the potency of S02-  The exact mechanism by which
potentiation occurs is  still controversial.
      Reports disagree as to  the potency of acute exposure to sulfate aerosols.
Some  investigators contend that sulfuric acid is highly irritating, producing
increases in pulmonary  flow  resistance at low concentrations and linear
concentration  responses.  The lowest effective concentration so far reported
was  0.1 mg/m   (1 hr) in the  guinea pig.  Particle size influenced  the results
in several  ways but the smaller sizes were generally more effective.  Others
have  observed  an "all or none" response (increased airway resistance) in
guinea  pigs exposed for 1 hr to 14.6, 24.3, or 48.3 mg/m3 H2S04. Exposure to
lower concentrations (1.2 or 1.3 mg/m ) caused no effects.  Some of these
conflicts may be due to differences in technique, strain of animal, or  species
of animal.  Discrepancies are particularly marked in the potency of sulfate
salt aerosols,  with older reports presenting  significant alterations  in
resistance to flow at low concentrations.  The largest data base for  the
effects of 1 hr exposure of  guinea pigs to sulfur oxides comes  from 1
                                   12-128

-------
laboratory.  This research has resulted in an apparent ranking of potency (for
increased flow resistence):  H2$04 > ZnS04(NH4)2$04 > Fe2(S04)3 > ZnS04 >
(NH4)S04 > NH4HS04, CuS04 > FeS04> Na2S04, MnS04.  The latter three caused no
effects.
     The toxicology of H2$04 is complicated by its partial
concentration-dependent conversion to (NH4)2S04 and NH4HS04 by ammonia in the
breath or in the air of animal exposure chambers.  While there is a
stoichiometry of this chemical reaction, the actual concentrations have not
been measured definitively.  Thus, comparing results of H2S04 studies using
animals to those using humans is confounded, particularly since extensive
neutralization would not be expected in the atmosphere of human exposure
chambers.  One theory for the ifn'tiatiftg action of sulfuric acid contends that
sulfate salts can act to promote release of histamine or other mediators of
bronchoconstriction and is supported by biochemical and pharmacological
evidence in 2 species.  Anionic release of histamine may play a role in the
bronchial constriction as evidenced by the blockade with antihistamines and
adrenergic drugs.  Certainly, the clearance of sulfurous acid, bisulfite,
sulfite, and sulfate from the lung is influenced by the cations present in the
aerosols inhaled simultaneously.  Since polluted air is such a complex mixture
of these aerosols, the question of the toxicity of ambient aerosols can not be
approached on a simplistic basis by estimating toxicity from the acidity
alone.
     Chronic exposure to H2S04 also produces changes in pulmonary function.
Monkeys exposed to 0.48 mg/m  H2$04 continously  for 78 wk had altered
distribution of ventilation early in the exposure period.  Higher
concentrations (2.43 and 4.79 mg/m ) changed the distribution of ventilation
                                   12-129

-------
and increased respiratory rate but caused no effects on other pulmonary
function measurements.   A lower concentration (0.38 mg/m ) caused no effects.
Morphological changes occurred at the lowest concentration tested (0.38
mg/m3).  The effects appeared to be related to size of the particle as well as
to concentration.  Major findings at 2.43 mg/m  H2S04 included bronchiolar
epithelial hyperplasia and thickening of the respiratory bronchioles and
alveolar walls.  Guinea pigs exposed continously for 52 wk to 0.08 or 0.1
mg/m   H2SO,  had  no effects on pulmonary function or morphology. Dogs which
inhaled 0.89 mg/m  H2SO. for 620 days (21 hr/day) also had no morphological
alterations.  However, CO diffusing capacity, residual volume and net lung
volume were  decreased.  Several other changes were noted, including an
increase  in  total expiratory resistance.
      Sulfuric acid also alters mucociliary clearance which is responsible for
clearing  the lung of viable or non-viable particles.  These particles impact
on the ciliated  airways during inhalation or reach this region as a result of
alveolar  clearance.  A 1 hr exposure of dogs to 0.5 mg/m  H-SO. increased
trachea!  mucocilary transport, whereas 1 mg/m  H^SO. depressed this rate.  A 2
to 3  hr exposure to 0.9 to 1 mg/m  H2$04 also decreased trachea 1 ciliary beat
frequency  in hamsters.  Lower concentrations (0.1 mg/m  HUSO., 1 hr/day, 5
days/wk)  caused  erratic bronchial mucociliary clearance rates in donkeys after
several wk of exposure.  Continued exposure of the donkeys which had not
received  pre-exposures caused a persistent slowing of bronchial clearance
after about  3 mo of exposure.  From these and other studies,  it appears that
low concentrations of H2$04 can slow mucociliary clearance.   This might imply
increased  lung residence times of materials that would ordinarily be cleared.
                                    12-130

-------
     Other host defense parameters, e.g., resistance to bacterial  infection,
are not altered by low concentrations of ^SCL, but are affected by metal
sulfates.  The apparent relative potency of various particles for increasing
susceptibility to infectious (bacterial) respiratory disease has been
determined in mice exposed for 3 hr:  CdSO^ > CuS04 > ZnN03, ZnS04 > A1-(S04)3
> AKNH^CSO,)*. At concentrations > 2.5 mg/m  the following particles had no
significant effects in this model system:  H2$04, (NH4)S04, NH4HS04, Na,,S04,
Fe2(S04)3, Fe(NH4)2S04, NaN03, KN03, and NH4N03.
     It is evident that accurate estimates of the toxicity of complex aerosols
occurring in urban air based solely on their sulfate contents are
inappropriate.  The chemical composition of the sulfate aerosols determines
their relative irritancies, which can be correlated with the permeability of
the lung to that specific sulfate salt.  The metallic ions associated with
sulfate aerosols are also not without toxicity.  Since urban air contains
sulfuric acid, ammonium sulfate, and metallic sulfates in varying proportions,
it is not possible to extrapolate from the currently inadequate toxicological
data on single compounds in animals to man as he exists in a complex
environment.
     No data are available on the toxicity of secondary or complex atmospheric
aerosols, since only a very few published reports of animal studies have
appeared. The problem is highly complex because of the variability of aerosols
from different urban localities and the compositional changes on collection.
Toxicity can be approached, at present, only from estimates of composition and
toxicity of individual components.  Fly ash has little toxicity when inhaled
at concentrations less than 100 mg/m  , but it has definite toxicity at 200
mg/m3 or greater.  Using i_n vitro tests, metal oxide-coated fly ash has
                                   12-131

-------
measurable toxicity which can be ascribed to the insoluble oxides when
alveolar macrophages are exposed. The effects of soluble salts of Ni and Cd,
for example, have major differences.  Nickel and Cd are removed from the lung
with relative rapidity but may be stored or bound to intracellular proteins to
an extent which is sufficient for accumulation on repeated short-term
exposures.  Two hr exposures to both Ni (0.5 mg/m ) and Cd (0.1 mg/m )
aerosols  impair the anti-bacterial defenses of the lung, leading to an
increased sensitivity to airborne pathogens in mice.  Ciliary beat frequency
in trachea  can be decreased by Cd and Ni also.  Humoral immunosuppression  in
mice has  been reported after a 2 hr exposure to 0.19 mg/m  CdCl2 or 0.25 mg/m
NiCl2.
12.6.3   Interactions of Gases and Particles
     Although man is exposed to  a complex mixture of gases and particles,  few
animal  studies have been conducted with mixtures.  Sodium chloride and  soluble
salts  (manganous chloride, ferrous sulfate, or sodium orthovanadate)
potentiated the effect  (increased flow resistance) of a 1 hr S02 exposure  of
guinea  pigs.  Hypothetically, these particles favored the conversion of SOp to
H-SO.,  thus increasing the response.
     The  effects of chronic exposure to a variety of mixtures of S02, H2$04,
and  fly ash were examined in guinea pigs and monkeys.  None of these studies
showed  effects on pulmonary function.  Morphological changes were observed in
monkeys after an 18 mo continuous exposure to 2.6 mg/m  (0.99 ppm)  S0?  plus
0.88 mg/m  H2S04; but the addition of fly ash did not potentiate the response.
     When dogs were exposed to S02 (13.4 mg/m3, 5.1 ppm) and H2$04  (0.89
mg/m )  alone and in combination  for 21 hr/day for 620 days,  no morphological
changes were observed.  Sulfur dioxide did not cause any significant changes
                                    12-132

-------
 in pulmonary  function  except  for an  increase  in N~ washout, but H^SO. caused a



 variety  of  changes which were interpreted as  the development of obstructive



pulmonary disease.



      In  another  series  of  studies, dogs were  exposed for 16 hr/day for 68 mo



 to raw or photochemically  reacted auto exhaust, oxides of sulfur or nitrogen,



 or their combinations.  The animals  were examined periodically during exposure



 and  at 32 to  36  mo after exposure ceased.   After 18 or 36 mo of exposure, no



 significant changes  in pulmonary function were observed.  After 61 mo, a few



 functional  alterations were observed in dogs  exposed to SO  (1.1 mg/m , 0.42
                                                          /\


 ppm  $62, and  0.09 mg/m H^SO^) alone and in combination with other pollutants



 in the study.  The animals had been  placed  in clean air for 32 to 36 mo after



 exposure ceased, at  which  time the SO group  had a variety of morphological
                                      A


 alterations.   These  included  a loss  of cilia  without squamous cell metaplasia,



 nonciliated bronchiolar hyperplasia, and a  loss of interalveolar septa in



 alveolar ducts.  The authors  hypothesized that these changes are analogous to



 an incipient  stage of human proximal acinar (centrilobular) emphysema.



      Combinations of carbon and HUSO, or SO-  were investigated also.  In mice



 exposed  for 3 hr/day,  5 days/wk for  up to 20  wk to a mixture of 1.4 mg/m



 FUSO. and  1.5 mg/m   carbon or carbon only,  morphological and immunological



 alterations were seen in both groups. In hamsters, a 3 hr exposure to 1.1


     3           3
 mg/m  +  1.5 mg/m carbon depressed ciliary  beat frequency, as did ^SO^ alone.



 Alterations of both  the pulmonary and systemic  immune systems were found in



 mice at  various  lengths of exposure  (100 hr/wk  up to 192 days) to 5.2 mg/m   (2



 ppm) SO- and  0.56 mg/m carbon, alone and in  combination.  Generally, carbon



 and  carbon  +  S0? caused more  extensive effects  than SO- alone.
                                    12-133

-------
     When the interaction of 03 and H2$04 was studied, the morphological



effects to the mixture [10 mg/m  H2$04 + 1.02 mg/m3 (0.52 ppm) 0,] of a 6 mo



intermittent exposure of rats and guinea pigs were attributed to 03 alone.

                                    3

However, combined exposure to 1 mg/m  H2$04 and 0.78 to 0.98 (0.4 to 0.5 ppm)



0, resulted in synergistic effects on glycoprotein synthesis in trachea and



certain indices of lung biochemistry.   Acute sequential exposure to first


          3                               3
0.196 mg/m  (0.1 ppm) 0, and then 0.9 mg/m  H2$04 caused additive effects on



increased susceptibility to infectious pulmonary disease and antagonistic



effects on depression of tracheal ciliary beat frequency.   From these studies,



the  interaction of 03 and H2$04 is quite complex and appears to be dependent



on the sequence of exposure as well as on the parameter examined.
                                  12-134

-------
12.7  REFERENCES

 1.    Tartar, H. V., and H. H. Garetson.  The thermodynaim'c  ionization
      constants of  sulfurous acid at 25°.  J. Am.  Chem.  Soc.  63:808,  1941.

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

 3.    Cecil, R.  Intramolecular bonds in proteins.   I.  The role  of  sulfur in
      proteins.  In:  The  Proteins.  Vol. I.  H.  Neurath, ed.  Academic  Press,
      New York, 1553.  pp. 370-476.

 4.    Fry, K., L. L. Ingrahama, and F.  H. Westheimer.   The thiamin-pyruvate
      reaction.  J. Am. Chem. Soc. 79:5225-5227,  1957.

 5.    Kaplan, D. M., D. L. Luchtel, and C. E. McJilton.  Chronic exposure to
      S09 -  Possible effects at the cellular  level.   Environ.  Lett. 7:303-310,
      1974.

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

 7.    Shapiro, R.,  and J.  M. Weisgras.  Bisulfite-catalyzed  transamination of
      cytosine and  cytidine.  Biochem.  Biophys. Res.  Commun.  40:839-843,  1970.

 8.    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.

 9.    Vonderschmitt, D. J.,  K. S.  Vitols, F.  M. Huennekens,  and  K.  G.
      Scrimgeour.   Addition  of bisulfite to  folate and dihydrofolate.  Arch.
      Biochem. Biophys. 122:488-493,  1967.

10.    Muller,  F., and V.  Massey.   Flavin-sulfite  complexes and their
      structures.   J. Biol.  Chem.  244:1007-1016,  1969.

11.    Abel,  E.  Theory of the oxidations of  sulfite to sulfate by oxygen.
      Monatsh.  82:815-834,  1951.

12.    Hayon, E., A. Treinin,  and J. Wilf.   Electronic spectra, photochemistry,
      and autoxidation mechanism of the sulfite-bisulfite-pyrosulfite systems.
      The S02, S03, S04,  and  S05  radicals.   J.  Am.  Chem.  Soc.  94:47-57,  1972.

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

14.    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.

15.    Asada, K., and K.  Kiso.   Initiation of aerobic oxidation of sulfite by
      illuminated  spinach chloroplasts.  Eur. J.  Biochem.  33:253-257, 1973.
                                      12-135

-------
16.    Reiser, G. D., and S. F. Yang. Chlorophyll destruction by
      bisulfite-oxygen system.  Plant Physio!. 60:277-281, 1977.

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

18.    Yip, C. C., and L. 0. Hadley.  The iodination of tyrosine  by
      myeloperoxidase and beef thyroids.  The possible involvement of free
      radicals.  Biochim. Biophys. Acta 122:406-412, 1966.

19.    Rotilio,  G., L. Calabrese, A. Finazzi Agro, and B. Mondovi.   Indirect
      evidence  for the production of superoxide anion radicals by  pig kidney
      diamine oxidase.  Biochem. Biophys. Acta 198:618-620, 1970.

20.   Nakamura, S.   Initiation of sulfite oxidation by spinach ferredoxin-NADP
      reductase and  ferredoxin system:  A model experiment on the  superoxide
      anion  radical  production by metallo-flavoproteins.  Biochem.  Biophys.
      Res. Commun. 41:177-183, 1970.

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

22.   Yang,  S.  F.  Biosynthesis of ethylene.  Ethylene formation from
      methional by horseradish peroxidase.  Arch. Biochem. Biophys.
      122:481-487, 1967.

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

24.   McCord, J. M., and I. Fridovich.  The utility of superoxide  dismutase in
      studying  free  radical reactions.  J. Biol. Chem. 244:6056-6063. 1969.

25.   Yang,  S.  F.  Sulfoxide  formation  from methionine or  its sulfide analogs
      during aerobic oxidation of sulfite.  Biochemistry 9:5008-5014. 1970.

26.   Schroeter, L.  C.  Sulfur Dioxide.  Pergamon Press, Oxford.  1966.   p.
      168.

27.   McCord, J. M., and I. Fridovich.  The reduction of cytochrome c by milk
      xanthine  oxidase.  J. Biol. Chem. 243:5753-5760. 1968.

28.    Yang,  S.  F.  Further studies on ethylene formation from
      cr-keto-methylthiobutyric acid or a-methylthiopriopionaldehyde by
      peroxidase in the presence of sulfite and oxygen.  J. Biol.  Chem.
      244:4360-4365, 1969.

29.    Beauchamp, C., and I. Fridovich.  A mechanism for  the production of
      ethylene from methional.  J. Biol. Chem. 245:4641-4646, 1970.

30.    Yang, S.  F.   Destruction of tryptophan during the  aerobic  oxidation of
      sulfite ions.  Environ.  Res. 6:395-402, 1973.
                                     12-136

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

32.    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.

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

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

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

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

37.    Wattiaux-DeConinck, S.,  and  R. Wattiaux.  Subcellular distribution of
      sulfite cytochrome  c reductase in  rat liver  tissue.   Eur.  J.  Biochem.
      19:552-556, 1974.   "

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

39.    Tager, J.  M., and N. Rautanen.  Sulphite  oxidation by a  plant
      mitochondrial system.   I. Preliminary observations.   Biochim. Biophys.
      Acta  18:111-121, 1955.

40.    Arrigoni,  0.  The enzymatic  oxidation of  sulphite in mitochondrial
      preparations  of  pea internodes.   Ital.  J. Biochem. 7:181-186, 1959.

41.    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.

42.    Cohen, H.  J., R. T. Drew, J.  L. Johnson,  and K. V. Rajagopalan.
      Molecular  basis  of  the  biological  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.

43.    Hayatsu,  H.,  and R. C.  Miller, Jr.   The cleavage  of  DMA  by the
      oxygen-dependent reaction of bisulfite.   Biochem. Biophys. Res. Commun.
      46:120-124, 1972.

44.    Yokoyama,  E., R. E. Yoder,  and N.  R.  Frank.   Distribution of 35S in  the
      blood and  its excretion in  urine  of dogs  exposed  to    SO-.  Arch.
      Environ.  Health  22:389-395,  1971.                        i
                                      12-137

-------
45.   Hazucha, M., and D. V. Bates.  Combined effect  of  ozone  and  sulfur
      dioxide on human pulmonary function.  Nature  London  257:50-51,  1975.

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

47.   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.

48.   Takebe,  I.  Isolation and characterization  of a new enzyme choline
      sulfatase.  J.  Biochem. 50:245-255,  1961.

49.   Zucker,  M., and A. Nason.  Hydroxylamine  reductase from neurospora
      crassa.  Methods Enzymol. 2:415-419,  1955.

 50.   Wilson,  D. F.   The inhibition of mitochondria!  respiration by bisulfite
       ions.   Fed.  Proc.  Fed. Am.  Soc.  Exp.  Biol.  27:830, 1968.

 51.   Ziegler, I.  Action of sulfite on plant malate dehydrogenase.
       Phytochemistry  13:2411-2416,  1974.

 52.   Oshino,  N.,  and B.  Chance.   The  properties  of sulfite oxidation in
       perfused rat  liver;  interaction  of  sulfite  oxidase with the
      mitochondria!  respiratory chain.  Arch.  Biochem.  Biophys. 170:514-528,
       1975.

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

 54.    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.

 55.    Shapiro, R.   Genetic effects of  bisulfite (sulfur dioxide).   Mutat. Res.
       39:149-176,  1977.

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

 57.   Schneider, L. K.,  and C. A.  Calkins.   Sulfur  dioxide-induced lymphocyte
      defects  in human peripheral  blood cultures.  Environ. Res.  3:473-484,
      1971.

58.   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, 1970.

59.   Shapiro, R.,  B.  I. Cohen, and R.  E.  Servis.  Specific deamination of  RNA
      by  sodium  bisulphite.  Nature London 227:1047-1048, 1970.
                                      12-138

-------
60.   Advisory Committee on the Biological Effects of lonixing Radiation. The
      Effects on Populations of Exposure to Low Levels of Ionizing Radiation.
      National Academy of Science, Washington, DC, 1972.  p. 52.

61.   Propping, P.  Comparison of point mutation rates in different species
      with human mutation rates.  Humangenetik 16:43-48, 1972.

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

63.   Amdur, M. 0.  Respiratory absorption data and SO, dose-response curves.
      Arch. Environ. Health 12:729-732, 1966.         c

64.   Amdur, M. 0.  Toxicologic appraisal of particulate matter, oxides of
      sulfur, and  sulfuric acid.  J. Air Pollut. Control Assoc. 19:638-646,
      1969.

65.   Alarie, Y.,  A. A. Krumm, H. J. Jennings, and R. H. Haddock.
      Distribution of ventilation in cynomolgus monkeys.  Measurement with
      real-time digital computerization.  Arch. Environ. Health 22:633-642,
      1971.

66.   Ames, B. N.  Identifying environmental chemicals causing mutations and
      cancer.  Science 204:587-593, 1979.

67.   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.

68.   Laskin, S.,  M. Kuschner, and R. T. Drew.  Studies in pulmonary carcino-
      genesis.  lr\: 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.

68a.  Petering, D. H. , and N. T. Shih.  Biochemistry of bisulfite - sulfur
      dioxide.  Environ. Res. 9:55-65, 1975.

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

70.   Erikson, B., and M. Rundfelt.  Reductive decomposition of
      S-sulfoglutathione in rat liver.  Acta Chem. Scand. 22:562-570, 1968.

71.   Sorbo, B.  On the metabolism of thiosulfate esters.  Acta Chem. Scand.
      12:1990-1966, 1958.

72.   Sorbo, B.  Mechanism of oxidation of inorganic thiosulfate and
      thiosulfate  esters in mammals.  Acta Chem. Scand. 18:821-823, 1964.

73.   Villarejo, M., and J. Westley.  Mechanism of rhodanase catalysis  of
      thiosulfate-lipoate oxidation-reduction.  J. Biol. Chem. 238:4016-4020.
      1963.
                                     12-139

-------
74.    Koj, A., J.  Frendo, and Z. Janek.    S thiosulfate oxidation by  rat
      liver mitochondria in the presence of glutathione.  Biochem. J.
      103:791-, 1967.

75.    Laster, L., F. Irreverre, S. H. Mudd, and W. D. Heizer.  A  previously
      unrecognized disorder of metabolism of sulfur  containing compounds -
      Abnormal urinary excretion of S-sulfo-c-cysteine, sulfite and
      thiosulfate in a severely retarded child with  ectopia  lentis.  J.  Clin.
      Invest. 46:1082, 1967.

76.   Carson, N. A., and D. N. Raine, (eds.).  Inherited Disorders of  Sulfur
      Metabolism.  Churchill-Livingstone, Edinburgh,  1971.   pp.  269-274.

77.   Frank,  N. R.,,R. E. Yoder, E. Yokoyama, and  F.  E. Speizer.  The
      diffusion of,-  S09 from tissue fluids into the lungs following exposure
      of  dogs to 3bS02.  Health Phys. 13:31-38, 1967.

78.   National  Air  Pollution Control Administration.  Air Quality Criteria for
      Sulfur Oxides.  AP-50, U.S.  Department of Health, Education, and
      Welfare,  Washington,  DC,  1970.

79.   Strandberg,  L. G.  SO, absorption  in the respiratory tract.  Arch.
      Environ.  Health 9:160*166,  1964.

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

81.   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.

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

83.   Reid,  L.   Evaluation  of model systems for study of  airway  epithelium,
      cilia,  and mucus.  Arch.  Intern. Med. 126:428-434,  1970.

84.   Frank,  N. R.   Studies on the effects of acute  exposure to  sulphur
      dioxide in human subjects.   Proc.  R. Soc. Med.  57:1029-1033, 1964.

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

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

87.   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,  1965.
                                     12-140

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

89.   Lewis, T. R., D. E. Campbell,  and T.  R. Vaught, Jr.  Effects  on  canine
      pulmonary function via induced N0?  impairment, particulate interaction
      and subsequent SOX-  Arch.  Environ. Health  18:596-601,  1969.

90.   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.  In:  Air  Pollution and the Politics  of Control.
      MSS Information Corporation, New York, 1973.  pp.  47-60.

91.   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.

92.   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.

93.   Amdur,  M.  0.   Animal studies.  In:  Proceedings of the  Conference on
      Health  Effects of Air Pollutants, Washington, D.C.  October 3-5,  1973.
      A  Report prepared  for the Committee on Public Works, United States
      Senate.  Serial No. 93-15,  U.S. Government  Printing Office, Washington,
      DC, 1973.  pp. 175-205.

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

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

96.   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.

97.   Amdur,  M.  0.   The  effect of aerosols  on  the response to irritant gases.
      In:   Inhaled  Particles  and  Vapors.  C.  N. Davies, ed.,  Pergamon  Press,
      Oxford,  1961.  pp. 281-294.

98.   Corn, M.,  N.  Kotsko, D.  Stanton,  W. Bell, and A.  P. Thomas.  Response of
      rats to inhaled mixture  of  S0? and SO- -  NaCl aerosol  in air. Arch.
      Environ. Health. 24:248-256, 1972.

99.   Frank,  N.  R., and  F. E.  Speizer.   S02 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.
                                      12-141

-------
100.   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.

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

102.  Islam, M.  S., E. Vastag, and W. T. Ulmer.  Sulphur-dioxide induced
      bronchial  hyperreactivity against acetylcholine.   Int.  Arch. Arbeitsmed.
      29:221-232, 1972.

103   Lee,  S.  D., and R. M.  Danner.  Biological  effects of S02 exposures on
      guinea  pigs.  Arch. Environ. Health 12:583-587, 1966.

104.  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.

105.  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.

106.  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.

107.  Rylander, R.   Alterations  of  lung defense mechanisms against airborne
      bacteria.   Arch.  Environ.  Health  18:551-555,  1969.

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

109.  Lebowitz,  M.  D.,  and  G.  A.  Fairchild.   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.

110.  Ferin,  J.,  and  L.  J.  Leach.  The effect of S02 on lung clearance of TiO?
      particles  in  rats.  J.  Am.  Ind. Hyg.  Assoc.  3_4:260-263, 1973.

111.  Hirsch,  J.  A.,  E. W.  Swenson, and A.  Wanner.   Tracheal mucous transport
      in  beagles  after  long-term  exposure to  1 ppm sulfur dioxide.  Arch.
      Environ.  Health 30:249-253, 1975.
                ' .• •''•
112.  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.
                                      12-142

-------
113.   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, 1970.

114.   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, 1970.

115.   Zarkower, A.  Alterations in antibody response induced by chronic
      inhalation of S02 and carbon.  Arch. Environ. Health 25:45-50, 1972.

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

117.   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.

118.   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.

119.   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.

120.   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, Cliicago, IL, 1977.  pp. 519-526.

121.   Amdur,  M. 0.  Effect of a combination of SO,, and H9SO. on guinea pigs.
      Pub. Health. Rep.  69:503-506, 1954.        *      *  *

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

123.   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.

124.   Amdur,  M. 0., and  D. W. Underhill.   Response of guinea pigs  to a
      combination  of  sulfur  dioxide and open  hearth  dust.  J. Air  Pollut.
      Control Assoc. 20:31-34, 1970.

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

126.   Nadel,  J. A., M.  Corn,  S. Zwi,  J. Flesch,  and  P. Graff.   Location  and
      mechanism of airway constriction  after  inhalation  of  histamine aerosol
      and inorganic sulfate  aerosol.   In:   Inhaled Particles  and Vapours.
      Volume  II, C. N.  Davies, ed.  Pergamon  Press,  Oxford,  1967.   p.  55-67.
                                      12-143

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

128.   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, 1977.

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

130.   Amdur, M. 0., J. Bayles, V. Ugro, and D. W. Underhill.   Comparative
      Irritant  Potency of Sulfate Salts.  Environ. Res,  16:1-8,  1978.

131.  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, 1977.

132.  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.

133.  LEFT OUT

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

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

136.  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.

137.  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,  1977.

138.   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,  1978.

139.   Sackner, M.  A., and M. Reinhardt.  Effect of microaerosols of sulfate
      particulate matter on trachea! mucous velocity in conscious sheep.  Am.
      Rev.  Respir.  Dis.  115:241, 1977.

140.   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, 1977.
                                     12-144

-------
141.   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.

142.   National Academy of Sciences.  Airborne  Particles.   University Park
      Press, Baltimore, MD, 1979.

143.   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.

144.   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.                                                    ~~

145.   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, 1977.

146.   Natusch, D.  F.  S., and J. R. Wallace.   Urban aerosol toxicity:  The
      influence of particle size.  Science 186:695-699,  1974.

147.   Office of Air Quality Planning and Standards.  Preliminary  Assessment of
      the Sources, Control  and  Population  Exposure to Airborne Polycyclic
      Organic Matter  (POM)  as Indicated by Benzo(a)Pyrene  (BaP).  External
      Review Draft No. 1, U.S.  Environmental  Protection  Agency, Research
      Triangle Park,  NC, May 1978.

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

149.   Waters, M.  D.,  D.  E.  Gardner, and D. L.  Coffin.  Cytotoxic  effects of
      vanadium on  rabbit alveolar macrophages  i_n  vitro.  Tox. Appl.  Pharm.
      28:253-263,  1974.

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

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

152.   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.

153.   Bingham, E., W. Barkley,  M. Zerwas,  K.  Stemmer,  and  P. Taylor.
      Responses of alveolar macrophages to metals.  I.  Inhalation of lead  and
      nickel. Arch. Environ. Health 25:406-414,  1972.
                                      12-145

-------
154.   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, 1977.

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

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

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

158.  Crofton,  J.,  and  A.  Douglas.  Respiratory Diseases.   2nd edition,
      Blackwell  Scientific Publishers, Oxford,  1975.   pp.  508-551.

159.  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.

160.  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.

161.  Exon,  J.  H.,  N.  M.  Patton, and  L.  D. Keller.  Hexamitiasis in Cadmium-
      Exposed Mice.   Arch.  Environ. Health 30:463-464, 1975.

 162.  Keller,  L. D.,  J.  H.  Exon, and  J.  G. Roan.   Antibody Suppression by
      Cadmium.   Arch.  Environ.  Health 30:598-601,  1975.

 163.  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.

164.  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.

165.  Saffiotti, U.,  F.  Cefis,  L.  H.  Kolb, and M.  J.  Grote.  Proc. Am. Assoc.
      Cancer Res. 4:59,  1963.

166.  Shabad, L. M.,  L.  W.  Pylev,  and T.  S.  Kolesnichenko.  Importance of the
      deposition of carcinogens  for cancer induction  in lung tissue.  J.  Natl.
      Cancer Inst.  33:135-141,  1964.

167.  Mudd,  S.  H.,  F.  Irreverre, and  L.  Laster.  Sulfite  oxidase deficiency  in
      man:   demonstration  of  the enzymatic defect.  Science 156:1599-1602,
      1967.                                                  	
                                      12-146

-------
168.   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.

169.   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 investigations  of a  hereditary
      metabolic disorder in sulfur metabolism.  N.  Eng. J.  Med.  297:1022-1028,
      1977.                                                      —

170.   Amdur, M. 0.  1974 Cummings Memorial  Lecture.  The  long road from
      Donora.  J. Am. Ind. Hyg. Assoc. 35:589-597,  1974.

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

172.   Amdur, M. 0., M.  Dubriel, and D. A. Creasia.   Respiratory  response of
      guinea Pigs to low levels of sulfuric acid.   Environ.  Res. 15:418-423,
      1978.                                                      ~~

173.   Amdur, M. 0.  lexicological Guidelines for  Research on Sulfur Oxides and
      Particulates.  Proc. 4th Symposium on Statistics and  the Environment.
      pp. 48-55.  1975.

174.   Waters, M. D., D. E. Gardner, C. Aranyi, and  D.  C.  Coffin.  Metal
      toxicity for  rabbit alveolar macrophages in vitro   Environ. Res.
      9:32-47, 1975.

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

176.   Gardner, D. E.  Impairment of pulmonary defenses following inhalation
      exposure to cadmium, nickel, and manganese.   J.  Aerosol Sci.,  in press,
      1980.

177.   Hatch, G. E., D.  E. Gardner, and D. B. Menzel.   Stimulation of  oxidant
      production in alveolar macrophages by pollutants and  latex particles.
      Environ. Res., in press, 1980.

178.   Ehrlich, R.   Interaction between environmental pollutants  and
      respiratory infections.  In:  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.

179.   Ehrlich, R.,  J. C. Findlay,  and D. E. Gardner.   Susceptibility  to
      bacterial pneumonia in animals  exposed  to sulfates.   Tox.  Lett.
      1:325-330, 1978.
                                      12-147

-------
180.   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.

181.   Grose, E. C.-, D. E. Gardner, and F< J. Miller.   Response of ciliated
      epithelium to ozone and sulfuric acid.  Environ.  Res., in press,  1980.

182.   Schiff,  L. J., M. M. Bryne, J. D. Renters, J.  A.  Graham, and D.  E.
      Gardner.  Cytotoxic effects of sulfuric acid mist, carbon particulates,
      and their mixtures on  hamster tracheal epithelium.   Environ.  Res.
      19:339-354, 1979.

183.  Renters, 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.

184.  Hemeon,  W. C.  L.  The  estimation of health hazards from air pollution.
      AMA Arch. Ind.  Health  11:397-402, 1955.

185.  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.

186.  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.

187.  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.  1J:299-305,  1976.

188.  Adkins,  Jr.,  B., G. H.  Luginbuhl, and D.  E. Gardner.   Biochemical
      changes  in pulmonary cells following manganese oxide inhalation.
      Toxicol.  Lett., in press,  1980.

189.  Adkins,  Jr.,  B., G. H.  Luginbuhl, F. J. Miller,  and  D. E. Gardner.
      Increased pulmonary susceptibility to streptococcal  infection following
      inhalation of manganese oxide.  Infect. Immun.,  in press, 1980.

190.   Adkins,  Jr.,  B., G. H.  Luginbuhl, and D.  .E. Gardner.   Acute exposure of
      laboratory mice to manganese oxide.  J. Am. Ind.  Hyg.  Assoc.  in press,
      1980.

191.   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.

192.   Rylander, R., M. Ohrstrom, P. A. Hellstron, and R. Bergstrom.  S0? and
      particles - synergistic effects on guinea pig  lungs.   In:  Inhalea
      Particles III.  Volume  I, W. H. Walton, ed., Unwin BrosT, Ltd., Surrey,
      England, 1970 pp. 535-541.
                                      12-148

-------
193.   No reference.

194.   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.^. Klingberg eds., John
      Wiley and Sons, New York, 1976.  pp. 190-213.

195.   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.

196.   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.

197.   Alarie, Y., W. M.  Busey, A. A. Krumm, and C. E.  Ulrich.  Long-term
      continuous exposure to sulfuric acid mist in cynomolgus monkeys and
      guinea pigs.  Arch. Environ. Health 27:16-24, 1973.

198.   MacFarland, H. N., C. E. Ulrich, A. Martin, A. Krumm, W. M.  Busey, and
      Y. Alarie.  Chronic exposure of cynamolgus monkeys to fly ash.  In:
      Inhaled Particles  III. Volume  1, W. H. Walton, ed., Unwin Bros.,"Ltd.,
      Surrey, England, 1971.  pp. 313-327.

199.   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, 1973.

200.   Summers, G. A., and J. W.  Drake.  Bisulfite mutagenesis in bacteriophage
      T4.   Genetics 68:603-607,  1971.

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

202.   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  DMA
      and phage 2  induced by bisulfite.   Mutat. Res. 20:433-434, 1974.

203.   Mukai, F., I. Hawryluk, and R. Shapiro.   The mutagenic  specificity of
      sodium bisulfite.  Biochem. Biophys.  Res. Commun.  39:983-988,  1970.

204.   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.

205.   Valencia, R. , S. Abrahamson,  P. Wagoner,  and  L.  Mansfield.   Testing  for
      food  additive-induced mutations  in  Drosophila  melanogaster.   Mutat.  Res.
      21:240-241, 1973.
                                      12-149

-------
206.   No reference.

207   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.

208.   Nulsen, A., P.  G. Holt, and D. Keast.  Sulfur dioxide.   Acute effects on
      cell metabolism in vitro.  IRCS Libr. Compend.  2:1464,  1974.

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

210.  Schneider,  L. K., and  C. A. Calkins.  Sulfur dioxide-induced lymphocyte
      defects  in  human peripheral blood cultures.  Environ.  Res.  3:473-484,
      1971.

211.  Timson,  J.  Action of  sodium  sulphite on the mitosis of human
      lymphocytes.  Chromosomes Today 4:211-214, 1973.

212.  Jagiello, G. M., J. S. Lin, and M. B. Ducayen.  S02  and its metabolite:
      effects  of  mammalian egg  chromosomes.  Environ. Res.  9:84-93, 1975.

213.  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:

214.  Newell,  G.  W., and W.  A.  Maxwell.  Mutagenic effects of sodium
      bisulfite,  U.S.  Nat. Tech.  Inform. Serv., PB Rep.  No.  221826/1,
      Springfield, Va., 1972.

215.  Lippmann, M., R.  E. Albert, D.  B. Yeates, K. Wales,  and G.  Leikauf.
      Effect of sulfuric  acid  mist  on mucociliary bronchial  clearance in
      healthy  non-smokers.   In:   Proceedings of GAP  7 -  Aerosols  in Science,
      Medicine, and Technology, Dusseldorf, October,  3-5,  1979.   In press,
      1980.

216.  No  reference.

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

218.  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, 1975.

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

220.  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.                                                     ~~
                                      12-150

-------
221.  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 cardiopulmonary functions  in dogs, sheep and
      humans.  Am. Rev. Respir. Dis. 118:497-510, 1978.

222.  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.

223.  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. Path.  Toxicol.,  in press,  1980.

224.  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.

225.  Allison, A. C., and D. M. L. Morgan.  Effects  of silica,  asbestos, and
      other particles on macrophage  and neutrophil lysosomes.   In:  Lysosomes
      in Biology and Pathology.   Volume 6,  J. T. Dingle,  P.  J.  3aques,  and I.
      H. Shaw, eds., North Holland,  NY, 1979.  pp. 149-159.

226.  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 Publications  No.  8,
      International Agency for Research on  Cancer, Lyon,  1973.  pp. 89-92.

227.  Morgan, A., P. Davies, J. C. Wagner,  G. Berry,  and  A.  Holmes.   The
      biological effects of magnesium-leached chrysotile  asbestos.  Br.  J.
      Exp. Pathol. 58:465-473, 1977.

228.  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.

229.  Schroeder, H. A.  A sensible look at  air pollution  by metals.   Arch.
      Environ. Health 21:798-806, 1970.

230.  Williams, S. J., K. M. Holden++M. Sabransky, and D.  B. Menzel.  The
      distributional kinetics of  Ni   ions  in the rat lung.  Toxicol. Appl.
      Pharmacol., in press, 1980.

231.  Saito, K., and D. B. Menzel.   Nickel  uptake and efflux from cultured
      type II pneumocytes.  Pharmacologist  20:275, 1978.

232.  No reference

233.  Frank, N. R., M. 0. Amdur,  J.  Worchester, andO.L. Whittenberger.   Effects
      of acute controlled exposure to S0? on respi/atory  mechanics  in healthy
      male adults.  J. Appl. Physio!. 177252-258, 1962.
                                      12-151

-------
234.   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

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

236.   Clutario, B. C.  Clinical pulmonary function,   In:   Pulmonary Physiology
      of the Fetus Newborn and Child.  E. M. Scarpelli,  ed.,  Lea and Febiger,
      Philadelphia, PA, 1975.  pp. 299-361.

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

238.  Bouhuys,  A.   In:  Breathing:   Physiology Environment and Lung Disease.
      Grune  and StraTton,  New York, 1974.   Chps. 8, 15,  and 16.

239.  Douglas,  J. S.,  P.  Ridgway, and C.  Brink.  Airway responses of the
      guinea pig in  vivo  and in vitro.   J. Pharmacol.  Exp.  Ther. 202:116-124.
      1977.                  ~ "

240.  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.

241.  Tomori Z.,  and J. G. Widdicomble.   Muscular,  bronchomotor and
      cardiovascular reflexes elicited by mechanical stimulation of the
      respiratous tract.   J. Physiol. 200:25-49, 1969.

242.  McFadden,  E.  R.,  and R. H. Ingram.  Exercise-induced asthma observations
      on  the initiating stimulus.  N. Engl.  J. Med.  301:763-769, 1979.

243.  Antonissen, L. A.,  R. W. Mitchell,  E.  A. Kroeger, W.  Kepron, K. S. Tse,
      and  N. L.  Stephens.  Mechanical alterations of airway smooth muscle in a
      canine asthmatic model.  J. Appl.  Physiol:  Respirat.  Environ. Exercise
      Physiol.  46:681-687, 1979.

244.  Drazen./M.  J., S. H. Loring, and R. Regan.  Validation of an automated
      determination of pulmonary resistance  of electrical substraction.
      J. Appl.  Physiol. 40:110-113,  1976.

245.  Alarie, Y., C. E. Ulrich, A. A. Krumm,  R.  H.  Haddock, and H. J.
      Jennings.   Mechanical properties of the  lung  in cynomolgus monkeys.
      Arch.  Environ. Health 22:.643-654,  1971.

246.  Ingram, R.  H., and  E. R. McFadden.  Localization and mechanisms of
      airway responses.   N. Engl. J. Med. 297:596-600,  1977.

247.  DeTroyer, A., J-C Yernault, and D.  Rodenstein.  Effects of vagae
      blockade  on lung mechanics in  normal man.   J. Appl. Physiol.:  Respirat.
      Environ.   Exercise Physiol. 46:217-226, 1979.
                                      12-152

-------
248.  Douglas, N. J., M. F. Sadlow, and D. C. Henley.  Effect of an  inhaled
      atropine-like  agent on normal airway function.  J. Appl. Physiol.:
      Respirat. Environ. Exercise Physiol. 46:256-262,  1979.

249.  Lee, L. Y., E. R. Bleecker, and J. A. Nadel.  Effect of ozone on
      bronchomotor response to inhaled histamine aerosol in dogs.  J. Appl.
      Physiol.:  Respirat. Environ. Exercise Physiol. 43:626-631, 1977.

250.  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.

251.  Nadel, J. A.,  H. Salem, B. Tamplin, and Y. Tokiwa.  Mechanism of
      bronchoconstriction during inhalation of  sulfur dioxide.  J. Appl.
      Physiol. 20:164-167, 1965.

252.  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,  in  press, 1980.

253.  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.

254.  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.

255.  Amdur, M. 0.   Respiratory absorption data and S0« dose-response curves.
      Arch.  Environ. Health 12:729-732, 1966.         *

256.  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.

257.  NO REFERENCE

271.  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.

272.  Takino, Y., K. Sugahara, and I.  Horino.   Two  lines of guinea pigs
      sensitive to chemical mediators  and anaphylaxis.  J. Allergy 47:247,
      1971.

273.  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.

274.  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.

275.  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.


                                     12-153

-------
276.   Office of Research and Development.  Air Quality Criteria  for  Lead.
      EPA-600/8-77-017, U.S. Environmental Protection Agency, Washington,  DC,
      December 1977.

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

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

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

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

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

282.  National Academy of Sciences.   Iron.   University Park Press,  Baltimore,
      MD,  1979.

283.  National Academy of Sciences.   Zinc.   University Park Press,  Baltimore,
      MD,  1979.

284.  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.

285.  Blunck,  J. J., and  C. E. Crowther.   Enhancement of azo dye car-
      cinogenesis  by dietary  sodium sulphate.   Europ. J.  Cancer, 11:23-31,
      1975.                                                       ~~

286.  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, pp. 41-48, 1977.

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

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

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

290.  Crisp, C. E.,  G. L. Fisher,  and J.  E.  Lammert.   Mutagenicity of
      filtrates from respirable coal  fly  ash.   Science,  199:73-75, 1978.
                                      12-154

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

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

293.  Cohen, H. J., and J. Fridovich.  Hepatic Sulfite Oxidase.  J. Biological
      Chemistry, 246(2):359-366, 1971.

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

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

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

297.  DiPaolo and  Casto, 1979.

298.  Di Paolo et al...  1978.

299.  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.

300.  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.

301.  Furst, A.  An overview of metal carcinogenesis. Adv. Exp. Biol. Med.,
      91:1-12, 1977.

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

303.  von  Nieding, G.  Possible mutagenic properties and  carcinogenic action
      of the irritant gaseous pollutants N0?, 0,, and S0?.   Environ. Health
      Perspectives, 22:91-92, 1978.

304.  Hadler, H. I.,  and G.  L. Cook.  The mitochondrial  activation  of sulfate
      and  arsenate and their role  in  carcinogenesis.  J.  Environ.  Path.
      Toxicol., 2:601-612, 1979.

305.  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.
      U.S. Environmental  Protection Agency, Health  Effects  Research Laboratory
                                      12-155

-------
      and Environmental Sciences Research Laboratory, Research Triangle  Park,
      NC.  EPA-600/9-78-027, 1977.

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

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

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

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

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

311.  International Agency for Research on Cancer.  IARC Monographs  on the
      Evaluation of Carcinogenic Risk of Chemicals to Man, Vol  1,  pp. 17-28,
      1972.

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

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

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

315.  Kotin, 1954.

316.  Kuschner, M.  The J. Burns Amberson lecture, the  causes of lung cancer.
      American  Review  of Respiratory Disease  98:573, 1968.

317.  Lau, T. J.,  R. L. Hackett, and F. W. Sunderman.   The carcinogenicity  of
      intravenous  nickel carbonyl in rats.  Cancer Res.  32:2253-2258, 1972.

318.  Lee, R. E. Jr.,  and F.  V. Duffield.  EPA's  catalyst  research program:
      environmental impact of sulfuric acid emissions.   APCA Journal 27:632,
      1977.                                                           —

319.  Leiter, J.,  and  M. J. Shear.  Production  of tumors in  mice with tars
      from city air dusts.  J. Nat. Cancer Inst.  3:167, 1942.
                                     12-156

-------
320.   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.

321.   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.

322.   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.

323.   Miller, E. C.   Some current perspectives on chemical carcinogenesis in
      humans and experimental animals:  presidential address.  Cancer Res.
      38:1479-1496, 1978.

324.   Mittler, S., and S. Nicholson.  Carcinogenicity of atmospheric
      pollutants.  Ind. Med. Surg. 26:135, 1957.

325.   Murray, M. J., and C. P. Flessel.  Metal-polynucleotide interactions. A
      comparison of carcinogenic  and  non-carcinogenic metals uj vitro.
      Biochimica et Biophysica Acta 425:256-261, 1976.

326.   Newell, G. W., and W. A. Maxwell.  Mutagenic effects of sodium
      metabisulfite.  U.S. Nat. Tech. Inform. Serv., PB Rep. No. 221825/3,
      1974.  104 pp.

327.   Peacock, P. R., and J. B. Spence.  Incidence of lung tumours in LX mice
      exposed to  (1) free radicals; (2) SO,.  Brit. J. Cancer 21:606-618,
      1967.                               L                   ~~

328.   Pitts, T. N., et al.  Atmospheric reactions of polycyclic aromatic
      hydrocarbons:  facile formation of mutagenic nitro-derivatives.
      Accepted by Science, June 23, 1978, 1978.

329.   Pott, F., R. Tomingas, and  J. Misfeld.  Tumours in mice after sub-
      cutaneous injection of automobile exhaust condensates.  Air  Pollution
      and Cancer  in Man, IARC Scientific Publications No. 16, 1977.   pp.
      79-88.

330.   Rigdon, R. H., and J. Neal.  Tumors  in mice induced by air particulate
      matter from a petrochemical industrial area.  Texas Reports  on  Biology
      and Medicine 29:109-123, 1971.

331.   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  27711,
      1979.

332.   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.
                                      12-157

-------
333.  Schneider, L K., and C. A. Calkins.  Sulfur dioxide-induced lymphocyte
      defects in human peripheral blood cultures.  Environ. Res. 3:473-482,
      1970.

334.  Sellakumar, A.  Proceedings Catalyst Research Program Sulfuric Acid
      Research Review Conference, Jan. 31, 1977.  pp. 36.

335.  Seelig, M. G., and E. L. Benignus.  Coal smoke soot and tumors of the
      lung in mice.  Am. J. Cancer 28:96-111, 1938.

336.  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.

337.  Shapiro, R.,  R. E. Servis, and M. Welcher.  Reactions of  uracil and
      cytosine derivatives with sodium bisulfite.  A specific deamination
      method.  J. Amer. Chem. Soc. 92:422-424, 1970.

338.  Shapiro, R.,  V. DiFate, and M. Welcher.  Deamination of cytosine
      derivatives by bisulfite.  Mechanism of the reaction.  J. Amer. Chem.
      Soc. 96:906-912, 1974.

339.  Shapiro, R.   Genetic effects of bisulfite (sulfur dioxide).  Mutat.  Res.
      39:149-176, 1977.

340.  Sirover, M. A., and L A. Loeb.  Infidelity of DNA synthesis HI vitro:
      screening for potential metal mutagens or carcinogens.  Science
      194:1434-1436, 1976.

341.  Sirover, M. A., and L. A. Loeb.  Metal activation of DNA  synthesis.
      Biochem. Biophys. Res. Commun. 70(3).-812-817, 1976.

342.  Stern, A. C.   Air Pollution, Vol. II, Analysis, Monitoring, and
      Surveying.  Academic Press, New York, London, 1968.

343.  Stoner, G. D., M. B. Shimkin, M. C. Troxell, T. L. Thompson, and  L.  S.
      Terry.  Test  for carcinogenicity of metallic compounds by the pulmonary
      tumore re-sponse in strain A mice.  Cancer Res. 36:1744-1747, 1976.

344.  Sunderman, F. W.  Metal carcinogenesis.  Advances in Modern Toxicol.
      2:256-295, 1979.

345.  Sunderman, F. W.  Carcinogenic effects of metals.  Fed. Proceedings,
      37(l):40-46,  1978.

346.  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.

347.  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.
                                     12-158

-------
348.  Towill, L E., C. R. Shrina, J. S. Drury, A. S. Hammons, and J. W.
      Holleman. Reviews of the environmental effects of pollutants:  III.
      Chromium. U.S. Environmental Protection Agency Health Effect Research
      Laboratory, Cincinnati, Ohio,  EPA-600/1-78-023, 1978.

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

350.  U.S. Environmental  Protection  Agency.  Air Quality Criteria for Lead.
      Office of Research  and Development, Washington, DC, EPA-600/8-77-017,
      1977.

351.  Wang, Y. Y., S. M.  Rappaport,  R. F. Swayer, R. E. Talcott, and E. T.
      Wei.  Direct-acting mutagens in automobile exhaust.  Cancer Letters,
      1978.  (In press)

352.  Wynder, E. L., and  D. Hoffman.  Some  laboratory and epidemilogical
      aspects of air pollution carcinogenesis.  J. Air Pollution Control
      Assoc. 15:155-159,  1965.

353.  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.

354.  Miller, M., and I.  Alefheim.   Mutagenicity and PAH-Analysis of Airborne
      Particulate Matter.  Atmospheric Environment, 1980.  (In press)

355.  Tokiwa, H., K. Shigeji, K. Takahashi, and Y. Ohnishi.  Mutagenic and
      chemical assay of extracts of  airborne particulates.  Mutation Research,
      77:99-108, 1980.

356.  Kubitschek, H. E.,  and L. Venta.  Mutagenicity of coal fly ash from
      electric power plant precipitators.   Env. Mutag. 1:79-82, 1979.
                                      12-159

-------
 Additional References Recommended for Consideration in Chapter 12

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

Costa, D.  L., and M. 0. Amdur.  Effect of oil mists on the irritancy of sulfur
     dioxide.  I.   Mineral Oils and Light Lubricating Oil,  Am. Indust, Hyg.
     Assoc. J. 40(8):680-685, 1979.

Costa, D.  L., and M. 0. Amdur.   Respiratory responses of guinea pigs to oil
     mists.  Am. Indust.  Hyg. Assoc. J. 40(8):673-679, 1979,

Schneider and Calkins.  Sulfur dioxide induced lymphocyte defects in peripheral
     blood cultures.  Environ. Res. 3:473-482, 1970,

-------
                                  APPENDIX I

 1.0  SULFONATION BY SULFITE AND BISULFITE
     Sulfite is a relatively strong nucleophile and can  attack  a  number  of
 biological compounds by nucleophilic substitution or addition.  Either sulfite
 or bisulfite may be responsible for sulfonation.   Nucleophilic  substitution
                                                                               •)
 through sulfite attack is called sulfitolysis  and has been  reported  for  epoxide,
 disulfide (Reaction 12-3),  and thiamine (Reaction 12-4).4
     RSSR' + HSO§   .«         RSSOJ+R'SH
       .^k..   -..     ./I
              — CH2	N
                            S   +  HS05
12-4
The equilibrium constant for Reaction 12-3  with  cysteine at 37°C and pH 7.75
           _o
is 8.9 x 10  .   If sulfite is incubated with  rabbit plasma for 45 min,
nearly 100 percent of the added sulfite  is  present as S-sulfonates (R-S-SO^).
     On this basis,  Kaplan et al.   calculated  that chronic exposure to an
unspecified concentration of S02 would convert 0.16 percent of total plasma
                                   12A-1

-------
proteins to S-sulfonates.   The metabolic  significance  of this level  of plasma

S-sulfonates is not yet clearly defined,  although Kaplan et al.  saw  it as

toxic.  On the other hand,  Gunnison and Benton  and Shapiro and  Weisgras

concluded that 0.16 percent is a relatively low level  of protein alteration

and that sulfitolysis is probably not metabolically significant.   S-sulfonation

may serve as a vehicle for  the widespread distribution and storage of bisulfite

in the body.  (See Section  12.2.1.3.1).

     Bisulfite adds in vitro to aldehydes (Reaction 12-5),  ketones (including
                                             p
sugars), conjugated alkenes, quinones, coumerins,   the pyridine  ring of NAD

(Reaction 12-6),  the pyrazine ring of folic acid (Reaction 12-4),  and the
isoalloxazine ring of flavine coenzymes (Reaction  12-7).


   RCHO + HSOJ  ,
                                                   10
 ?H
RCHSOJ
12-5
            —NH-
                      SO
                        -2
          OgS «w^^ H  O
            (V-
                                                                12-6
                                                                12-7
                               12A-2

-------
     The ionic reaction of bisulfite with NAD  and flavins i_n vitro has been



described by several authors.  Bisulfite adds reversibly to the 4 position of



NAD  with an equilibrium constant of 36 M   at pH 7.   The bisulfite adduct is



greatly stabilized in the presence of proteins since a stoichiometric reaction



of bisulfite at low concentrations occurs with protein bound NAD+.  Enhancement



of the reaction of bisulfite with flavins bound to proteins has also been



observed.  Two reaction mechanisms of bisulfite with NADH are discussed below.



The first is an ionic reaction in which bisulfite acts as a general acid



catalyst to hydrate the 5,6  unsaturation; this hydration reaction is rela-



tively slow.  The second is  a free radical oxidation of NADPH to the



pyridinium salt.



2.0  AUTOXIDATION OF SULFITE AND BISULFITE



     Oxidation of sulfite to sulfate through the free radical chain mechanism



jj} vitro can be initiated by metal ions,   ultraviolet irradiation,  '



charge transfer complexes from the illuminated dyes,      electrolytic gener-


                 17                        17-22
ation of radicals   or enzymatic reactions.       These reactions are



important for their ability  to generate free radicals.  The autoxidation of



sulfite can be initiated by  superoxide radical (-D- ), but is inhibited by


                     23 24
superoxide dismutase.  '     This suggests that -Op  radical is involved in



propagation as well as initiation.  Thus, the reactive species generated



during the aerobic oxidation of sulfite includes -Op  , *OH, and -SO^ .  The


                                                             12-25
following scheme describes the sulfite oxygen chain reaction.
                                   12A-3

-------
    Initiation:
                                                                      12~ 8
         S032 * °2  *   'S°3~ +  *°2~
    Propagation:
                                                                      12-9
          •so3  +  o2  -   so5
          S05"  *  SO]2   +  S04"  + SO;2                                 12-10

          S04"  +  SO'2   -  SO^2  + S03"                                 12-11

          S04"  +  OH" •>  SO^2  +  -OH                                    12-12

          •OH  +  S03"2   -» OH"  + S03"                                 12-13

          -02  +  S03"2   + 2H+   -»  2-OH + S03"                        12-14

     Termination:

          •OH + S03"   *  OH" + S03"                                  12"15
          S03" + -02"  ->  2H+  ->  S03"+ H202                          12-16

          (H202 +  S032   -»  H20  + SO^2

           S03 +  H20  -^   S0^2+  2H+)                                   12-17
     Initiation (Reaction 12-8) is caused by metal ions,  ultraviolet  light  or
enzymatic reactions.   The chain is propagated by Reactions  12-9  through 12-14,
forming sulfate ion.   Chain length of the reaction has  been estimated at 30,000
moles/mole -02  in the xanthine-xanthine oxidase system   and 300 moles/mole
•02  in the isolated chloroplast under illumination.15   The metal initiated
autoxidation of sulfite is inhibited by EDTA, organic acids, alcohols, thiols,
                                   12A-4

-------
amines, and proteins that occur in cells and may act as radical scavengers
                        26 27
inhibiting autoxidation.  '    Peroxidase initiated sulfite oxidation is not
                              25
inhibited by these scavengers,   suggesting that in vivo the oxidation of
sulfite is catalyzed by enzymes.   The non-enzymatic autoxidation outlined
above produces oxy- and sulfur oxide radicals that may be highly deleterious,
since they may cause lipid peroxidation.  (See discussion below.)
     Evidence for the formation of the highly reactive -OH and •()«  species
                                                                       22 28
has come mainly from studies of peroxidase catalyzed sulfite oxidation.   '
In these studies, methional is used to scavenge hydroxyl free radicals generat-
                                                                            29
ing ethylene as a characteristic oxidation product.  Beauchamp and Fridovich
have demonstrated that  *OH is responsible for ethylene formation from methional.
Methionine is rapidly oxidized to the sulfoxide (Reactions 12-18 and 12-19).
      R-S-R + -OH  ->  R-S-R + OH                                      12-18
        +               +
      R-S-R + -OH  ->  R-S-R  -»•  R-S-H + H+
                                                                      12-19
                        OH        0
In addition to methionine, tryptophan is also oxidized during the oxidation of
sulfite.
                                                                               8 21
     Co-oxidation of NADH and NADPH during sulfite oxidation has been reported, '
suggesting the following chain reaction:
                                   12A-5

-------
      SO ~  + Initiator  ->  -S03~                                      12-20

                               _ p    j.
      NADH   -S03~ ->  NAD- + S03   + H                                 12-21


      NAD-  + 02  •*  NAD+ + -02"                                       12-22


      S0~2+ -0~ + 2H+  -  -S0~2 + H202                                12-23


The autoxidation of sulfite could deplete NADH and NADPH needed for metabolism,

but the amount of NADH or NADPH oxidized will not be significant at concen-

trations of S02 which occur in the ambient air.

3.0  BISULFITE-INITIATED LIPID PEROXIDATION

     Kaplan et al.31 demonstrated that bisulfite (0.5 to 10 mM) initiates

peroxidation of aqueous emulsions of corn oil.  Peroxidation was measured by

the formation of 2-thiobarbituric acid (TBA) reactive substances.   Most likely,

these TBA reactive substances correspond to bicyclic peroxides formed during

the autoxidation of linolenic acid present in corn oil.  The reaction was

inhibited by the addition of the phenolic antioxidant BHT (2,6-di-t-butyl-4,4-

hydroxymethyl phenol).  Addition of manganous ion (10   to 10   M) also inhibited

the reaction.  Therefore, autoxidation initiated by bisulfite seems to proceed

through some oxygenated intermediary.  It is most probable that the reaction

proceeds through -OH or -02  (see Section 12.2.1.1).  Kaplan et al. suggest that

peroxidation of cell membranes is a mechanism of inhaled S02 toxicity.  This

hypothesis  has not been supported by whole animal inhalation data.

4.0  POTENTIAL MUTAGENIC EFFECTS OF SULFITE

     This section will review the biochemistry by bisulfite and sulfite.

While there is data suggesting a weak mutagenic effect  uj vitro and in micro-

organisms,  the question of mutagenesis ui vivo has not  been demonstrated

in animals.
                                   12A-6

-------
     As pointed out in Section 3 above, alterations in DNA and RNA produced by


sulfite are detected only at high concentrations of sulfite, acid pH and i_n


vitro.   Microbial systems validated for chemical mutagenesis have not been


used in these experiments.  The biological viability of sulfite-induced alter-


ations in DNA remains an important unanswered question.  If the alterations


were not transcribable, then cytotoxicity, rather than mutation, would be the


outcome.   Further, the rapid metabolism of sulfite to sulfate j_n vivo might


preclude the accumulation of sufficient sulfite to react with DNA.  This is


very important for the DNA contained in chromatin of higher organisms where


its reactivity towards sulfite is especially obscure.   An additional factor,


so far not addressed experimentally, is the rate of DNA repair after sulfite


damage.  Repair, without errors, may be sufficiently rapid to preclude trans-


cription of erroneous information.  Lastly, if sulfite damage to DNA were


expressed as carcinogenesis, this would undoubtedly be a multistep process


involving many stages.  It is still unknown how chemical carcinogens would


go through this process.  However, the most conservative course would be


to avoid exposure to all mutagens, since there presently is no known way to


reverse carcinogenesis.


4.1  REACTIONS OF BISULFITE/SULFITE WITH DNA AND RNA AS RELATED TO MUTAGENESIS


     The reactivity of bisulfite with nucleic acids and subsequent mutagenesis


induced by bisulfite have been reviewed by Shapiro   and by Fishbein.    The


deamination of cytosine to uracil in single-stranded, but not double-stranded,

                  CO
DNA is of interest   (Reaction 12-26).   This reaction also occurs in yeast

    eg
RNA.     The optimum conditions for both reactions are pH 5 and high bisulfite


concentrations on the order of 1M.  Deamination results in the conversion of


GC to AT sites and could be mutagenic.   GC to AT in DNA conversion  has been
                                   12A-7

-------
subsequently confirmed.   (See the discussions on the effects of bisulfite on


cultured cells.)  Decomposition of the uracil bisulfite complex is the rate


limiting step.   The chemistry of this reaction is discussed in detail by


Shapiro.55  He calculated the rate of deamination of cytosine under physiological


conditions to evaluate the potential  environmental  genetic hazard.  While it


is true that mammalian DNA is double-stranded, during the translational process


some regions of single-strandedness in the DNA may  be susceptible to attack.


Double-strandedness does not completely prevent deamination of cytosine to


uracil and, therefore, the introduction of a point  mutation.   Using estimates


of the spontaneous mutation in man at 10 /gene/generation,  '    or approxi-

         _q                                 2                        fil
mately 10  /base pair/generation assuming 10  base  pairs to a genome,   Shapiro


calculated that a concentration of 3  x 10   M bisulfite is sufficient to


double the spontaneous mutation rate.   This estimate is probably high since


the deamination reaction is second order in bisulfite,  whereas Shapiro cal-


culated the rate to be first order at low concentrations of bisulfite.   In


doing as Shapiro assumes,  other general  acids or bases  could substitute for
                                                                      12-26
                                                       A
                                  12A-8

-------
bisulfite in catalyzing the deamination step (Reaction 12-26).  However,



Shapiro points out that double-strandedness markedly reduces the reactivity of



cytosine.  The structure of DNA in eukaryotic chromatin and its reactivity



with bisulfite are not known.



     Transamination can be carried out via the same chemical mechanism as



deamination (Reaction 12-27).  The bisulfite adduct readily reacts with primary



amines, decomposing to the transaminated base.  This reaction has been studied



in some detail.    If transamination were to occur, then cross-linking of DNA



through reactions with other biopolymers containing free amine groups (lysyl



groups, for example) is theoretically possible.  Thus far, it has been diffi-



cult to substantiate covalent cross-linking reactions resulting from this



reaction.  Cross-linking of single-stranded MS2/phage has been observed.



Hi stones present in mammalian chromatin are rich in lysine and a DNA-histone



cross-link might occur jj} vivo.  The biological consequences of such a



cross-link are not known at the present time.
                            NH,                       NHR'




                                        RH?         *,^X           12-27
                                                       NHR'
                                    12A-9

-------
     The very addition of sulfite to uracil  and cytosine to form reversible

adducts could disrupt DMA function.   Reaction of these bases with sulfite  is

likely to reduce their hydrogen bonding with other bases, leading to disrup-

tion of the tertiary structure of the gene.   Disruption of messenger RNA

function and translation could occur.   The experiments reported to date are

not wholely convincing, but have been reviewed in detail by Shapiro.

5.0  FREE RADICAL REACTIONS WITH DMA

     Sulfite catalyzed oxidation reactions are likely candidates as mechanisms

for sulfite/SO? damage to DMA at low concentrations of DMA.  As discussed

above,  the oxidation of sulfite produces a number of complex free radicals and

multistep chain reactions involving reactive oxygen and sulfur species such as

•SO,",  -OH,  -OOH, and  -Q^.  The effect of bisulfite-initiated free radical
                                                            CO
reactions on mutational events has been reviewed by Hayatsu.    Sulfite also

initiates the free radical catalyzed autoxidation of unsaturated fatty acids.

It  is  possible that the combination of the oxygen and sulfur species generated

by  bisulfite autoxidation or those generated by lipid peroxidation reactions

could  damage DNA or RNA.  While the deamination and transamination reactions

require considerable concentrations of bisulfite to achieve appreciable rates,

the free radical pathway need not consume or require large quantities of

bisulfite.   Thus, free radical reactions could be carried out at trace concen-

trations which could result from environmental exposure to S0? or bisulfite.

If so, the free radical reaction initiated by bisulfite assumes greater theo-

retical interest, although direct evidence for this reaction j_n vivo is still

lacking.


6.0  EVIDENCE FOR SULFITE/S02 MUTAGENESIS


     Studies  on the  genetic effects of bisulfite/S02 have taken two forms:

exposures at  acidic  pH and high bisulfite concentrations designed to
                                   12A-10

-------
initiate cytosine deamination; and studies carried out at low bisulfite con-



centrations and/or neutral pH designed to investigate free radical  or more



obscure reaction mechanisms.



     In viruses, phage, bacteria, and yeasts, experiments carried out with



high concentrations of bisulfite support the conversion of GC to AT with



intact DNA and, therefore, cytosine deamination reactions.         However,  these



studies have not determined whether the cytosine deamination reaction



catalyzed by bisulfite can be carried out with double-stranded DNA in chroma-


                                                          _2      -3
tin.  Studies with microorganisms are complicated since 10   to 10  M bisulfite



is a growth inhibitor.  The inhibition of microbial growth is the principal



reason for the use of bisulfite in foodstuffs and particularly in oenology



Reactions with RNA and inhibition of protein synthesis by other means might



likewise occur.



     The effects of SCL/bisulfite on plants have been well documented, but it



is not well established whether these toxic effects are due to inhibition of



photosynthesis or to mutations.



     The picture of genetic effects of SOp/bisulfite becomes clouded when



considering the experiments on multicellular organisms or cultured mammalian



cells.  In Drosophila (fruit flies), clear-cut mutagenesis has not been observed



in all studies.  The results have been muddled by experimental design defects



such as the choice of the medium in which the bisulfite was presented to the


            205
fruit flies.     Reducing sugars in the growth medium could have decreased the



bioavailable bisulfite.  No definite conclusion can be drawn at the present



time.


                                                                         207-212
     Experiments with cultured human and animal cells have been reported.



Cytotoxicity, but not clear-cut mutagenesis. was observed in most of these
                                   12A-11

-------
studies.   For example, human HeLa cells in culture showed decreased growth



when exposed to SO-,207 and mouse fibroblasts and peritoneal macrophages


                                ?0ft
showed decreased cell viability.      Human lymphocytes in culture showed



decreased growth, DNA synthesis,  and mitotic index when exposed to either S02



or bisulfite solutions.210'211  No mutations or chromosomal breaks were



detected in these studies.     Inhibition of meiosis has also been reported



with mouse, ewe, and cow oocytes  exposed to low concentrations of



bisulfite.212  Some of the observed effects may be directly due to the



toxicity of S0?/bisulfite.   For example, fuzziness and clumping of chromosomes



may represent stages of degeneration of dead cells.



     In experiments to detect mutations directly, mice were either injected


                                                             213
with bisulfite or fed 1 percent sodium bisulfite in the diet.      No effects



were found on the oocytes, and a  reduced number of chromosomal abnormalities


                                           212
was found in the livers of treated animals.     In these experiments, only a



small number of animals were exposed to a single dose.  The survey for



chromosomal abnormalities inappropriately used a model based upon regeneration


                                                                 ?1 ^
of liver cells following acute carbon tetrachloride intoxication.     In the



host-mediated assay using rats and Saccharomyces cerevisiae, no effects were



observed.43'232



     At the present time, the equivocal results of these assays leave open the



question of SCL-induced mutations in higher organisms.



7.0  TECHNICAL NOTES ON THE MEASUREMENT OF AIRWAY RESISTANCE AND LUNG- COMPLIANCE

     IN EXPERIMENTAL ANIMALS



7.1  RESISTANCE AND COMPLIANCE



     Sulfur dioxide inhalation initiates contraction of bronchoconstrictor



muscles in  humans  >233 and in a  number of animal species.98'99'234'235  This
                                   12A-12

-------
tubular narrowing will in turn inhibit air flow in and out of the lungs.   The



measured degree of inhibition is called airway resistance.  The reciprocal of



airway resistance is airway conductance.   The actual resistance to air flow in



the lungs is due to friction between gas molecules in the gas stream and gas

                                poc

molecules along bronchial walls.     Alterations in the cross-sectional area



of the trachea and larger bronchi account for major changes in resistance;



thus, resistance is a measurement that represents the central airways and is


                                                237
not sensitive to peripheral changes in the lung.     Other mechanical factors,



such as flow direction, volume history, lung tissue resistance, gas viscosity,



and lung volume, contribute directly or indirectly to the measurement of


           236~238                                   239 24-f)
resistance.         Humoral or pharmaceutical agents,   '    mechanical


        241                           242                   238 243
stimuli,    respiratory heat exchange,    and disease states   '     also



influence resistance.



     Compliance is a ratio of volume change in the lung and the pressure



required to overcome elastic resistance of the lung in order to attain the new



volume.  (Compliance = volume change/pressure change.)  This measurement



indicates the state or a change in the state of the parenchyma of the lung.



Lungs that are stiff (high elasticity) have a low compliance.  Compliance is



decreased by constriction of alveolar duct smooth muscle, alveolar cellular



infiltration, edema, airway closure, pulmonary vascular congestion, fibrosis


                                                                  236 237
of the lung, pneumonia and pulmonary distress syndrome in infants.   '



     Compliance is determined at periods of no air flow so that the value is



not influenced by frictional resistance.   It can be measured in two ways.



Static compliance is computed by allowing the lung and thorax to  inflate (or



deflate) to measured volumes in a stepwise fashion; the changes in volumes are



then related to the changes in pressures.  Dynamic compliance is  measured



during spontaneous breathing and is calculated at points when air is not
                                   12A-13

-------
flowing, i.e., during pauses after inflation and deflation.  Static  compliance
equals dynamic compliance at normal tidal volumes (the volume of  air moved
during normal breathing); however, physiological factors not necessarily
related to disease (such as lung volume and lung volume history)  can alter  the
compliance measurement.  Dynamic compliance will also decrease with  increased
breathing frequency or be frequency dependent if there is a non-uniform
                                         236-238
distribution of ventilation in the lungs.         It is probable  that broncho-
constriction following the inhalation of irritants results in non-uniform
distribution of ventilation.
     Computation of airway resistance and dynamic compliance requires
simultaneous measurement of intrapleural pressure (P_/i) and tidal volume (VT)
or  flow (V).  Assuming that inertial losses are small, the following relation-
ship occurs during normal breathing.  Transpulmonary pressure (P-™)  or the
pressure difference between the mouth and the intrapleural space  at  any given
time is:

               PTP = v/R + -c7\T                                     ">
where R is airway resistance and C is the compliance of the lung.  Dynamic
compliance (Cdyr|) is determined during tidal breathing at points  in  time when
the flow is zero.


               Cdyn = SPT; (Vins ' Vexp>/           <">
To compute resistance, P and V  are measured during inspiration and during
expiration at points  of equal  lung volume on the assumption that  at  that time
                                   12A-14

-------
inspiratory and expiratory compliance are equal.   Equation I can then be



solved for total airway resistance (R).
                      P    = V    + V    R                          (IV)
                       exp    exp    exp                            u '

                               C
      assume          V.   = V
                       ins    exp

                        C      C
then
                      R = Ap = (P.   - P   )                        (V)
                          -^   v ins    expy                        v '
                          AV   (V.   - V   )
                               v ins    exp'
                                                                ?37
     Electrical subtraction is another method for calculating R.      Signals



representing P-™ and V are displayed on the X and Y axis of an oscilloscope



and a signal proportional to the volume change is subtracted from the total



pressure signal.  This is equivalent to subtracting the elastic component of



Pyp leaving only the resistive component.   The electrical subtraction technique



allows separation of inspiratory and expiratory resistance and determination



of resistance at a specific flow rate as well as at any specified lung volume



over a small tidal range.  Electrical subtraction has been programmed for


                                                                    244
rapid computer analysis of airway resistance and dynamic compliance,    greatly



enhancing accurate and uniform data collection.



     These basic mechanical lung function tests, if correctly carried out, can



determine whether a response to a pollutant is located in the small airways



and parenchyma or in the central upper airways.  However, when both resistance



and compliance change, it is more difficult to define the site of pulmonary



action.236'237



     Methods used for obtaining intrapleural pressure and tidal volume or flow



from experimental animals are technically difficult and can impose various
                                   12A-15

-------
artifacts on the final  results.   Measurement of VT or V requires the use of
either a whole body plethysmograph or a pneumotachograph flow meter.  Intra-
pleural pressure is obtained by a fluid-filled catheter placed directly in the
intrapleural space or in the lower one-third of the thoracic esophagus.  The
plethysmograph or pneumotachograph and the catheter are each connected to
calibrated pressure transducers that relay the signals to the recording equip-
ment.  To ensure accuracy of resistance and compliance measurements, the
equipment should be tested over a range of frequencies to confirm compati-
bility with the animal  signals and to rule out phase angle shifts in the
signal.  For example, if the frequency response of the equipment is
inadequate, identical pressure signals would be artificially decreased or
increased at various breathing rates.  Also, the P.  signal from a small animal
breathing rapidly may be impeded as it travels through the long narrow
fluid-filled catheter,  and the pulse would not match with the signal in the
plethysmograph.  Thus,  calculation of R and C ,   would yield erroneous or
misleading results.
7.2.  ANIMAL PREPARATION FOR MEASUREMENT OF PULMONARY FUNCTION
7.2.1  Unanesthetized Guinea Pig
     The following procedure was used to measure pulmonary function in guinea
pigs for all of the studies93"97'253 cited in Chapter 12.  Guinea pigs were
lightly anesthetized with ether and a length of 0.03 I.D. polyethylene tubing
containing a wire stylet was pushed through the skin on the back into and out
of the chest cavity.  The stylet was then removed and the catheter was filled
with heparinized saline.   This intrapleural catheter was positioned so three
small holes  were located inside the pleural cavity.   The catheter was
connected to three-way  stopcocks and regularly flushed with saline solution.
For the measurement of  tidal  volume, the guinea pig was placed in a body
                                   12A-16

-------
plethysmograph with an airtight seal at the neck.  (This method was originally


                            189
described by Amdur and Mead.   )  In this procedure, the following factors may



influence the response of the animal to the pollutant and confound the



results:  strain of guinea pig, age, existing disease, effects of residual



ether anaesthesia, extent of surgical trauma (catheter ± tracheostomy),



pneumothorax, volume of saline and heparin used to flush the catheter, and



irritability of the animal due to pain, confinement, fit of the neck seal or



noise in the room.  In addition, the uniformity of conditions within the



exposure chamber, principally the temperature, humidity, and rate of flow, can



contribute to the degree of animal response.



7.2.2  Unanesthetized Monkey



     Studies of pulmonary function in the monkey    discussed in Chapter 12



were similar to those for guinea pigs.  Disease-free animals were acclimated



to the procedure.  Pulmonary function tests were conducted while the animal



was seated in a restraining chair wearing a face mask.  A polyethylene



intrapleural catheter was inserted into the chest after subcutaneous



administration of 1 percent procaine hydrochloride.  Transpulmonary pressure



was monitored between the intrapleural space and the face mask and airflow was



measured with a pneumotachograph in the face mask.  All signals from the



animal were analyzed by a computer.



7.2.3  Anesthetized Dog and Anesthetized Cat


             99
     The dogs   were anesthetized with sodium thiopental, and measurements



were taken while the animals were lying on their backs in a plethysmograph.



Tracheal and intrapleural catheters were inserted on the day of the

                     GO

experiment.   The cats   were anesthetized with I.P. pentobarbital sodium,



given I.V.  gallamine triethiodide (a muscle relaxant), and placed on a
                                   12A-17

-------
respirator.   A tracheostomy and the insertion of an  intrapleural  catheter were
done on the day of the experiment.
     Because of the extreme deviation from a normal  physiological  state,  these
experiments might better be used to shed light on the mechanisms  of S02  action
on the respiratory system rather than to assess the  minimal  effective concen-
tration.
7.3  GENERAL COMMENTS ON EXPERIMENTAL TECHNIQUES
     Bronchoconstriction is dependent upon intact motor parasympathetic  path-
ways in the human,87'246"248 cat87'126 and dog.249   Although bronchocon-
striction  is under the control of the same neurological pathways  in guinea
     230 971
pigs,    '    mucous secretory activity is more pronounced  in the  guinea  pig
               GO
than in the cat   and may contribute to the sizeable difference  seen in  the
response to a  given level of pollutant.  There is wide variability in airway
response to SO-  in the measurement of R and C .   between different
               Z                              dyn
        45 98  99 234
species.   '   '   '     Differences have been noted in airway  responsiveness in
                           272
members of the same species    tested on different days as well  as between
                  239
individual animals    tested on the same day.  In order to normalize these
differences, it has become the practice to discuss response  in terms of
percent change from control period values.  Adequate numbers of  animals  in
each group and careful statistical  analysis are required for understanding the
                      93 233
response of "reactors"  '    in studies with such a  high degree  of variability
with so many confounding factors.
                                   12A-18

-------
                         13.   CONTROLLED HUMAN STUDIES








13.1  INTRODUCTION



     Precise evaluation of health effects induced by exposure to air pollutants



requires that studies be conducted under rigorously controlled conditions.



Controlled studies provide a necessary bridge between epidemiology and animal



toxicology data.   In general, such studies should provide situations which



realistically simulate the exposures experienced by man in his normal  environ-



ment.  However, the complexity and variability of the ambient environment is



such that most controlled studies initially have been designed to evaluate  the



effects of exposure to single pollutants, and then later have been extended to



the more complex mixtures of pollutants actually present in the environment.



     The high cost and minimal number of subjects who can be studied under



controlled conditions make it imperative that studies be conducted under



stringent conditions in order to generalize to the entire population.   Ideally



the design of such controlled trials should include normal individuals of both



sexes and all age groups, subjects especially sensitive to some particular



pollutant, and individuals from populations suspected to be at special rrsk.



Consideration must also be given to the activity levels of the subjects,



ambient environmental conditions prevailing prior to the subjects' testing,



and exposure variables that realistically simulate ambient conditions,



including such factors as temperature, humidity, duration of exposure,



and mode of exposure.  Controlled studies also require proper experimental



design (including purified air conditions) as well as comprehensive



statistical treatment of the data obtained.   In addition, adequate



(even duplicate) pollutant monitoring equipment with documentation
                                   13-1

-------
of quality control  are needed.   Proper attention must also be given to the



presence of potentially interfering pollutants inadvertently present or develop-



ing under certain conditions.   Ideally not only should physiological and



biochemical evidence be obtained,  but subjective symptoms and/or changes in



performance capability should also be assessed.   Since the respiratory tract



is the initial target of many air  pollutants,  proper and sensitive respiratory



function measurements are a primary requirement.   However, various biochemical



systems may be secondarily affected if pollutants (or their reaction products



or substances absorbed on particulates) pass into the circulatory and other,



systems from the cellular level.



     The above criteria need to be applied to  any evaluation of clinically



controlled studies.  However, due  to particular restraints placed on



investigators, no studies meet all of these ideal requirements.  Nonetheless,



certain basic information may be derived from  a number of studies.  This



chapter provides an overview of controlled air pollutant exposure studies of



certain human health effects of sulfur compounds.  It should be noted that



laboratory studies utilizing man have been limited to the evaluation of acute



effects; thus the potential for subsequent health effects cannot be predicted



from such exposures.



13.2  SULFUR DIOXIDE



     Exposure of man to sulfur dioxide has been shown to induce a number of



physiological responses.   Alterations in sensory system responses such as



irritation of eyes and nose, changes in odor perception, and dark adaptation



have been reported.   Various changes in the respiratory system have also been



reported varying from cough to altered mucociliary clearance.  The  following



sections address these various functional  changes in greater detail.  (See



Chapter 11 for more detailed discussion of S0? deposition).
                                   13-2

-------
13.2.1  Subjective Reports



     The perception of odor and the sensation of irritation in the eyes,  nose,



throat, or other parts of the body are difficult to measure precisely.   Thus



subjects may be observed for qualitative changes (coughing, rhinorrhea,



lacrimation) or asked to report whether they detect something in the air they



are breathing.   Several studies have used such subjective reports as an  indica-



tion of the effects of SO- on human subjects.



     A number of early investigators exposed themselves to high concentrations



of SO- (>500 ppm) and experienced coughing, irritation of the eyes and nose,



and difficulty in breathing (e.g., Ogata, 1884; Yamada, 1905; Kisskalt,  1904).



In the course of investigating the effects of SO- on industrial workers,



Lehman (1893) and his associates experienced nasal irritation during exposures



of 10 to 15 minutes to 6.5 ppm SO-.  Holmes et al. (1915 -- cited by Greenwald,



1954) carried out an extensive study of 60 subjects, 28 of whom were unaccustomed



to breathing SO-, and 32 of whom were familiar with it.  All of the subjects



already familiar with the gas seemed to detect it (either as SO- or as "some-



thing foreign") at 3 ppm.  But only 10 of 28 unaccustomed subjects detected



something in the air at 3 ppm SO-.  Few subjects found momentary whiffs of 5



ppm disagreeable, although "Long-continued breathing of air containing slightly



more than 5 parts per million would probably cause discomfort to most people..."



(Holmes et al., 1915).  Amdur et al. (1953) noted that during exposure to 1 to



2 ppm their subjects could not usually detect the odor of SO,,; even at 5 ppm



most subjects could not smell the gas, although they did complain of dryness



in the throat.   One subject, however, objected so strongly to 5 ppm S02 odor



that exposure was terminated.  Above 5 ppm the odor was definitely detected by



all subjects.
                                   13-3

-------
     A number of more recent studies  have asked subjects to report their
subjective experiences (e.g.,  Greenwald,  1954;  Tomono,  1961;  Frank et al.,
1962; Toyama and Nakamura,  1964;  Nadel  et al.,  1965;  Speizer  and Frank, 1966a,b;
Melville, 1970;  Weir and Bromberg,  1972,  1973;  Lawther  et al., 1975; Horvath
and Folinsbee, 1977), but the  results seem to be quite  variable at exposures
less than 5 to 10 ppm SOp.   Also, Frank et al.  (1962) have shown that subjective
reports are in some situations an unreliable indicator  of physiological responses,
since coughing and a sense of  throat  irritation tended  to subside in their
subjects after a few minutes while  other changes in respiratory effects were
still maximal.
13.2.2  Sensory Effects
     Among the physiological functions  that may reflect the effects of exposure
to S0? are certain sensory processes.   These studies  have investigated not
only odor threshold but also sensitivity of the dark-adapted  eye to light and
interruption of the alpha (a)  rhythm  in electroencephalograms (see Table
13-1).  Most of these investigations  have been summarized by  Ryazanov (1962).
13.2.2.1  Odor Perception Threshold—In the Russian studies odor threshold is
typically determined in a. well-ventilated chamber containing  2 orifices from
which emerge 2 small streams of gas,  one being very pure air  and the other
other being a stream of the test gas.   The subject sits in front of the apparatus,
sniffs both orifices, and points out  the odorous one.  This experiment is
repeated with the same concentration  of test gas over a period of several
days.  The experiment is performed  with increasingly reduced concentrations
until the subject,  in the majority  of instances, denies the presence of an
odor or gives erroneous answers.    The  threshold concentration for  the most
sensitive subject in a group of volunteers is defined as the threshold for
odor perception.
                                   13-4

-------
                                              TABLE  13-1.   SENSORY  EFFECTS  OF  SO,
  Concentration
    S0  (ppm)
Exposure
 mins.
Effects
    Reference
       400

       6.5

   140, 210, 240

      210, 240

      1,  2,  5

     3, 5, plus


V*  0.17  - 4.6
en
   0.34  -  6.9


       0.23


   0.2 - 1.7

    1 -  10
  120

10 - 15

   30

   30
   15
 0.33
Dyspnea

Nasal irritation

Marked nasal irritation, sneezing

Eye irritation, lacrimation

All subjects detect odor above 5 ppm

Discomfort to all subjects exposed to 5 plus.
  Some noted disagreeable odor at 5 ppm.

Average SO,, odor threshold was 0.8 - 1.0 ppm

Positive recognition of SO,, was 0.47 ppm

Light sensitivity increased at 0.34 - 0.63 ppm
  and above.

Ocular sensitivity to light increased at SO,,
  levels of 0.23 ppm and above

Attenuation of cr-waves at levels above 0.2 ppm

Organoleptic effects at levels 2 ppm and above
Ogata,  1884

Lehman,  1893

Yamada,  1908

Yamada,  1908

Amdur et al. , 1953
Holmes,-19546^

Dubrovskaya, 1957

£dor Threshold^  1968


Dubrovskaya, 1957


Shalamberidze, 1967

Bushtueva ot al., 13611

Greenwald, 1954

-------
     Using the 2-orifice apparatus  described above,  Dubrovskaya (1957) conducted



sulfur dioxide odor perception threshold tests  on 12 subjects.   Sulfur dioxide



concentrations of 0.5 mg/m3 to 13 mg/m3 (0.17 ppm to 4.6 ppm) were used in 530



threshold determinations.   Six test subjects sensed  the odor of sulfur dioxide



in the range 2.6 mg/m3 to 3.0 mg/m3;  four subjects sensed the odor in the



range 1.6 mg/m  to 2.0 mg/m ; one sensed the odor in the range 2.1 mg/m  to



2.5 mg/m3; and one sensed the odor  in the range 3.1  mg/m  to 3.6 mg/m .   Thus,



the average sulfur dioxide odor threshold concentration was 0.8 ppm to 1 ppm



(~2.3 mg/m3 to -2.9 mg/m ), and for the more sensitive of these persons it was


                             3             3
0.5 ppm to 0.7 ppm (-1.5 mg/m  to -2.0 mg/m ).   It should be noted, however,



that most of the subjects were of an age at which odor perception was presumed



to be most sensitive.



     Determination of sulfur dioxide odor thresholds (1968) conducted for the



Manufacturing Chemists'  Association in the United States gave somewhat lower



values than those cited above (Arthur D.  Little,  Inc., 1968).  The concen-



trations at which first one-half and then all of the panel members could



positively recognize the odor were  reported to  both  be 0.47 ppm (1.3 mg/m ).



The details of the test procedure are thoroughly discussed in the report, but



one important aspect is reiterated  as a reminder that odor thresholds usually



represent values derived under ideally suited conditions and with trained



individuals.   The investigators, who were highly qualified to judge on the



basis of substantial  experience with consumer evaluation of known flavor and



odor situations, derived threshold  values under ideal conditions lower than



those which would be recognized by  the majority of a population under ordinary



atmospheric conditions.   This does  not mean that normal individuals exposed to



sulfur dioxide under ideal  test conditions could not perceive the 0.47 ppm
                                   13-6

-------
level  indicated.   However, because of background odor and lack of awareness  or



concern with ambient odor conditions, such individuals in an everyday situation



would probably be less responsive to this low concentration.



13.2.2.2  Sensitivity of the Dark-Adapted Eye--The sensitivity of the eye to



light while a subject is in darkness increases with time.  Several  investigations



have been made of the effects of inhalation of sulfur oxides on this  sensitivity.



Typically, measurements of a subject's normal sensitivity are taken in a dark,



well-ventilated chamber in complete silence (sudden stimuli, including noise,



may affect the subject's response).  Each subject is tested once daily following



preliminary stimulation at a high light level.  Light sensitivity is  measured



at 5-minute or 10-minute intervals, and a curve of increasing sensitivity to



light is established from measurements taken over a period of 7 to 10 days.



     Dubrovskaya (1957) studied the effect of inhaling sulfur dioxide in



concentrations from 0.96 mg/m  to 19.2 mg/m  for 15 minutes before measuring



light sensitivity during dark adaptation.  She reported that light sensitivity



was increased by sulfur dioxide concentrations of 0.96 mg/m  to 1.8 mg/m



(0.34 ppm to 0.63 ppm), that the increase in sensitivity reached a maximum at



concentrations of 3.6 mg/m  to 4.8 mg/m  (1.3 ppm to 1.7 ppm). and that further



increases in the sulfur dioxide concentration resulted in progressive lowering



of eye sensitivity to light until at 19.2 mg/m  the sensitivity was identical



with that of the unexposed subject.



     In exposures during light adaptation, sulfur dioxide concentrations of



0.6 mg/m3 to 7.2 mg/m  (0.21 ppm to 2.5 ppm) caused slight increases  in eye



sensitivity.  Maximum sensitivity was attained at 1.5 mg/m  (0.52 ppm); at



higher concentrations the increased sensitivity began to abate.  Two  human



subjects were used in these experiments.  The odor threshold was between
                                   13-7

-------
2.5 mg/m3 and 3.0 mg/m3 for one subject and between 3.0 mg/m  and 3.6 mg/m
for the other, so that changes in sensitivity to light during dark adaptations
were caused by sulfur dioxide concentrations below the odor threshold.
     Shalamberidze (1967) investigated the effects of S02 and NC^, singly and
in combination, on visual light sensitivity as determined by measures of dark
adaptation.  According to this report, S02 concentrations of 0.6 mg/m  (0.23
ppm) and higher caused "a considerable increase in the ocular sensitivity to
light" (Shalamberidze, 1967, p. 11).   So few details on methods or results
were presented, however, that this report cannot be accepted without reserva-
tions.
13.2.2.3  Interruption of Alpha Rhythm--The electroencephalogram is a composite
record of the electrical activity of the brain recorded as the difference in
electrical potential between two points on the head.  In the adult, the electro-
encephalogram characteristically shows a fairly uniform frequency from 8
cycles to 12 cycles per second in the posterior head regions (alpha).  Variations
occur with age, the state of wakefulness and attentiveness, or as a result
of incoming sensory stimuli from exteroceptive or interoceptive receptors.
The dominant frequency (a) is inhibited or attenuated by eye opening and by
mental activity.
     Subjects with well defined o-rhythms studied in a silent and electrically
shielded chamber show a temporary attenuation of the o-rhythm each time they
are given a light signal.  When the light is excluded, the a-rhythm returns to
normal.   A concentration of test gas is determined which is so low that by
itself it does not cause attenuation of the a-rhythm.  A subject breathes the
gas at this concentration, and then he receives the light signal.  After
exposure to this  sequence (gas then light) several times (5 to 30 times in
                                   13-8

-------
1 day), a subject will show attenuation before he receives the light signal;

that is, he responds to the unperceived odor.  The unperceived odor thus

becomes the conditioning stimulus and brings about the so-called conditioned

electrocortical reflex.
                       I1G>*>
     Bushtueva e^t-ai. (19£&i) reported that 20-second exposures of six human
subjects to sulfur dioxide concentrations from 0.9 mg/m  to 3 mg/m  (-0.3 ppm

to -1.0 ppm) produced attenuation of the cr-wave lasting 2 to 6 seconds; at

concentrations of 3.0 mg/m  to 5.0 mg/m  (-1.0 ppm to 1.7 ppm) attenuation

lasted throughout the 20-second exposure.  Exposures to 0.6 mg/m  (-0.2 ppm)

did not cause attenuation of the cr-wave.  The threshold for attenuation of the

crwave was the same as the odor theshold or the threshold of irritation of the

respiratory tract.  In other experiments, Bushtueva demonstrated that electro-

cortical conditioned reflexes could be developed with sulfur dioxide at 0.6

mg/m  (-0.2 ppm) but not with lesser concentrations of the mixture.

13.2.3  Respiratory and Related Effects

     A number of studies have documented the various respiratory and cardio-

vascular effects deriving from exposure to SO- (see Table 13-2).  (See Chapters

11 and 12 for further discussion of respiratory effects of SO-.)  One of the

first clinical studies of the effects of inhaling SO- was reported by Amdur et

al. (1953).  They had 14 resting subjects breathing SO- for 10 minutes through

a face mask in concentrations ranging from 1 to 8 ppm.  Pulse rate and respiration

rate increased and tidal volume decreased during exposure to as little as  1

ppm SO-.  Several investigators attempted to replicate Amdur et al.'s  (1953)

findings, including Mcllroy et al. (1954), Lawther  (1955), and  Frank et  al.

(1962).  None was able to find consistent respiratory or cardiovascular  effects

of SO, below 5 ppm.  Nevertheless, these and other  studies have documented a

variety of subjective and physiological effects under various conditions of
                                   13-9

-------
13-2.   IMHMONARY [FFFCTS OF SO-

Concentration
50^ (pp*)
1.0
3.0
5.0
9 - 60
1 - 8


--

.- 5. 10
V 20
o

1, 5. 13



1.3 - 00

1 - 45


2.'j, 5 0. 10.0

4 - 6

*lnlcr mi tlcul
Oral or
Duration of Nu**er of nasal Rest (R) or
exposure («ins) sulijccls exposure exercise (£)*
3 8-10 0 R * F
3 8-9 0 H • I
3 10 0 N
5 25 N - 0 R
10 14 Face mask R


10 -- N R

10 IB 0 - N R
10 6 0 K


10 12 0 N



10 8 - 1? Face Mask R
«
10 46 Face Mask R


10 15 0. N R

10 /OR

Exercise


Effects
Light exercise potentiates
effect of SO. MtF tnt
. . c su*
decreased
Airway resistance increased
Pulse rate, respiratory
increased; tidal volume
decreased
Could not duplicate Amdur's
results
No changes in pulse rate,
respiratory rate or tidal
vohme (5. 10 ppn) 2 sub-
jects had bronLhospasn
No changes in pulse rate,
respiratory rate. I'ulaonary
flow resistance increased at
5 and 13 p|>n
Bronchocunslric t ion

Decreased peak flow, decreased
expiratory c.i|i, icily above
1 . 6 ppn
SC decreased less with nasal
HPr.i Hi iny
Airway conductance decreased
rel lex vl lecl



Reference
Kreisnan et al .
1976

Nakanura, 1964
Awlur et al. ,
rale 1953

Hcllroy et al. ,
1954
I awl her. 1955



Frank et al. ,
1962


Sia and Pallle.
1957
TmM>no, 1961


Helvillo, 1970

Nadel, 1965



-------
13-2.   (continued)

Concentration Duration of
SO. (ppm) exposure (mins)
15, 28 10
5 10
2.5 - 50 10
6.6 - 7.3 10
1.3-80 10
0.5. 1.0. 5.0 15
1. 5. 13 10 - 30
16.1 25
1.5, 15 30
1.1 - 3.6 30
•j 30
1 - 2~\ 60
1 60
Number of
subjects
8
5
5
variable
8 - 12
9
11
7
12
10
10
8 - 1?
-
Oral or
nasal
exposure
0
N
0
M
0
ON
Face mask

0
N
Face mask
0 - N
0
0
0
Mask, chamber
N
N
Rest (R) or
exercise (E)
R
R
R
R
R
R
R
R
R
R
I
R
R
Effects
Pulmonary flow resistance
increased less with nasal
breathing
MEF,-,. decreased less with
nasll inhalation
Increased respiratory and
inspiratory resistance
No changes in airway
resistance
Bronchoconslriction
MEFr-w. decreased at
Pulmonary flow resistance
increased at 5 and 13 ppm
but less during nasal
breathing '^r/^a^r"/ ^ "^^
,", // J /,j ^,~/^r st^Z
'&'*• jf&-Uf^Si&^3£&f,!&y£-
-------
13-2.   (continued)
Concentration Duration of Number of
S0_ (ppm) exposure (mins) subjects
5 60

5-30 10
1 50
3
10, 15, 25, 50 60
•Intermittent

0.37 120

0.37 120
0.40 120

0.75 120

1.0, 5.0 120


5.0 120


5.0 120

25.0 120
9

10
13
17
Exercise

8

4-12
9

4 - 8

15


11


10

15
Oral or
nasal Rest (R) or
exposure exercise (E)
0

Co. stimulus
ChSmber (N)
0


Chamber

Chamber
Chamber

Chamber

N


Chamber


Chamber
(l)ldl)
N
R

(0) R
R
R


E

E
E

E

R


E


E

R
Effects
No effect or MUCUS
transport
Deep breathing significantly
increased SRaw
At higher cone, of SO.
mucociliary activity
decreased
No pulmonary effects

No pulmonary effects
No pulmonary effects

Significant decrease in/^/yf }'
•fVC, FEV. ... MMFR, M£FR / '
Increase in nasal air flow
resistance; decrease in
nasal mucus flow
Insignificant changes in
R and P n2
e aO
MMFR decreased 8 5X increased
Iracheobronchial clearance
Increased nasal airfow
Reference
Wolff et al., 1975a

Lawther. 1975

Cralley, 1942

Bates and Hazucha, 1973;
"Hajuchj 3nd fiatet 1975 •
Bell et al. , 1977
Horvath and Follnsbee. 1977
Bedi et al. , 1979
Bates and Hazucha, 1973;
Ha/ucha and Bates, 1975
'—A&**(^*'
Andersen et al. , 1974


von Neiding et al., 1979


Newhouse et al. . 1978

Andersen et al. , 1974
                      resistance;  decreased nasal
                      mucus  (low

-------
13-2.   (continued)

Concentration Duration of Number of
SO- (ppm) exposure (mins) subjects
0.50 180 40 (asthmatics)
5 180+ 10
0.3, 1.0 96 - 120 12 (normal)
and 3.0 Hours 7 (COPO)
.- 1. .0, 5.0 Up to 6 hrs/day 15
£ and 25.0
OJ
5 4.5 hours 32
(16 exposed)
Oral or
nasal
exposure
Oral
0
Chamber
Chamber
(N)
Chamber
Rest (R) or
exercise (E) Effects
R MMFR decreased 2.7% recovery ,
within 30 minutes ^3>^fJ^
-------
exposure to S02-   Sim and Rattle (1957) performed extensive clinical studies
over a 10-month period on an unspecified number of (8 to 12) "healthy males
aged 18 to 45."  SCL was administered either by face mask at concentrations
ranging from 1.34 to 80 ppm for 10 minutes or in an inhalation chamber at
concentrations of 1.0 to 23.1 ppm for 60 minutes.   Regardless of exposure
route, the only notable effects of S02 were said to be bronchoconstriction
(increased resistance to air flow) and high-pitched chest rales at 49 ppm and
greater concentrations.  They also reported that when ammonia (no value given)
was also present in the chamber (9.9 ppm SOp) the subjective impressions of
bronchoconstriction disappeared.
     Frank et al. (1962) examined the effects of acute (10 to 30 minute)
exposures to SO- via mouth in 11 subjects.  Each subject received approximately
1, 5, and 13 ppm of the gas in separate exposures at least 1 month apart.  The
only significant effects were a 39 percent increase (p <0.01) in pulmonary
flow resistance at 5 ppm and a 72 percent increase (p <0.001) at 13 ppm.  The
recovery of some subjects was complete within a few minutes.  As in Sim and
Rattle's study (1957), other cardiovascular or pulmonary measures did not show
any significant effects.
     Tomono (1961) tested 46 men for the effects of S02 on their pulmonary
physiology.  The subjects inhaled 1 to 45 ppm S02 through a face mask for 10
minutes.  Decreases in expiratory capacity and peak flow rate were proportional
to the concentration of S02-   Such effects were detected at a concentration as
low as 1.6 ppm.  Slight increases in pulse and respiration rates were observed
in about 10 percent of the subjects but were not proportional to S0?  exposures.
Nakamura (1964) exposed 10 subjects each to a different concentration of  S02
(9 to 60 ppm)  for 5 minutes.   Airway resistance increased an average  of  27
percent.  Since each subject was exposed to only one concentration  of S02 and
                                   13-14

-------
there was considerable variability in response to the different concentrations,
the significance of those isolated findings may be questioned.   No significant
correlation between dosage and response was discovered.   For example,  a subject
had a 17 percent increase after exposure to 9 ppm, another 9 percent after
exposure to 16 ppm, another 75 percent after exposure to 4 ppm and another
22 percent after exposure to 57 ppm.
     Snell and Luchsinger (1969) also found significant decreases in pulmonary
function consequent to S02 exposure.   Nine subjects inhaled through a mouth
piece S02 at concentrations of 0.5, 1.0, and 5 ppm for 15 minutes each, with
15-minute control periods interspersed.  Maximum expiratory flow (MEF5Q~ vc)
was significantly lower after exposure to 1 ppm SOp (p <0.02) as well  as 5 ppm
(p <0.01).  Reichell (1972) found no significant changes in airway resistance
in normal subjects and patients with obstructive lung diseases exposed to 6.6
to 7.3 ppm SO--  Jaeger et al. (1979) exposed 40 normal  non-smokers and 40
asthmatics (mild to moderate but with no recent exacerbations) subjects to 3
hours to 0.5 ppm SO-.   Oral inhalation was forced by having the subjects wear
a nose clip.  These resting subjects were also studied during exposure to
ambient air having an average SO- content of 0.005 ppm.   Three pulmonary
function tests (VC, FEV, and MMFR) were performed at intervals during the
exposure and a more intensive series of tests were made prior to and after the
exposure.  The only significant (p <0.04) effect observed was a 2.7 percent
decrease in MMFR in the asthmatic subjects.  This minimal change had little
physiological importance.  One normal and two asthmatic subjects exhibited
adverse reactions—the asthmatics requiring standard asthma medication.  No
changes in pulmonary functions were observed during 60 minutes of  exposure  to
1 ppm S02 (McJilton et al., 1976).
     Nadel et al. (1965) have helped elucidate the mechanism of  bronchoconstric-
tion resulting from S02 exposure.  They exposed  seven subjects to  4 to 6  ppm
                                   13-15

-------
SO- for 10 minutes via mouth in a closed plethysmograph.   The mean decrease in



specific airway conductance was 39 percent (p <0.001).   Injecting the subjects



with 1.2 to 1.8 mg atropine sulfate 20 minutes before S02 inhalation resulted



in only a 3 percent (p >0.20) decrement in specific airway conductance/thoracic



gas volume.  However, atropine did not affect the coughing or sensation of



irritation in the pharynx or substernal area.   From this and other evidence,



Made! et al. concluded that the bronchoconstriction induced by S02 depends on



changes in smooth muscle tone mediated by parasympathetic motor pathways.



Thus, when sensory receptors in the tracheobronchial region are irritated by a



substance such as S0?, a reflexive bronchospasm may be triggered.



     Apart from fairly consistent bronchoconstriction effects, a common element



in these and other reports of the effects of SO- has been the notable variability



among subjects in their responses to such exposures.  In Frank et al,'s



study (1962), for example, 9 of 11 subjects showed no effects at 1 ppm, but 1



subject showed a significant (p <0.01) decrease in pulmonary flow resistance,



whereas the remaining subject showed a significant (p <0.01) increase.  Sim



and Rattle (1957) reported that they themselves appeared to be exceptionally



sensitive to SC^ encountered in the course of their research.  They experienced



persistent and uncomfortable spells of coughing and wheezing upon contact with



the gas.  Other investigators (e.g., Burton et al., 1969; Frank, 1964; Nadel



et al, 1965; Lawther-aftd=Bnnd-, 1955; Lawther et al., 1975; Jaeger et al.,



1979) have reported "hyper-reactors" among their subjects.   Indeed, some



investigators have suggested that about 10 percent of the total population  is



made up of especially sensitive persons (Amdur, 1973, 1974;  Horvath and



Folinsbee, 1977).   However, in at least one instance (Andersen et al., 1974),



a subject's response was exaggerated even under control conditions, which
                                   13-16

-------
raises the possibility of psychological factors contributing to this observed
sensitivity.
13.2.3.1  Water Solubility--Qne of the first points to note is that because of
its high solubility in water, S02 is readily absorbed when it comes in contact
with the moist surfaces of the nose and upper respiratory passages (Frank et
al., 1973).   This has a number of important implications for the analysis of
the effects of S02 on respiratory functions.  These considerations will be
illustrated in the following sections (see Chapter 11).
13.2.3.2  Nasal Versus Oral Exposure—A number of studies have demonstrated
significant response differences between the nose and mouth as routes of
exposure to SO,,.   Speizer and Frank (1966a), for example, compared the effects
of S02 (10-minute exposures at 15 and 28 ppm) in eight subjects breathing the
gas either by nose or by mouth.  The subjects coughed less and reported less
irritation of the throat and chest when breathing through their noses.  Also,
pulmonary flow resistance increased less during nasal exposure than during
oral exposure.
     A second study by the same investigators (Speizer and Frank, 1966b)
refined their analysis of these effects, using seven subjects and a specially
designed face mask.  Air was sampled at various points,  including:  (1) within
the face mask before being inspired, (2) within the subject's nose, and (3)
within the subject's oropharynx.  Exposures lasted 25 to 30 minutes.  The
average concentration of S0? within the mask was 16.1 ppm; within the oropharynx
the concentration was too low for the investigators' equipment to measure.   Thus,
essentially all of the S02 (90 to 99 percent) in the inspired air was  removed by
the nose.   Similar results were obtained by Andersen et  al. (1974)  in  a study that
will be described in detail below.
                                   13-17

-------
     Melville (1970) also compared oral  and nasal  routes of administration.



He used 15 subjects and exposed them (for 10 minutes) sequentially to 2.5, 5,



and 10 ppm SO-.   More SO- was cleared per minute with nose breathing than with



mouth breathing.   There was a clear dose-dependent response reflected in



measures of the subjects' specific airway conductance (SGflw):  as the S02



concentration increased, SGau/ decreased  (p <0.05).  This was true regardless
                           oW


of administration route (for 2.5 ppm SOp), but the average decrease under oral



administration was greater (in 80 percent of subjects), than the decrease under



nasal administration (p <0.05).  During  exposure to 5 ppm S02 no significant



difference was observed in SG   regardless of whether the 49 subjects breathed
                             aW


through mouth or nose.



     Snell and Luchsinger (1969) also examined the differences between nasal



and oral exposure using SO- at 5 ppm.  Five subjects' average maximum expiratory



flow (MEFr-y .,-) was 10 percent lower following oral exposure than following



nasal exposure.   This difference, however, was not statistically significant.



See Chapter 11 for further discussion of SO- deposition.



13.2.3.3  Subject Activity Leve]--0ne of the practical implications of the



above findings is that vigorous activity, such as heavy exercise or work, may



significantly affect the actual dose received by a person during exposure to



S02.  At some level of ventilation, inhalation of air shifts from nasal  to



mouth breathing.   Studies under way (Horvath, personal communication) suggest



that subjects who are nasal breathers at rest move to mouth breathers when



ventilatory exchange is approximately 30 L/min.  However, it should be



remembered that many individuals are always mouth breathers.  Kreisman et  al.



(1976), for example, reported that exercise may potentiate  the  effect of SO- on



respiratory function.   In their study, subjects inhaled a mixture of S02 in



air for 3 minutes while exercising on a bicycle ergometer at a  pace  sufficient
                                   13-18

-------
to double their resting minute ventilation rate.   Eight subjects recieved 1
ppm S02 and nine subjects received 3 ppm.  Those receiving 3 ppm showed a
significant (p <0.05) decrease in maximal expiratory flow (MEF^ /pj compared
to a control (untreated air) exposure.  However, it is not clear that this
change differed significantly from the change in MEF.   ,p.. occurring in
resting subjects.  Bates and Hazucha (1973) and Hazucha and Bates (1975)
reported significant decreases in FVC (10 percent), FEV1 Q (10%), MMFR (10%),
and MEFR (23%) in 4 subjects (who exercised intermittently during the exposure)
exposed in a chamber containing 0.75 ppm SO^.   At 0.37 ppm SCL, Hazucha and Bates
(1975) observed no pulmonary function changes.  Horvath and Folinsbee (1977)
and Bedi et al. (1979) exposed nine intermittently exercised subjects in
a chamber to 0.4 ppm SCL and found no pulmonary function changes.
     Lawther et al. (1975) have demonstrated that simply instructing 12 subjects
to take 25 deep breaths by mouth resulted in a significant (p <0.001) increase
in specific airway resistance (SR=v) during exposure to S00 at 1 ppm.  While
                                 aw                       t
sitting quietly in an inhalation chamber, the same subjects had previously
shown no such  increase after breathing concentrations of 1 to 3 ppm SO- for an
hour.  As part of a series of experiments in this study, 17 subjects also
received 3 ppm S0~ by a mouthpiece and were instructed to talce 2, 4, 8, 16,
and 32 deep breaths at 5-minute intervals.  Increases in SR   due to SO^
were significantly greater after 16 (p <0.01) or 32 (p <0.001) deep breaths.
     Burton et al. (1969), however, found no consistent effects  in 10 subjects
exposed to S0? at 1.1 to 3.6 ppm for 30 minutes, regardless of whether the
subjects breathed normally or at a forced hyperventilation rate  of up to 2.5
L/sec.  One (other) difference between these two studies was the duration  of
exposure.  Burton et al . (1969) exposed their subjects for 30 minutes, whereas,
Lawther et al. (1975) maintained exposures for an hour.  This raises another
                                   13-19

-------
important consideration in reviewing the effects of SO,, on human subjects.



namely,  temporal  parameters.


13.2.3.4  Temporal  Parameters—Early studies (e.g., Lehman, 1893) suggested



that workers chronically exposed to relatively high concentrations of S02 were



less conscious of its presence in the atmosphere than persons not as familiar


with the gas.   However, Holmes et al.'s data (1915) indicated that subjects



already accustomed to SO- could detect its odor at lower concentrations than


could persons unaccustomed to it.  Nevertheless, it would seem plausible that



"self-selection" would tend to reduce the number of relatively sensitive


persons among the population of workers chronically in contact with supra-



threshold levels of S02-


     As previously noted, a study by Frank et al.  (1962) has indicated that


subjective reports are not a reliable indicator of physiological responses in


any event.  After 5 to 10 minutes of exposure to either 5 or 13 ppm SO- their


subjects' pulmonary resistance measures were just reaching their peaks, while


subjective reports of an odor of SO- had already subsided.



     In a later study by Frank et al. (1964) the increase in pulmonary resistance


induced by S02 peaked at about 10 minutes and then gradually decreased over


the next 15 minutes.   This finding corresponds closely to Sim and Rattle's



(1957) report that, if lung resistance increased at all in individual subjects,


the increase occurred within the first 10 minutes.



     Similar short-term responses (within 5 to 10 minutes after the start of


exposure) have been recorded by other investigators.   Melville (1970) found



that percentage increases in specific airway conductance (SG  ) were greatest
                                                            3W

during the first 5 minutes of up to 60 minutes of exposure to S0? by



mouth/nasal  breathing.   At 5 ppm, for example, he noted that SG   decreased
                                                               9W
                                   13-20

-------
significantly (p <0.05) within 5 minutes of exposure and stabilized slightly



above the values recorded under control conditions of no SO,.



     Similar results were obtained by Lawther et al. (1975), who noted that



SRflw increased most during the first 5 minutes of exposure.   Recovery to



baseline levels generally required about 5 minutes, although 3 "S02 sensitive"



subjects out of a total of 14 took 10 to 65 minutes to recover from higher



exposure levels (up to 30 ppm S02).  In this last regard, similar findings



were reported by Gb'kenmeijer et al. (1973) for bronchitic patients exposed to



10 ppm S02.  Respiratory effects were maximal at the end of a 3-minute



inhalation period, and recovery required 45 to 60 minutes.



     Abe (1967) compared the temporal course of SOp exposures.  His five



mouth-breathing subjects were given 2.5 or 5.0 ppm SO-.  He reported immediate



significant (p <0.05) increases in expiratory resistance (42 percent) and



inspiratory resistance (25 percent).  Effects of repeated exposures are noted



by Frank et al. (1964) and Tomono  (1961).



     Longer term effects (over a period of hours) have been reported by Andersen



et al.  (1974), who investigated nasal mucus flow rates as well as airway



resistance and subjective responses.  Nasal mucociliary flow was measured by



placing a radioactivity labeled resin particle on the superior surface of the



inferior turbinate and tracking its position with a si it-collimator detector.



A total of 15 subjects were exposed via an inhalation chamber to increasing



concentrations (1, 5, and 25 ppm)  of S02 for approximately  6  hours per day



over 3 consecutive days.  Baseline measurements were made under conditions



of filtered air on a day prior to  experimental exposures.   This study found  a



number of effects reaching their maximum after 1 to 6 hours of exposure.



Nasal cross-sectional airway area  generally decreased throughout the  6-hour
                                   13-21

-------
daily trials,  but the decreases were only significant (p <0.05) at 1 ppm and 5
ppm, since there was an overall drop in this measure (approaching a "floor
level") by the time 25 ppm was administered on the third day of the study.
Significant (p <0.05 or less) decreases in forced expiratory flow (FEF25-75%^
and forced expiratory volume (FEV, Q) also occurred both within daily exposures
and across days (i.e., increasing concentrations), although the within-day
decrease in FEV, n was only significant on day 3 (at 25 ppm) (see Andersen et al.,
1974, Figure 7).
13.2.3.5  Mucociliary Transport—Grail ey (1942) investigated mucociliary clearance
when sophisticated radioactive measurement techniques were not available.  A
drop of red dye was placed in the active ciliary region of the inferior meatus
of  a volunteer subject.  The rate of mucus clearance was reflected in the time
between the dye's introduction and its appearance in the expelled mucus.
Exposure to SOp at 10 to 15 ppm for 60 minutes produced only a small decrease
in  the rate of mucus removal.  A 30- to 60-minute exposure to 25 ppm S0?
resulted in a 50 percent reduction in mucociliary transport and a 65 to 70
percent reduction at 50 to 55 ppm.  Mucostatis in the anterior region of the
nose was observed in 14 of 15 subjects after 4 to 5 hours of exposure to 25
ppm S02 (Andersen et al., 1974).   In addition, the mucus flow rate in the
anterior nose was reduced by 50 percent after 1 to 3 hours exposure to  as
little as 1 ppm S02-  At this concentration some subjects also had sporadic
mucostasis, although there were pronounced individual differences  in these
measures even at baseline.
                                                    (177
     Wolff and his co-workers (Wolff et al., 1975a, t^5b; Newhouse et  al.,
1978) have also measured the rate of mucociliary transport.   In Wolff  et  al.'s
(1975a) first study, nine subjects were exposed to 5 ppm  SO-  for  1 hour
while sitting quietly in an inhalation chamber and breathing  through their
                                   13-22

-------
mouths.  Mucociliary clearance was assessed by having the subjects first


inhale a radioactively tagged aerosol and then monitoring its subsequent


tracheobronchial deposition and retention during S02 exposure.   No significant


effects were found in mucociliary clearance, except for a small transient


change (p <0.05) after 1 hour of exposure.

                                           /???
     In their second study, Wolff et al. (1075b) used similar methods to


compare subjects while resting or exercising.  Exercise was performed on a


bicycle ergometer for 0.5 hour at a pace to yield heart rates 70 to 75 percent


of estimated maximum values.  Exposure  in this study lasted for 2.5 to 3


hours.  The combination of exercise and exposure (via mouth) to 5 ppm S0?


resulted in a significantly (p <0.05) greater rate of tracheobronchial muco-


ciliary clearance.  This result contrasts with Andersen et al.'s findings (1974)


that nasal clearance rates were reduced by exposure to 5 ppm S0?.  Of course,


the two studies focused on different regions of the respiratory tract


(tracheobronchial versus nasal), but this in itself provides no cogent account


for these contrasting effects.  Both of these investigators replicated their


findings in later studies [Andersen et  al., (1977) and Newhouse et al.,  (1978)].


Extension of these studies was made by  Newhouse et al. (1978) whose 10 subjects


breathed either SO- (5 ppm) or H2S04 mist (1 mg/m ) delivered as an aerosol of


0.58 urn MMAD.  An aerosol containing a  0.025 percent solution of   mTc-albumen


was inhaled prior to pollutant exposure.  The bolus technique (exposure to short-


term peak concentrations) employed achieved deposition of the aerosol, primarily


in the large airways.  One-half hour later the subjects were exposed to the


pollutants.  They immediately exercised for the next 0.5 hour.   A total  of 20


minutes of exercise at approximately 70 to 75 percent of predicted maximum heart


rate was performed, followed by an additional 1.5 hours of rest  exposure.  The
                                   13-23

-------
subjects breathed through the mouth to eliminate nasal ventilation and absorption



of pollutants.   Pulmonary function tests conducted at the end of 2 hours' exposure



to S0? indicated no changes in FVC or FEV,^ Q but maximum mid-expiratory flow rate



(MMFR) decreased 8.5 percent, possibly due to a reflex bronchoconstriction.  No



pulmonary changes were found consequent to the HpSO^ mist exposures.  Tracheo-



bronchial clearance increased in both S02 (6 of 10 subjects) and H2$04 (5 of 10



subjects) exposures.  The investigators did not present their data in a manner



which would provide information as to the relationship between clearance rates



and MMFR.  It should be noted that even replicated data are in contrast to the



replicated observations by Andersen et al. (1977), who showed a slowing of nasal



clearance on exposure to 5 ppm SO,,.



     Mucociliary transport is a significant aspect of the respiratory system's



defense against airborne agents.  A disturbance in this function might have



important implications for a number of health effects, such as susceptibility



to cold-virus infections.  Andersen et al. (1974), for example, noticed that



4 of 17 subjects caught colds within a week of their participation in a



study where mucostasis generally occurred during SOp exposure.  Andersen et al.



(1977) followed up this observation by inoculating volunteers with a



strain of rhinovirus (RV3).  The basic design of the study and reactions of



the subjects are shown in a table (Andersen et al., 1977, p. 121).  Although



there was no difference in the number of colds that developed in the  two



groups of subjects (all nose breathers), cold symptoms were judged  (under  a



double-blind procedure) to be less severe (p <0.05) in the group exposed to



S02.   It was unknown, however, whether this result reflected a direct effect



of S02 on the host, the rhinovirus, or both.  In addition, the average  incuba-



tion period was  somewhat shorter for the group exposed to SO- (p <0.06).
                                   13-24

-------
Virus shedding (a measure of infection determined from nasal washings) also
seemed to be somewhat decreased in the SOp exposed group, but not significantly
13.2.3.6  Health Status—Some studies have considered the preexisting health
status of subjects as a variable in assessing the physiological effects of
S02.  Weir and Bromberg, for example, conducted separate studies on 12 healthy
subjects (Weir and Bromberg, 1972) and on 7 smokers who showed early signs of
chronic obstructive pulmonary disease (Weir and Bromberg, 1973).  The subjects
were exposed to 0, 0.3, 1, and 3 ppm S02 in an inhalation chamber for 96 or
120 hours (smokers or nonsmokers, respectively), with several days separating
each trial.  The individual variablity among the smokers in their daily lung
functions was so great that no effects could be attributed to SOp exposure.
Also, subjective complaints also appeared to be randomly distributed throughout
the course of the study and could not be related to S02 exposure levels.
     Gunnison and Palmes (1974) compared heavy smokers (7) and  non-smokers
(13) with respect to blood plasma levels of S-sulfonate after exposure to 0.3,
1.0, 3.0, 4.2, and 6.0 ppm SO^.  Both groups showed highly significant correla-
tions (p <0.001) between S02 concentrations and S-sulfonate  levels.  But there
was no significant differentiation between the two groups of subjects  in this
regard.
     Several other studies of SO,, (e.g., Snell and Luchsinger,  1969; Andersen
et  al., 1974; Gokenmeijer et al., 1973; Burton et a!., 1968, 1969)  have
included asthmatic patients or smokers, but have not  provided  even  qualitative
ratings of their health status.  This alone would make it difficult to  compare
the results of different studies using "healthy" or "impaired"  subjects.
Morever, the great individual variability among both  normal  and impaired
persons in these studies makes it difficult to reach  any conclusions about
                                    13-25

-------
the relative importance of an individual's health status in determining his



physiological response to S02>



13.3.  PARTICIPATE MATTER


     One of the most significant factors influencing physiological responses



to S0? is the presence of particulate matter in the atmosphere (Amdur, 1969)



(see Table 13-3). Particulate matter interacts with S02 in at least two distinct



ways: as a carrier of S02 and as a factor in chemical reactions resulting in



the  conversion of S02 to other forms.  In their carrier role, particles may



adsorb S02 and, depending on their size, solubility, and other characteristics,



transport it deep into the respiratory system (see Chapter 11, Section 11.2



for  more detailed discussion of deposition.)



     This point is illustrated by the results of studies by Nakamura  (1964)



and  Toyama (1962), who reported that sodium chloride (NaCl) aerosol potentiated



the  response of human subjects to SCL.  In Nakamura 's (1964) study, 10 subjects

                                                  £ftf
were first exposed to NaCl aerosol (CMD = 0.95 umj/yestimate of MMAD =5.6 urn)



alone for 5  minutes, allowed to recover for 10 to 15 minutes, exposed to S02


alone at 9 to 60 ppm for 5 minutes, allowed 20 to 30 minutes to recover, and



then exposed to S02 and the NaCl aerosol together for 5 minutes.  Airway



resistance was greater after the combination exposure than after  exposure to



S02  alone (see Table 1 and Figure 4a, Nakamura, 1964).  As noted, the combina-



tion condition always followed exposure to S02 alone, thus raising the



possibility  that the effects of the latter exposure were confounded.  However,



on average, the subjects'  airway resistance measures returned to  only 4 percent



above their pre-exposure control levels, thus making it more likely that the



reported effects were independent of preceding conditions.



     Toyama (1962) also reported that S0? in combination with submicronic  (0.22 \in
Misestimate of MMAD = 0.36 urn) particles of NaCl aerosol  produced synergistic
                                   13-26

-------
13-3.   PULMONARY EFFECTS OF AEROSOLS

Duration of
Concentration exposure (mins)
SO, (1.6 - 5 ppm) 5
NSC1 0.22 urn HMD
SO, (9-60 ppm) 5
NSC1 (CMO = 0.95 urn)

S0« (0.5. 1.0 and 5.0 ppm) 15
Saline particles 7.0 urn

Ibid 30

^*
£SO, (1.1 - 3.6 ppm) - 30
^ N5C1 2.0 - 2.7 ug/ni
MHO = 0.25 urn
SO, (1-2. 4-7. 14-17 ppm) 30
N3C1 10-30 mg/nr
MMO 0.15 urn
SO, (1 ppm) - 60
NlCl 1 mg/mj
MMO 0.9 u og = 2.0 pm
Ibid 60

Ammonium tulfate 150
100 ug/nt


Ammonium bisulfate 150
85 ug/m aerosol size
distribution
0.4 urn (MMAO)
Number of
subjects
13

10


9

9
(asthmatics)

10


12


9
(asthmatics)

(normals)

5 (normal)
4 (ozone
sensitive)
6 (asthmatics)
16


Source
Mask

Mask


Oral

(Mask
(Exercise for
10 minutes)

Oral


Oral


Oral

Mask

Chamber
(exercise)


Chamber
(exercise)


Effects
Synergistic increases in
airway resistance with aerosol
Airway resistance greater after
exposure to aerosol than to
exposure to SO- alone
MEF,,j£ significantly greater
decreases in aerosol (NaCl)
condition
v M> v t,
significantly in aerosol
condition
No effect on pulmonary functions


Changes in pulmonary function
similar to changes due to SO-
alone not influenced by aerosol
Significant decreases in V ,-nv
• A IH3X jU*
and Vmax 75X

No pulmonary effects demon-
strated
No changes in pulmonary
functions


No changes in pulmonary
functions


Reference
Toyama. 1962

Nakamura, 1964


Snell and Luchslnger,
1969

Koenig et al., 1979


Burton et al. . 1969


Frank et al. . 1964
i
JLA^\
Koenig^ 1979
»~$-#jL^
Koenlg.^ 1979

Bell and Hackney. 1977;



Kleinman and Hackney,
Avol et al. . 1979



-------
increases in airway resistance in 13 subjects, even at levels as low as 1.6 to



5 ppm SO .   There was also a linear relationship between SOp concentration and



percentage increase in airway resistance.



     On the other hand, Burton et al.  (1969) were unable to demonstrate comparable



effects in 10 subjects exposed to S02 (1.1 to 3.6 ppm) in combination with



NaCl aerosol (2.0 to 2.7 ug/m3; 0.25 urn MMD^estimate of MMAD = 0.4 urn).



There was, however, a great deal of variability within and between subjects in



this study, including one or two possible "hyper-reactors" who did show effects



below 3 ppm.  Frank et al. (1964) studied 12 subjects who were exposed to



three conditions of SOp and NaCl aerosols.  There were six subjects in each



group, but the same subjects were not evaluated under each of the three conditions



The purpose of this study was to determine whether acute changes in respiratory



dynamics Rl (pulmonary flow resistance) noted to occur during SOp exposure



were intensified by the presence of sodium chloride particles.  The NaCl



aerosols had a mean geometric diameter of 0.15 urn ^"estimate of MMAD =0.3 urn)



and a concentration of 10 to 30 mg/m ; SO- concentrations were 1 to 2, 4 to 7,



and 14 to 17 ppm.  The subjects' response to the SO- exposures were as previously



noted in that Rl was not affected by the  lower levels of S0? and progressively



increased at the higher levels.  The only statistically significant difference



(p <0.05) between the effects of the gas alone and the gas-aerosol mixture was



a slightly greater average increase in pulmonary flow resistance at 4  to 7 ppm



S02 than under the combination condition.   Addition of the NaCl aerosol resulted



in similar changes as observed to S02 alone.  This effect was interesting  in



that earlier work was cited suggesting that H2S04 may have been formed in  the



droplets.  (See discussion of similar animal studies in Chapter 12).



     Snell and Luchsinger (1969) also compared the effects S02 alone and  in



mixture with aerosols of either NaCl or distilled water.  Nine subjects inhaled
                                   13-28

-------
SOp at 0.5, 1, and 5 ppm alone and in combination with aerosols for 15-minute



periods separated by 15-minute control periods.  For the saline aerosol condi-



tion, decreases in maximum expiratory flow rate (MEFcnv v-) were significant



(p <0.01) at all exposure levels (0.5, 1, and 5 ppm SO,,) (See Figures 3 and 4,



Snell and Luchsinger, 1969).   The authors noted that the size of the aerosol



particles differed considerably, saline particles averaging around 7 urn in



diameter and water aerosols averaging less than 0.3 urn in diameter (see Figure 5,



Snell and Luchsinger, 1969).   (See also Ulmer, 1974.)  Koenig (1979) exposed



nine adolescent resting subjects (extrinsic asthmatics) for 60 minutes to



either filtered air, 1 ppm SO,, and 1 mg/m  of sodium chloride droplet aerosol



or 1 mg/m  of NaCl droplet aerosol (HMD 0.9 urn, unable to estimate MMAD, and



o  of 2.0 urn).  Exposure to SOp alone was not conducted.  Oral breathing was



forced on all subjects.  Total respiratory resistance (R-,-), maximal flow at 50



and 75 percent of expired vital capacity (partial flow volume). FEV, Q, and



functional residual capacity were measured before, during (30 minutes), and



after exposures.  No significant changes were found during exposures to filtered



air or NaCl aerosol.  Significant decreases (p <0.025) were observed in V
                                                                         iTiaX


and V    7r
-------
during the exposures.   Vma/ 50% and Vmax 75% decreased some 53 and 46 percent
respectively after the exercise.  Significant changes in FEV1 Q and Ry were
also observed, suggesting that exercise and SC^-NaCl exposure resulted in
effects on both large as well as small airways.
     As chemical interactants. particles such as aerosols of certain soluble
salts (e.g., ferrous iron, manganese, vanadium) may act as catalyst to convert SO.
to H?SO..  H?0 from atmospheric humidity or from physiological sources figures
prominently in these reactions.  The following sections deal with common
compounds of sulfur oxides and point up the influence of a number of variables
that affect human physiological response to these compounds.
13.4  SULFUR DIOXIDE AND OZONE
     Sulfur dioxide and ozone  (03) may combine to form sulfuric acid on the
warm, moist surfaces of the  respiratory tract.  Studies have not yet demonstrated,
however,  that a true synergistic bond exists between SO- and 0, (see Chapters 6, 7,
and 11).
     Bates and Hazucha (1973)  and Hazucha and Bates (1975) exposed  eight
volunteer male subjects to a mixture of 0.37 ppm 03 and 0.37 ppm  S0? for  2
hours.  Temperature, humidity, concentrations and particle sizes  were  not measured.
Sulfur  dioxide alone had no  detectable effect on lung function, while  exposure
to ozone  alone resulted in decrements in pulmonary  function.   The combination
of gases  resulted in more severe (10 to 20% decrement) respiratory  symptoms  and
pulmonary function changes than did ozone alone.  Using the  maximal  expiratory
flow rate at 50 percent vital capacity as the most  sensitive  indicator,  it was
evident that after 2 hours exposure to 0.37 ppm S02 no change  occurred.   However,
during exposure to 0.37 ppm 03 a 13 percent reduction was  observed,  while exposure
to the mixture of 0.37 ppm 03 and 0.37 ppm S02 resulted in a  reduction of 37
                                   13-30

-------
percent in this measure of pulmonary function.   The effects resulting from 0-



and SO- in combination were apparent in 0.5 hours, in contrast to a 2-hour



time lag for exposure to 0, alone.



     Bell et al. (1977) attempted to replicate these studies alone with four



normal and four ozone-sensitive subjects.   They showed that 03 + SO- mixture



had greater detrimental on all pulmonary function measured than 0, alone.



However, only some of these parameters showed statistical significants decrement



when compared to 0,.  Four of Hazucha and Bates' subjects were also studied by



Bell et al. (1977).  Two of these subjects had unusually large decrements  in


                                                                            ffi ?^
FVC (40 percent) and FEV.^ (44 percent) in the first study (Bates and Hazucha^,



while the other two had small but statistically significant decrements.  None



of the subjects responded in a similar manner in the Bell study.  Restrospective



sampling of the ambient air conditions utilizing particle samplers and chemical



analysis in the chamber showed that acid sulfate particles could have been 10-



to 100-fold higher  in Hazucha and Bates' chamber and thus might have been



responsible for the synergistic effects observed.  In the Montreal chamber,



concentrated streams of SO- and 0., exited from tubes separated by 8 inches  (20


                                   3           3
cm) under a fan which forced 167  ft /min (4.7 m /min) of air conditioned



laboratory air with SO- and 0., through the chamber and out an exhaust  line  on



the opposite wall.  The concentrated streams of SO- and 0- could have  reacted



rapidly with each other and with  ambient impurities like olefins, to  form a



large number of H-SO. nuclei which grew by homogenous condensation, coagulation,



and absorption of NH3 during their 2-minute average residence time  in  the



chamber.



     Horvath's group (Horvath and Folinsbee, 1977; Bedi  et al.,  1979)  exposed



nine young men (18  to 27 years old) to 0.4 ppm 0,  and 0.4  ppm SO-  singly  and



in combination for  2 hours in an  inhalation chamber at 25°C  and 45  percent  RH.
                                   13-31

-------
The subjects exercised intermittently for one-half of the exposure period.   A


large number of pulmonary function tests were conducted before, during, and


after the exposure.   Subjects exposed to filtered air or to 0.4 ppm SO^ showed


no significant changes in pulmonary function.  When exposed to either 0., or 03


plus SCL, the subjects showed significant decreases in maximum expiratory


flow, forced vital capacity, and inspiratory capacity.  There were no signifi-


cant differences between the effects of CL alone and the combination of 0^ +


SCL.  Although particulate matter was not present in the inlet air, it is not


known whether particles developed in the chamber at a later point.


     Von Nieding et al. (1979) exposed 11 subjects to 03, NCL and SCL singly


and in various combinations.  The subjects were exposed for 2 hours with 1


hour devoted to exercise which doubled their ventilation.  The work periods


were of 15 minute duration interspersed with 15-minute periods at rest.  In


the actual exposure experiments, no significant alterations were observed for

P     P
 A02'  AC02' pHa' and tnoracic 9as volume (TGV).  Airway resistance total (R )

    p                                      p
and  AQ2 were altered in certain studies.   a02 was decreased (7-8 torr) by


exposure to 5.0 ppm NCL but was not further decreased following exposures to


5.0 ppm N02 and 5.0 ppm S02 or 5.0 ppm N02, 5.0 ppm SCL and 0.1 ppm 0, or 5.0


ppm N02 and 0.1 ppm 0,.  Airway resistance increased significantly [0.5 to 1.5


cm H20/(L/s)] in the combination experiments to the same extent as in  the


exposures to N02 alone.  In the 1-hour post exposure period of the N02, S02>


and 03 experiment, Rt continued to increase.  Subjects were also  exposed to


0.06 N02, 0.12 S02,  and 0.025 03 (all in ppm).   No changes in any of the measured


parameters were observed.   These same subjects were challenged with a  1, 2, and


3 percent solution of acetylcholine following control (filtered air) exposure


and to the 5.0 N02>  5.0 S02> and 0.1 03 (ppm) as well as after the 0.06 NC>2,


0.12 S02> and 0.025 03 (ppm) exposures.  The expected increase in airway
                                   13-32

-------
resistance was observed in the control study.   Specific airway resistance  (R.



x TGV) was significantly greater than in the control  study following the



combined pollutant exposures.  (See Table 13-4 for a  summary of the pulmonary



effects of SOp and other air pollutants.)



13.5  SULFURIC ACID AND SULFATES



13.5.1  Sensory Effects



     A number of studies have been directed toward determining threshold



concentrations of hLSO. for various sensory response  (see Table 13-5).   In a



study with 10 test subjects, Bushtueva (1957) found that the minimum concentration



of sulfuric acid aerosol (particle size not given) which was sensed by  odor


                    33                   3
ranged from 0.6 mg/m  to 0.85 mg/m  (average 0.75 mg/m ).  In tests with  five



subjects (Bushtueva, 1961), a combination of sulfur dioxide at 1 mg/m  (0.35



ppm) and sulfuric acid mist at 0.4 mg/m  was below the odor threshold.   Amdur



et al. (1952) reported on 15 subjects (males and females) exposed for 5 to 15



minutes to various concentrations of sulfuric acid mist the subjects breathed



via a face mask.  It was found that 1 mg/m  was usually not detected, while 3



mg/m  was detected by all subjects.



     Bushtueva (1957) studied the effect of sulfuric  acid mist on the light



sensitivity of two test subjects.  Sensitivity was measured every 5 minutes



during the first half-hour of each test, then at 10-minute intervals thereafter.



A control curve was established  for each subject by seven repeated tests, and



then sulfuric acid aerosol was administered for 4 minutes and for 9 minutes at



the 15th and 60th minutes, respectively.  With sulfuric acid mist of undetermined



particle size at a concentration of 0.6 mg/m  , a just detectable increase  in



light sensitivity occurred with  the first exposure but not with the  second.



Concentrations in the range of 0.7 mg/m  to 0.96 mg/m  brought about a well-



defined increase in light sensitivity.  With 2.4 mg/m  ,  increased  sensitivity
                                   13-33

-------
13-4.   PULMONARY EFFECTS OF S02 AND OTHER AIR POLLUTANTS
Concentration
S02 (0. 37 ppm)
and
03 (0.37 pp«)
S02 (0.37 ppm)
and
03 (0.37 ppm)

V S02 (0.40 ppm)
and
0, (0.40 ppm

S02 (5 ppm)
and
N02 (5 ppm)
S0? (5 ppm)
NO- (5 ppm)
and
03 (0.1 ppm)
S02 (0.12 ppm)
N0? (0.06 ppm)
and
03 (0.025 ppm)
Duration of Number of
exposure (mins) subjects Source
120 8 Chamber
(exercise)
120 4 (normal) Chamber
4 (ozone (exercise)
sensitive)
4 (from Bates)
120 9 Chamber
(exercise)


120 11 Chamber
(exercise)
120 11 Chamber
(exercise)

120 1 1 Chamber
(exercise)

Effects
Decrease pulmonary functions
(in synergistic effect of
S0? on 03) FRC. FEVj n,
uurD IIP CD
ririr n ) "tr Hrny
Unable to confirm
synergistic effects
pulmonary decrement due
to 0, alone
Unable to confirm
synergistic effects
changes due to ozone
alone
No changes in Pa02> PaCQ2.
pHa or TGr -R.
increased
No changes in Pa02. PaC()2.
pHa or TGr -R. increased

No changes in pulmonary
functions

Reference
Hazucha and
Bates. 1973, 1975
Bell et al. , 1977

Horvath and Folinsbee
(1977);
Bedi et al. (1979)

von Nieding et al.. 1979
von Nieding et al., 1979

von Nieding et al. , 1979


-------
I
w
tn
                                         13-5.  SENSORY EFFECTS OF SULFURIC ACID AND SULFATES
     Concentration       Subjects                               Effects                                  References



       0.75 \ig/m            5                         Threshold detected by odor                    Bushtueva, 1957, 1961

                                                        - increase in light sensitivity

                                                        - increase in optical chronaxie


       1-3 pg/m             15  (exposed 5-15 *in)     3 mg/m  detected by all subjects              Amdur et al., 1952

-------
to light was elicited by the exposures at both the 15th and 60th minutes of
the test; normal  sensitivity was restored in 40 to 50 minutes.
     Bushtueva (1961) studied the effect of sulfur dioxide, sulfuric acid mist
and combinations  of the two on sensitivity of the eye to light in three subjects
The combination of sulfur dioxide at 0.65 mg/m  (0.23 ppm) with sulfuric acid
mist at 0.3 mg/m  resulted in no change in sensitivity of the eye to light.
An increase of approximately 25 percent in light sensitivity resulted from
exposure to either sulfur dioxide at 3 mg/m  (-1.0 ppm) or sulfuric acid mist
at 0.7 mg/m .  The combination of sulfur dioxide at 3 mg/m  with sulfuric acid
mist at 0.7 mg/m  resulted in an increase of approximately 60 percent in light
sensitivity.  Exposures lasted for 4 1/2 minutes.
     Bushtueva (1962) demonstrated that combinations of sulfur dioxide
            3                                                3
at 0.50 mg/m  (0.17 ppm) with sulfuric acid mist at 0.15 mg/m  or sulfur
dioxide  at 0.25 mg/m  (0.087 ppm) with sulfuric acid mist at 0.30 mg/m  could
produce  electrocortical conditioned reflexes.  There are some uncertainties
regarding this study.
     Bushtueva (1961) studied the effects of different concentrations of
sulfur dioxide, sulfuric acid mist, and combinations of the two on the optical
chronaxie of three subjects.  Optical chronaxie was determined in each test
subject at 3-minute intervals as follows:  at the start and on the 3rd, 6th,
9th, 12th and 15th minutes.  Between the 6th and 9th minutes the subjects
inhaled sulfur dioxide, sulfuric acid mist, or their combination for 2 minutes.
In each subject,  the threshold concentrations of sulfur dioxide and sulfuric
acid mist were first determined independently, and then threshold concentra-
tions for combinations of the two were determined.  Sulfuric acid mist  (750
     ) increased optical chronaxie.
                                   13-36

-------
13.5.2  Respiratory and Related Effects
     Amdur et al. (1952) found respiratory changes in all  subjects  exposed  for
15 minutes to HpSO^ aerosol at concentrations of 0.35 mg/m  to 5 «g/m  .
Vapors from an electrically heated flask containing concentrated sulfuric acid
were carried by compressed air into the main air stream and then Into  a  lucite
mixing chamber, delivering a mist of HMD 1 urn.   The subjects breathed  through
a pneumotachograph, permitting measurement of inspiratory and expiratory flow
rate.  In 15 subjects, exposed to 0.35, 0.4, or 0.5 mg/m , the respiration
rate increased about 35 percent above control values, while the maximum  in-
spiratory and expiratory flow rates decreased about 20 percent.   Tidal volume
decreased about 28 percent in subjects exposed to 0.4 mg/m .  These changes
occurred within the first 3 minutes of exposure and were maintained throughout
the 15-minute exposure period.  Lung function returned rapidly to baseline
levels after the exposure ended.  The tidal volume rose above control  values
during the first minute after termination of the exposure and then returned to
preexposure levels.  Breathing through the same apparatus without the  acid
mist was done as a control, and no such changes were observed.  Some subjects
showed a marked reaction to 5 mg/m .  Individual responses were much more
varied at this level, the main effect being a decrease in minute volume.
The investigators suggest that bronchoconstriction may have been the response
to sulfuric acid.
     The effect of breathing sulfuric acid mist at different  relative humidities
(RH) was studied by Sim and Rattle (1957).  Healthy males (variable number of
subjects), 18 to 46 years of age, breathed 3 to 39 mg/m  concentrations of
H?SO. at 62 percent RH either via mask or exposure chamber.   Subjects were
also exposed in the chamber to 11.5 to 38 mg/m  concentrations  at  91 percent
RH.   At the lower RH, particles were 1 \im in size.  The addition of water
                                   13-37

-------
vapor to raise RH increased the mean particle size to 1.5 urn and intensified
irritant effects of exposure.   For example, the irritancy of wet mist at 20.8
mg/m  was much more severe ("almost intolerable at the onset") than that of
the dry mist at 39.4 mg/m  ("well tolerated by all").  Air flow resistance
ranged from 43 to 150 percent above normal in response to the wet mist, compared
to increases ranging from 35.5 to 100 percent above normal in response to the
dry mist.  Two subjects exposed to sulfuric acid mist developed bronchitic
symptoms but may have been previously exposed to other substances.  Adding
ammonia  (quantity not given) to the acid mist annulled its irritant properties.
There was no consistent evidence that the acid mist caused changes in respiratory
functions or blood pressure, pulse rate, or other cardiovascular functions.
     Toyama and Nakamura (1964) investigated the synergistic effects of S02 in
combination with hydrogen peroxide (H^Op) aerosol mixtures, the latter of
which oxidizes SOp to form HpSO..  SOp concentrations ranged from 1 to 60 pptn;
                                      3
 the  HO  concentrations were 0.29 mg/m  for particles of 4.6 |jm CMD  (aotimatcd-
                        o                             c
 MMAD = 13) and 0.33 mg/m3 for particles of 1.8 urn CMD (-estimated- MflAD = 5).
 Airway resistance increased significantly in the combination  (hLO- + S02)
 exposure, particularly for the group of 15 subjects inhaling  the larger particles
 (p <0.01).  Toyama and Nakamura (1964) exposed subjects to  a  mixture of S0?
 and H2S04 aerosols.   They used an inadequate method to measure  airway resistance.
 They described the aerosols as having a 4.5 pm diameter.  They  found a  strong
 constricting effect on the upper airways.
     Sackner et al.  (1978) studied normal resting young adults  and  seven
 asthmatic middle-aged subjects who breathed, by mouth, either sodium chloride
or sulfuric acid aerosols for 10 minutes at concentrations  of 10,  100,  and
1000 ug/m .   Measurements on these individuals continued  for up to 3 hours
after exposure.  The asthmatic patients represented  a  wide  range of clinical
                                   13-38

-------
status and treatment.  Neither normal nor asthmatic individuals showed significant
alterations of lung volumes, distribution of ventilation, earoxlmetry, dynamic
mechanics of breathing, oscillation mechanics of the chest-lung system, pulmonary
capillary blood flow, diffusing capacity, arterial oxygen saturation,  oxygen
uptake, or pulmonary tissue volume.  No delayed effects were observed  during a
follow-up period of a few weeks.
     Kleinman and Hackney (1978) and Avol et al. (1979) reported on the pulmonary
responses of six normal and six asthmatic subjects exposed in an ambient
environment of 88°F dry bulb and 40 percent relative humidity, and 94  ug/m
HpSO^.  The asthmatics had pulmonary function test results which ranged widely
from normal to abnormal.  A sham exposure was followed by 2 consecutive days
of acid exposure.  Sufficient excess acid aerosol to neutralize the NHL present
(about 56 ug/m  ammonia neutralization product) was added to the air to provide
for the desired acid concentration (75 ug/m ).  The aerosol MMAD was approximately
0.48 to 0.81 urn.  The effective exposure time was 2 hours, with the first 15
minutes of each half-hour devoted to exercise which increased ventilation to
twice the resting level.  Only one subject was exposed at a time to minimize
the effects of ammonia neutralization.  The normal subjects showed no exposure-
related changes.  The lung functions of the asthmatics showed no significant
changes.  Two asthmatics, the extent of their disease state not given, exhibited
increases in respiratory resistance on both exposure days.  Nonetheless,  it
was concluded that there were no convincing adverse short-term health effects
of sulfuric acid.  However, they also noted the  small size of their subject
pool and recommended additional studies.
     Lippmann et al. (1979) had 10 non-smokers  inhale via  nasal mask  0.5  urn
(a  = 1.9) H2S04 at 0 and approximately, 100, 300. and 1,000  ug/m   for 1  hour.
The exposures were random over the 4 days of  testing.  Pulmonary  functions
                                   13-39

-------
(assessed by body plethysmograph,  partial  forced expiratory maneuver,  and
nitrogen washout) were measured before,  and at 0.5,  2,  and 4 hours post exposure.
99mTc-tagged monodispersed Fe203 aerosol (7.5 urn WAD,  o  = 1.1) was Inhaled
10 minutes before exposure for the determinations of lung retention of these
particles.  Trachea! mucus transport rates (TMTR) and bronchial nucociliary
clearance were determined.  No significant changes in respiratory mechanics or
TMTR were observed following H^SO^ exposure at any level.  However, bronchial
mucociliary clearance halftime (TB,) was on the average markedly altered at
all concentrations of HpSO. inhaled.  Bronchial clearance was increased (p
<0.02)  following exposure to 100 ug/m  ^SO^, while  following exposure to
1,000 ug/m  , it was significantly (p <0.03) reduced.  Mucociliary transport in
the airways distal to the trachea was affected more by F^SO. exposure than was
transport in the trachea.  Out of ten subjects four did not respond.  "The
alterations in bronchial clearance half-time were all transient, which was
consistent with the results seen earlier in similar inhalation tests on donkeys
                      wr
(Schlesinger, et a!., 19680.  However, when donkeys were repeatedly exposed to
sulfuric acid at comparable concentrations, four of six animals developed
persistently slowed clearance, which remained abnormal for at least several
months  (Schlesinger, et al., 1978, 1979).   Taken together, these results
suggest that at the concentrations employed persistent changes could occur  in
mucociliary clearance in previously healthy individuals and exacerbate preexisting
respiratory disease.
     Bell and Hackney (1977) presented preliminary data on a limited number of
subjects supporting a hypothesis that no adverse short-term (2.5  hours)  effects
result from exposure to polydisperse ammonium sulfate particles  in the respirable
size range (see Avol et al., 1979).   Sixteen individuals were  studied, each
being exposed from two to six times to ammonium sulfate.  They  exercised for
                                   13-40

-------
the first 15 minutes of each half-hour.   Ventilation volumes  were  approximately
double the resting volume during the four exercise periods.   A battery  of
pulmonary function measurements (FVC, FEVX Q) MMF, AN2>  RV, TLC, CV/VC, CC/TLC
•nd IL) were administered to the subjects.  Five normal  and  four "sensitive"
(i.e., sensitive to ozone exposures) subjects had 3 successive days of
exposures preceded by 2 days of purified air exposures.   Ambient temperature
conditions were 88°F dry bulb and 40 and 85 percent relative humidity.   Six
asthmatic subjects were studied at the lower humidity condition.   Their first
day was a purified air exposure followed by 2 days in the ammonium sulfate
condition.
     Kleinman and Hackney (1978) and Avol et al. (1979) further evaluated the
effects of various sulfate compounds on normal subjects, ozone-sensitive
subjects, and asthmatic subjects (requiring medical treatment).  The exposures
were approximately 2.5 hours in duration, with the subjects exercising the
first 15 minutes of each half hour at a pace sufficient to double their
ventilation rates.  Measurements of pulmonary functions, which included FVC,
FEV,, MEFR, FEFr0«£, FEF75%' TLC> Rv> de1ta nitrogen (AN.), closing volume, and
total respiratory resistance (R.) were made before and 2 hours after the
work-rest regimen began.  The ambient conditions were 88°F dry bulb and
either 40 or 85 percent relative humidity.  Most of the exposure  studies were
made on five to seven subjects.  Four to five sensitive subjects  and six
asthmatics completed the subject pool.  Subjects were first exposed to  a
control (no pollutant) environment and then to  2 or 3 consecutive days  of  the
pollutants.  The asthmatics were not studied  in the high  humidity conditions,
but were exposed to a higher concentration (up  to  372 ug/m  )  of  (NH^SO^
Nominal exposure concentrations were 100 ug/m   for ammonium bisulfate  (NH^HSO.)
                                   13-41

-------
and 85 pg/m  for ammonium sulfate [(NH^KSO^].   The sulfate aerosol  size
distribution was nominally 0.4 urn MMAD (a  2.5 to 3).   There was some ammonia
(NHL) in the exposure chamber.  Pulmonary functions were unaffected by exposure
to the two types of aerosol.
     An interesting side observation was made on the asthmatics.  On their
first day of exposure to NH.HSO. aerosol, they exhibited worse lung functions
in the pre-exposure measurements than they had on a control day.  Their functions
improved consequent to the pollutant exposure.   Subsequent analysis of local
ambient conditions showed that these subjects arrived for their aerosol testing
after a 3-day period of increased SO- and ozone levels during a "mild air
pollution episode."  (See Table 13-6 for a summary of the pulmonary effects of
sulfuric acid.)
13.6  SUMMARY
     Human experimental studies of the health effects of exposure to pollutants
in the ambient environment require strict controls so that their findings can
be generalized to the entire population.  Although no studies meet all the
requirements for strict control, some basic information can be garnered from
many published studies.
     S02 has been found to have effects on several physiologic  functions.
Through subjective reports, the reliability of which has been questioned, a
level of 5 ppm has been established for detecting S0~, with considerable
variation below that level.  Several sensory processes are affected  by  generally
agreed-upon levels of concentration of S02>  The odor threshold  averages  0.8
to 1 ppm, with 0.47 ppm set in one study performed under ideal  conditions.
The sensitivity of the eye to light increases at 0.34 to 0.63 ppm,  is  maximal
at 1.3 to 1.7 ppm, and decreases to normal by 19.2 mg/m3 during dark adaptation.
                                   13-42

-------
13-6.   PULMONARY EFFECTS OF SULFURIC ACID

Duration of
Concentration exposure (mins)
0.35 - 5.0 mg/m3 H-SO. 15
MMO 1 pm £ *
3-39 Bg/m3 H.SO. 10 - 60
MMO 1-1.5 pfc
SO. (1-60 ppm) plus Variable
fCO. to form H.SO.
i-> aerosol
£ CMD 1.8 and 4.6 pm
u
H.SO. mist 3 120
f 1000 (jg/m
MMO 0.5 pm (og = 2.59)
H.SO. aerosol - 10
fo/100, 1000 ug/mj
MMO 0.1 pm
H,SO. (75 j.g/m3) 120
MMAD 0.48 - 0.81 pm
M.SO. (0, 100, .300. 60
6r 1,000 pg/mj
MMAD 0.5 pm
(og = 1.9)
Number of
subjects
15
Variable
10
6 normal
6 asthmatics
6 normal
6 asthmatics
10
Source
Mask (rest)
Mask (rest)
Chamber (rest)
(Rest)
Chamber
(exercise)
Oral
Chamber
(exercise)
Nasal
Effects
Respiratory rates increased,
max. insp. and expiratory
flow rates and tidal
decreased volumes
Longer particles due to "wet
mist" resulted in increased
flow resistance cough, rales
bronchoconslriction
Airway resistance
increased especially
with larger particles
No pulmonary function
changes but increased
tracheobronchial clearance
No pulmonary function
changes, no alterations
in gas transport
No pulmonary effects
in either group
No pulmonary function
effects
Broncial mucociliary
clearance t following
100 pg/m .but * following
Reference
Amdur et al., 1952
Sim and Pattle, 1957
Toyama and Nakamura,
1964
Newhouse et al. , 1978
Sachner et al. . 1978
Kleinman and Hackney,
1978. Avol et al.. 1979
Lippmann et •!., 1979
                                   clearance  distal  to  trachea
                                   more  affected

-------
During light adaptation, the figures increase and decrease similarly but at



slightly higher levels of exposure.  The alpha-wave has been found to be attenuated



by 0.9 to 3 mg/m  SO- during 20 seconds of exposure.



     Studies of the effects of S02 on the respiratory system of the body have



arrived at conflicting conclusions.   Although one study found respiratory



effects after exposure to as little as 1 ppm S02, others could find no effect



below 5 ppm.  At the latter level, pulmonary flow resistance increased 39



percent in one study.  Respiratory effects have been found to be proportional



to the concentration of S02 to which study subjects are exposed.  In asthmatic



subjects, MMFR was significantly reduced after oral exposure to 0.5 ppm S02



for  3 hours.  Although the bronchoconstrictive effects of exposure to S02  have



been found to be fairly consistent, subjects vary considerably  in response to



exposures, and there are some especially sensitive subjects, possibly as much



as 10 percent of the population.



      Because S02 is  readily water soluble, and nasal passages are high  in



humidity, the route  of exposure will affect the response of  individuals.



Subjects  report less throat and chest irritation when breathing through the



nose, and pulmonary  flow resistance increases less in subjects  who  are  nose



breathing.  Regardless of the route of exposure, 5 ppm S02 had  no effect  on



specific  airway conductance, although higher levels had a  dose-dependent



effect; that is. greater concentrations decreased  SG   more  than  lower  concen-
                                                    aw


trations.  The average decrease was greater after  oral exposure than  after



nasal administration.



     The  level of activity of the subjects tested  affects  the  results  because



the  actual dose received is greater when subjects  breathe  through their mouth,



as during exercise.  Just having subjects breathe  deeply  through the  mouth
                                   13-44

-------
significantly affected specific airway resistance during exposure  to  1  ppm  SO-
in one study, although another study found no such effect.   Respiratory effects
of exposure either by nose or by mouth are greatest after 5 to 10  ninutes of
exposure. Recovery takes about 5 minutes in normal subjects, but »uch longer
(10 to 60 minutes) in sensitive subjects and those who are asthmatic.   Studies
of nasal mucus flow rates and airway resistance following about 6  hours of
exposure to SOp per day for 3 days found some effects maximal after 1 to 6
hours.
     An early study found mucus clearance reduced increasingly as  length and
concentration of exposure to SO- increased.  Long exposures to 5 ppm SOp
increased mucociliary clearance in one study; a decrease had been  found in
nasal clearance rates in another study.  Available studies have not found a
significant interaction of smoking with SOp.
     The interaction of S02 and particulate matter is an important factor in
Lunn's experimental studies.   Airway resistance increased more after combined
exposure to S0« and sodium chloride than after exposure to SOp or  sodium
chloride alone in several studies although others have failed to reach  the
same conclusion.   This may have been due to formation of sulfuric  acid  mist
during the study.  MEFcQ^ was found to be significantly reduced after exposure
to a combination of saline aerosol and SOp.  After exposure to combined hydrogen
peroxide and sulfur dioxide, airway resistance was found to be significantly
increased.   The combination of SOp and ozone may have synergistic effects on
lung function.  At low concentrations  (0.37 ppm) SOp had no effect on  lung
function, ozone impaired lung function, and the combination  impaired lung
function even more.  A similar study did not find the same  results.  Other
studies have found reductions in pulmonary function after exposure to  low
                                   13-45

-------
levels of SOp and ozone combined with S02 or to ozone alone, but no synergistic



effect of the combined exposure.



     Sulfuric acid and sulfates have been found to affect both sensory and



pulmonary function in study subjects.   The odor threshold for sulfuric acid


                                 3                        3
aerosol has been set at 0.75 mg/m  in one study and 3 mg/m  in another.   Light



sensitivity has been found to be consistently increased by 25 percent at 0.7



to 0.96 mg/m  concentration of sulfuric acid mist (0.3 mg/m ).   Optical  chronaxie



has also been found to be increased after exposure of subjects to 750 um/m



sulfuric acid mist.

                                                                            o

     Respiratory effects from exposure to sulfuric acid mist (0.35 to 5  mg/m )



include increased respiratory rate and decreased maximal inspiratory and



expiratory flow rates and tidal volume.   Several studies of the pulmonary



function of asthmatic and normal subjects suggested that pulmonary function



was not affected when the subjects were exposed to sulfuric acid. Mucociliary



clearance was affected by exposure to sulfuric acid, being significantly



increased after exposure to 100 um/m  and significantly decreased after exposure



to 1000 ug/m .   Another study found no pulmonary effect of exposure to sulfuric



acid, ammonium bisulfate, and ammonium sulfate by normal and asthmatic subjects.
                                   13-46

-------
 Additional References Recommended for Consideration  in Chapter  13

Anderson, L., G. R. Lundgvist, D. F. Proctor, and K.  L. Swift.   Human  response
     to controlled levels of inert dust.  Am. Rev.  Resp. Dis.  119:619-627,
     1979.

Camner, P. and K. Philipson.  Human alveolar deposition of 4 urn  Teflon particles
     Arch. Environ. Health 33(4):181-185, 1978.

Chaney, S., W. Blomquist, K. Muller, and G. Goldstein.  Biochemical  Changes  in
     humans Upon Exposure to Sulfuric Acid Aerosol  and Exercise.
     EPA-600/1-79-032, U.S. Environmental Protection  Agency, 1979.

Chaney, S., W. Blomquist, K. Muller, and P. Dewitt.   Biochemical Effects of
     Inhalation of Sulfuric Ackl Mist by Human Subjects While at Rest.
     EPA-600/1-79-042, U.S. Environmental Protection  Agency, 1979.

Coates, J. E.  Lung Function:  Assessment and Application in Medicine.   Fourth
     edition.  Blackwell Scientific Publications, London, 1979.  pp.  329-387.

Utell, J. J., A. T. Aquilina, W. J. Hall, D. M. Speers, R. G. Douglas,  F. R.
     Gibb, P. E. Morrow, and R. W. Hyde.  Development of Airway  Reactivity to
     Nitrates in Subjects with Influenza.  Am. Rev. Resp. Dis. 121:233-241,
     1980.

-------
13.7  REFERENCES

Abe, M.  Effects of mixed N0?, SCL on human pulmonary  functions.   Effects of
     air pollution on the human body.  Bull. Tokyo Med. Dent.  Univ.  14:415,
     1967.

Amdur, M.  Animal studies on sulfur acids and particulates.   Proceedings  of
     Conference, Health Effects of Air Pollutants.  U.S. Government  Printing
     Office, 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 subjects.  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.   Determination of Odor Thresholds  for 53
     Commercially Important Organic Compounds.  The Manufacturing  Chemists'
     Association, Washington,  DC,  January 11,  1968.

Avol, E. L., M.  P. Jones, R. M. Bailey,  N. N.  Chang, M. T. Kleinman,  W. S.
     Linn, K. A. Bell, and J.  D. Hackney.   Controlled exposures of human
     volunteers to sulfate aerosols.   Am.  Rev. Respir. Dis. 120:319-326,  1979.

Bates, D. V., and M. Hazucha.   The short-term effects of ozone on  the lung.
     In:  Proceedings of the Conference on Health Effects of  Air  Pollutants.
     Serial No.  93-15, U.S. Government Printing Office, 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  CAPM  - 27-75),
     1977.

                                     13-47

-------
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.

Burton, G.  G., M. Corn, 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,  D. A.  New studies of the effect of sulfur dioxide and of sulfuric
     acid aerosol on reflex activity of man.  In:  Limits of Allowable Concen-
     trations of Atmospheric Pollutants.  Book 5, B.  S. Levine, translator,
     U.S. Department of Commerce, Office of Technical Services, Washington, DC,
     March 1962.  pp. 86-92.

Bushtueva,  K. A.  The determination of the limit of allowable concentration of
     sulfuric acid in atmospheric air.  J.n:  Limits of Allowable Concentrations
     of Atmospheric Pollutants.  Book 3, B. S. Levine, translator, U.S. Department
     of Commerce, Office of Technical Services, Washington, DC, 1957.  pp. 20-36.

Bushtueva,  K. A.  Threshold reflex effect of SO, and sulfuric acid aerosol
     simultaneously present in the air.  In:  Limits of Allowable Concentrations
     of Atmospheric Pollutants.  Book 4, B. S. Levine, translator, U.S. Department
     of Commerce, Office of Technical Services, Washington, DC, January 1961.
     pp.  72-79.

Cralley,  L.  V.  The Effect of irritant gases upon the rate of ciliary activity.
     J. Ind. Hyg. and Toxicol. 24:193-198, 1942.

Dubrovskaya, F. I.  Hygienic evaluation of pollution of atmospheric air of a
     large city with sulfur dioxide gas.  In:  Limits of Allowable Concentrations
     of Atmospheric Pollutants.  Book 3, B. S. Levine, translator, U.S. Department
     of Commerce, Office of Technical Services, Washington, DC., 1957.  pp. 37-51.

Frank, N. R.  Studies on the effects of acute exposure to sulfur dioxide  in
     human subjects.  Proc. R. Soc. Med. 57:1029-1033, 1964.

frank, N. R., M. 0. Amdur, and J. L. Whittenberger.  A comparison of the  acute
     effects of S0? administered alone or in combination with NaCl particles
     on the respiratory mechanics of healthy adults.    Int. J. Air Water Pollut.
     8:125-133, 1964.

Frank, N. R., M. 0. Amdur, J. Worcester, and J.  L. Whittenberger.
     Effects of acute controlled exposure to S0? on  respiratory mechanics
     in healthy male adults.  J. Appl. Physiol.  17:252-258, 1962.

                                     13-48

-------
Frank, R., C. E. McJilton, and R. J. Charlson.  Sulfur oxides and particles;
     effects on pulmonary physiology in man and animals.  In:  Proceedings  of
     Conference on Health Effects of Air Pollution.  National Research
     Council, Oct. 3-5, 1973.  Serial No. 93-15, U.S. Government Printing
     Office, Washington, DC.

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 o.i
     human pulmonary  function.  Nature (London) 257:50-51, 1975.

Holmes,  J. A.,  E. C.  Franklin, and R. A. Gould.  Report of the Selby  Smelter
     Commission.  Bulletin 98,  U.S. Department of the Interior, Bureau of  Mines,
     Washington, DC,  1915.

Horvath, S.  M.  (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.

Jaeger,  M. J.,  D. Tribble, and H. J. Wittig.  Effect of 0.5 ppm sulfur
     dioxide on the respiratory function of normal and asthmatic
     subjects.  Lung  156:119-127, 1979.

Kisskalt, K.   Uber den Einfluss der inhalation schwelfiger Saure auf  die
     Entevickelung der Lungentuberculose:  Ein Bietrag zum Studien der  Gewer-
     bekrankheiten.   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.

Koenig,  J. Q. ,  W. E.  Pierson, and R. Frank.  Acute effects of inhaled S0p  plus
     NaCl droplet aerosol on pulmonary function in asthmatic adolescents.   Environ.
     Res. (in  press), 1980.

Koenig,  J. Q.,  W. E.  Pierson, and R. Frank.  Acute effects of
     inhaled SO,, and  exercise on pulmonary function  in asthmatic
     adolescents..  J. Allergy Clin. Immunol. 64:154, 1979.

Kreisman, H.,  C. A. Mitchell, H. R. Hosein, and A. Bouhuys.  Effect  of low
     concentrations of sulfur dioxide on respiratory function in man.  Lung
     154:25-34, 1976.
                                        13-49

-------
Lawther, P. J.  Effects of inhalation of sulfur dioxide on respiration and
     pulse-rate 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.  Experimented Studien liber den Einfluss technisch  und hygienisch
     wichtiger Case und Da'mpfe auf den Organismus.  VI.  Schwefliger Sa'ure.
     Arch. Hyg.  18:180-191, 1893.

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, 1979-1980.

Mcllroy, M. B., R. Marshall, and R. V. Christie.  Work of breathing in normal
     subjects.  Clin. Sci. 13:127-136, 1954.

McJilton, C.  E., R. Frank, and R. J. Charlson.  Influence of relative
     humidity on functional effects of an inhaled S0?-aerosol mixture.
     Am. Rev. Respir. Dis. 113:163-169, 1976.       *

Melville, G.  N.   Changes in specific airway conductance in healthy volunteers
     following nasal and oral inhalation of S09.  West Indian Med. J.  19:231-235,
     1970.                                    *

Nadel,  J., H. Salem, B. Tamplin, and Y. Tokiwa.  Mechanism of bronchoconstriction
     during inhalation of sulfur dioxide.  J. Appl. Physio!. 20:164-167, 1965.

Nadel,  J. A., H. Salem, B. Tamplin, and Y. Tokiwa.  Mechanism of bronchoconstriction.
     Arch. Environ. Meth. 10:175-178, 1965.

Nakamura, K.   Response of pulmonary airway resistance by interaction of  aerosols
     and gases in different physical and chemical nature.  Nippon Eiseigaku Zasshi
     19:38-49, 1964.

Newhouse, M.  T., M. Dolovich, G. Obminski, and  R. K. Wolff.  Effect of TLV
     levels of S0? and HUSO, on  bronchial clearance in exercising man.   Arch.
     Environ. Heafth 33:24-32, 1978.

Ogata,  M.  Uber die Giftigkeit der schweffigen  Sa'ure.  Arch. Hyg. 2:223-245,
     1884.

Reichel, G.  Die Wirkung von Schwefeldiovyd auf den Atemivegsvilderstand
     des Menschen.  Verh. Dtsch. Arbeitsmed.  12:135-141, 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 Adam Wanner.  Effects of  sulfuric acid
     aerosol on cardiopulmonary  function of dogs, sheep, and humans.  Am.  Rev.
     Respir.  Dis.   118:497-510,  1978.
                                       13-50

-------
Schlcoinger, R. B., M. Lippmann, and R. E. Albert.  Effects of  Short-term
     Exposures to Sulfuric Acid and Ammonium Sulfate.  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.

Shalamberidze, 0. P.  Reflex effects of mixtures of sulfur and  nitrogen  dioxides
     Hyg. Sanit. 32:10-15, 1967.

Sim, Van 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 S0? by  mouth  and by
     nose.   Br. J. Ind. Med. 23:75-79, 1966a.

Speizer, F., and Frank, N. R.  The Uptake and Release of S0? by the Human
     Nose.   Arch. Environ. Health 12:725-728, 1966b.       *

Tomono, Y.   Effects of S09 on human pulmonary functions.  Sangyo Igaku
     3:77-85, 1961.      *

Toyama, T.   A medical study of aerosols.  I.  Sangyo Igaku 4:86-92, 1962.

Toyama, T.,  and K. Nakamura.  Synergistic response to hydrogen  peroxide  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.

von Nieding, G., H. M. Wagner, H. Krekeler, H. Lollgen, W. Fries, and
     A. Beuthan.  Controlled studies of human exposure to single and
     combined action of NO,,, 0, and S0«.  Int. Arch. Occup. Environ.
     Health  43:195-210, 1979. J       L

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?. 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 tracheobronchial clearance  in  man.   Arch.  Environ.  Health  30:521-527,
     1975a.                                                         —

                                       13-51

-------
Wolff, R. K., M. Dolovich, G. Obminski, and M. T. Newhouse.  Effect of
     sulphur dioxide on tracheobronchial clearance at rest and during exercise.
     In:  Inhaled Part. Proc. Int. Symp. 4th, Edinburgh, Scotland, September
     22-26, 1975.  Pergamon, Oxford, UK, 1977.  pp. 321-332.

Yamada, J.  Untersuchunger iiber die quantitative Absorption der Da'mpfe einiger
     Sauren durch Tier und Mensch.  Dissertation, Wurzburg, 1905.  (See Lehmann,
     K. B., Arch. Hyg. 67:57-98, 1908.)
                                      13-52

-------
13.7  REFERENCES


Abe, M.  Effects of mixed N02,  S02 on human pulmonary  functions.  Effects of
     air pollution on the human body.  Bull. Tokyo Med. Dent. Univ. 14:415,
     1967.                                                          ~

Amdur, M.  Animal studies on  sulfur  acids  and particulates.  Proceedings of
     Conference, Health  Effects of Air Pollutants.  U.S. Government Printing
     Office, Washington, DC,  1973.   pp.  175-205.

Amdur, M. 0.  The long road from  Donora.   1974  Cummings Memorial Lecture.  J.
     Am. Ind. Hyg. Assoc. 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 subjects.  Arch.  Ind.  Hyg. Occup. Med. 6:305-313, 1952.

Andersen, I., P. L. Jensen, S.  E. Reed,  J. W. Craig, D. F. Praetor, and 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.  Determination of  Odor  Thresholds for  53
     Commercially Important Organic  Compounds.  The Manufacturing Chemists'
     Association, Washington,  DC, January  11, 1968.

Avol, E. L., M. P. Jones, R.  M. Bailey,  N. N. Chang, M. T. Kleinman,  W.  S.
     Linn, K. A. Bell, and J.  D.  Hackney.  Controlled  exposures of  human
     volunteers to sulfate aerosols.  Am.  Rev.  Respir. Dis.  120:319-326,  1979.

Bates, D. V., and M. Hazucha.   The short-term effects  of  ozone  on the lung.
     In:  Proceedings of the  Conference  on Health Effects  of Air Pollutants.
     Serial No. 93-15, U.S. Government Printing Office, 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 and Hackney 1977.
                                    13-47

-------
Bell, K. A., W. S. Linn, M. Hazucha, J. D. Hackney, and D. V. Bates.
     Respiratory effects of exposure to ozone plus sulfur dioxide  in  Southern
     Californians and Eastern Canadians.  J. Am. Ind. Hyg. Assoc.  38:696-706,
     1977.

Burton, G. G., Corn, M., Gee, J. B. L., Vassallo, D., and Thomas,  A.   Absence
     of "synergistic response" to  inhaled low concentration  gas-aerosol  mixtures
     in healthy adult males.  Presented at 9th  Annual Air Pollution Medical
     Research Conference,  Denver,  Colorado, July 1968.

Burton, G. G., M. Corn, J. B. Gee, C.  Vasallo,  and A. P. Thomas.   Response  of
     healthy men to inhaled concentrations of gas-aerosol mixtures.   Arch.
     Environ. Health 18:681-692, 1969.

Bushtueva  et al. 1960.

Bushtueva,  D. A.  New  studies of the effect of  sulfur dioxide and  of  sulfuric
     acid  aerosol on reflex activity of man.  Jji:  Limits of Allowable Concen-
     trations  of  Atmospheric  Pollutants.  Book  5, B. S.  Levine,  translator,
     U.S.  Department of Commerce,  Office  of Technical Services,  Washington,  DC,
     March 1962.  pp.  86-92.

 Bushtueva,  K.  A.  The  determination of the  limit of  allowable concentration of
     sulfuric  acid  in  atmospheric  air.  ^n:   Limits  of  Allowable Concentrations
     of Atmospheric Pollutants.  Book  3,  B. S.  Levine,  translator, U.S.  Department
     of Commerce, Office  of Technical  Services, Washington,  DC,  1957.   pp.  20-36.

 Bushtueva,  K.  A.  Threshold reflex effect of  SO- and sulfuric acid aerosol
     simultaneously present  in  the air.   In:  Limits of Allowable  Concentrations
     of Atmospheric Pollutants.  Book  4,  B~ S.  Levine,  translator, U.S.  Department
     of Commerce, Office  of Technical  Services, Washington,  DC,  January 1961.
     pp.  72-79.

 Cralley,  L.  V.   The Effect of irritant gases  upon the rate  of ciliary activity.
     J. Ind.  Hyg. and  Toxicol.  24:193-198,  1942.

 Dubrovskaya,  F-  I.  Hygienic  evaluation of  pollution of atmospheric air of a
      large city with  sulfur dioxide gas.  In:   Limits of Allowable Concentrations
     of Atmospheric Pollutants.  Book  3,  B. S.  Levine,  translator, U.S.  Department
     of Commerce, Office  of Technical  Services, Washington,  DC., 1957.  pp. 37-51.

 Frank,  N.  R.   Studies  on  the  effects  of acute exposure  to  sulfur dioxide in
     human subjects.   Proc. R.  Soc. Med.  57:1029-1033,  1964.

 Frank,  N.  R.,  M.  0. Amdur, and  J.  L. Whittenberger.  A  comparison of the acute
     effects  of SO- administered alone or in  combination with  NaCl particles
     on the respiratory mechanics  of  healthy  adults.   Int.  J  Air Water Pollut.
     8:125-133,  1964.

 Frank,  N.  R.,  M.  0. Amdur, J. Worcester,  and  J.  L.  Whittenberger.
     Effects  of acute  controlled exposure to  S0?  on  respiratory mechanics
     in healthy male adults.  J. Appl.  Physiol.  17:252-258, 1962.
                                    13-48

-------
Frank, R. ,  C.  E.  McJilton, and R. J. Charlson.  Sulfur oxides and particles;
     effects on pulmonary physiology in man and animals,   ^n:  Proceedings of
     Conference on Health Effects of Air Pollution.   National Research
     Council,  Oct. 3-5, 1973.  Serial No. 93-15, U.S.  Government Printing
     Office, Washington, DC.

Go'kenmeijer, J. D. M. ,  K. DeVries, and N. G. M. Orie.   Response of the bronchial
     tree to chemical  stimuli.  Rev. Inst.  Hyg. Mines (Hasselt) 28:195-197,
     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-Sulfanates in human plasma following
     inhalation of sulfur dioxide.  J. Am.  Ind. Hyg. Assoc. 315:288-291, 1974.

Hazucha, M.  , and D. V.  Bates.  Combined effect of ozone and sulphur dioxide on
     human pulmonary function.  Nature (London) 257:50-51, 1975.

Holmes, J.  A., E. C. Franklin, and R. A. Gould.  Report of the Selby Smelter
     Commission.   Bulletin 98,  U.S. Department of the Interior, Bureau of Mines,
     Washington,  DC, 1915.

Horvath personal  communication.

Horvath, S.  M., and L.  J. Folinsbee.  Interactions of Two Air Pollutants,
     Sulfur Dioxide and Ozone, on Lung Functions.  Grant ARB-4-1266, California
     Air Resources Board, Sacramento, CA, 1977.

Jaeger, M.  J., D. Tribble, and H. J. Wittig.   Effect of 0.5 ppm sulfur
     dioxide on the respiratory function of normal and asthmatic
     subjects.  Lung 156:119-127, 1979.

Kisskalt, K.  Uber den Einfluss der inhalation schwelfiger Sa'ure auf die
     Entevickelung der Lungentuberculose:  Ein Bietrag zum Studien der Gewer-
     bekrankheiten.  Z. Hyg. 48:269-279, 1904.

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.

Koenig, J.  Q.   Inhaled SO?-NaCl in young asthmatics.  Environ.  Res.
     In press, 1979.

Koenig, J.  Q., W. E. Pierson, and R. Frank.   Acute effects of
     inhaled SO- and exercise on pulmonary function in asthmatic
     adolescents.  J.  Allergy Clin. Immunol.  64:154, 1979.

Kreisman, H.,  C.  A. Mitchell, H. R. Hosein, and  A. Bouhuys.  Effect of  low
     concentrations of sulfur dioxide on respiratory function  in man.   Lung
     154:25-34, 1976.
                                   13-49

-------
Lawther and Bond 1955.

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 liber den Einfluss  technisch  und  hygienisch
     wichtiger Case und Dampfe auf den Organismus.  VI.   Schwefliger  Sa'ure.
     Arch. Hyg. 18:180-191, 1893.

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, 1979-1980.

Mcllroy, M. B., R.  Marshall,  and R. V. Christie.  Work of breathing in  normal
     subjects.  Clin. Sci. 13:127-136, 1954.

McJilton,  C. E., R.  Frank, and R. J. Charlson.  Influence of relative
     humidity on functional effects of an inhaled S0?-aerosol  mixture.
     Am.  Rev. Respir. Dis. 113:163-169, 1976.       *

Melville,  G. N.  Changes  in specific airway conductance  in  healthy  volunteers
     following  nasal  and  oral inhalation of S09.  West Indian  Med.  J.  19:231-235,
     1970.                                     *

Nadel,  J. , H. Salem,  B. Tamplin, and Y. Tokiwa.  Mechanism  of  bronchoconstriction
     during  inhalation of sulfur dioxide.  J.  Appl. Physiol. 20:164-167, 1965.

Nadel,  et  al.   Arch.  Environ. Meth. 10:175-178, 1965.

Nakamura,  K.  Response of pulmonary airway resistance  by  interaction of aerosols
     and  gases  in different physical and chemical nature.   Nippon Eiseigaku Zasshi
     19:38-49,  1964.

Newhouse,  M. T., -M.  Dolovich, G. Obminski, and R. K. Wolff.  Effect of  TLV
     levels  of  S0? and H?SO.  on  bronchial clearance  in exercising man.   Arch.
     Environ. Heafth  33:24-32, 1978.

Ogata,  M.  Uber die  Giftigkeit der  schweffigen Sa'ure.  Arch. Hyg. 2:223-245,
     1884.                                                         -

Reichel,  G.  Die Wirkung  von  Schwefeldiovyd auf den AtemivegsviIderstand
     des Menschen.   Verh. Dtsch. Arbeitsmed.  12:135-141,  1972.

Ryazanov,  V. A.  Sensory  Physiology as Basis  for  Air  Quality Standards.  Arch.
     Environ. Health  5:479-494,  1962.

Sackner, M. A., et al.  Effects  of  sulfuric acid  aerosol  on cardiopulmonary
     function of dogs, sheep  and humans.  Am.  Rev.  Respir.  Dis.  118:497-510,
     1978.                                                        	
                                    13-50

-------
Schlesinger, R. B., M. Lippmann, and R. E. Albert.  Effects of Short-term
     Exposures to  Sulfuric Acid and Ammonium Sulfate.  J. Am. Ind. Hyg. Assoc.
     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.

Sim, Van M., and R. E. Pattle.  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., and Frank, N. R.  The Uptake and Release of SO, by the Human
     Nose.   Arch.  Environ. Health 12:725-728, 1966b.

Tomono, Y.   Effects of SO, on human pulmonary functions.  Sangyo  Igaku
     3:77-85, 1961.      *

Toyama, T.   A medical study of aerosols.  I.  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.

von Neiding, 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 NO,,  0, and SO,.  Int. Arch. Occup.  Environ.
     Health  43:195-210, 1979. J       i

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,
     1975.
                                    13-51

-------
Wolff et al. 1975a.

Wolff et al. 1975b.

Yamada, J.  Untersuchunger uber die quantitative Absorption der Dampfe einigei"
     Sauren durch Tier und Mensch.  Dissertation, Wurzburg, 1905.   (See  Lehmann,
     K. B., Arch. Hyg. 67:57-98, 1908.)
                                   13-52

-------
               Chapter 14.  Epidemiology Studies Corrigenda
     Before listing specific minor errata (insertions/deletions) for text contained
in Chapter 14 of the April 1980, External Review Draft, several general  comments
should be noted regarding planned reorganization and certain other major changes
to be made in the chapter.  The chapter reorganization and other changes are
based in part on comments received both from within and outside EPA
and further technical information obtained since finalization and release of the
April, 1980, external review version of the chapter.
     In regard to reorganization of the chapter, the present introduction (Section
14.1) discussing general epidemiology methodology considerations and the discussion
of air quality measurement considerations (Section 14.2) are to be retained,
with certain specific revisions noted later.  Similarly, much of the later discussion
of caveats and limits contained in Section 14.6 is to be retained, again with certain
revisions as noted later.  The materials between the above sections (dealing with
evaluation of specific studies), however, is to be reorganized using the following
format:
     14.3 - Acute Exposure Effects
          14.3.1 - Mortality
          14.3.2 - Morbidity
                   Adults
                   Children
     14.4 - Chronic Exposure Effects
          14.4.1 - Mortality
          14.4.2 - Morbidity
                   Adults
                   Children

     Resequencing of the discussion of specific studies in the above manner both:
(1) better matches the presentation format followed for summary text and tables later
in Chapter 14 and in Volume I; and (2) better organizes discussion
of technical data related to development of health criteria for short-term  (24-hour)
or long term (annual average) ambient air quality standards, respectively.  Text on

-------
the bottom of pg. 14-14 is, therefore, to be revised to reflect the reorganization

of subsequent materials in Section 14.3 and 14.4, and to indicate that a new

Section 14.5 will contain integrative summary and interpretation discussion

materials of the type dealt with under the present Section 14.6.

     Also, at the end of Section 14.1, following the above revisons of text at

the bottom of Pg. 14-14, new text to be inserted is to note that certain criteria

are to be followed, generally, in the selection of specific studies to be

discussed in detail under new Section 14.3 and 14.4.  The criteria to be employed

in narrowing down the detailed discussion to potentially key studies are as

follows:

     1.  The studies have been peer-reviewed and published or are
"in press" to be published, such that final versions of the published reports
are (or can be made) publically available.  Also, the results or analyses contained
in the published reports represent completed analyses of data, rather than "preliminary"
analyses subject to change before publication in "final" form.

     2.  The published information is sufficient to allow for reasonably clear
evaluation of the methodology employed in collection and analysis of
data leading to  the results reported  (or such information is satisfactorily
alternatively obtained or clarified).

     3.  Evidence exists for major confounding factors having been appropriately
controlled for or taken into account  in the published analyses, e.g. especially
temperature in studies of acute effects and smoking, race, and socioeconomic
status in chronic exposure studies.

     4.  The published results, together with any alternatively obtained
information, appear to provide a reasonably clear potential basis by which to
define quantitative dose-effect or dose-response relationships for health
effects associated with sulfur oxides and particulate matter. Emphasis
is to be placed  on studies yielding information on effects associated
with exposures below 1000 yg/m  (24 hour average) that are most germane for
present criteria development purposes.

     In addition to detailed discussion of studies meeting all of the above

criteria, certain other studies failing to meet one or more of the criteria may

also be considered or reviewed, based on their findings likely providing

important information bearing on the  overall assessment of epidemiologic evidence

of significance  for present purposes.
                                        -2-

-------
     Following the above modifications of introductory materials in Section 14.1,

the next section (14.2) on air quality measurement considerations is to be expanded

to include summary statements derived from Chapter 3 discussions of intercomparisons

between estimates of particulate matter levels obtained by various measurement

techniques.  Thus, immediately before the start of Section 14.3 at the bottom of

Pg. 14-34, there is to be inserted a relatively brief summary discussion concerning

the main conclusions derived from Chapter 3 regarding intercomparisons of particulate

matter measurement data obtained by means of high-volume (TSP) sampling, British

smoke (BS), and other (e.g., the AISI) particulate measurement techniques.  Note

will be made of the difficulties and limitations inherent in making such intercomparisons

and, based on this, the particulate matter measurement results employed in

particular studies discussed in Sections 14.3 and 14.4 are to be expressed there

only in terms of units appropriate for the specific measurement methodology
                                    o
employed (e.g., in CoH units or yg/m  of either BS or TSP).  Only following

summarization of study results in terms of such original measurement units are

discussions of any potential interconversions between measurement units to be

included as part of later summary and conclusions materials in Section 14.5 and

elsewhere (e.g., Volume I).

     No attempt will be made here to list myriad changes in sequencing of text

materials now under Sections 14.3 to 14.5 of the April, 1980, External Review

Draft necessary to accomplish the reorganization of materials into the new Sections

14.3 and 14.4 listed under the revised format outlined above.  Rather, only

certain planned substantive content revisions (mainly large text deletions) of

existing materials -in Sections 14.3 to 14.5 of the April draft are summarized

below before presentation of more detailed lesser errata corrections for the


Chapter.
                                        -3-

-------
     On pg. 14-47, Table 14-7 is to be deleted along with revisions and reduction
in text at the bottom of pg. 14-46 and top of pg. 14-48, discussing the Osaka and
Rotterdam studies.  The revisions are to note that the Biersteker    and Watanabe
studies report data or information on quantitative dose-effect relationships, but
insufficient information was reported to allow for evaluation of the adequacy of
study design (especially in regard to adjustments made for temperature effects).
     On pg. 14-51 to 14-52, the discussion of multiple regression studies by
Hodgson,158 Buechley,159'160 Lebowitz,170 and Lebowitz et al.171 is to be shortened
considerably. Note is to be made that these studies provide mainly qualitative
data on associations between sulfur oxides (SO ) or particulate matter (PM) and
                                              A
observed mortality effects but generally do not provide clear data on quantitative
levels of SO  or PM likely associated with such effects, with the exception of
            X
the Beuchley studies    '     finding significant increases in mortality when 24
hour mean S02 levels exceeded approximately
     On pg. 14-56, 14-58, 14-59, the extensive quotation of material from Holland
et al.    concerning the Martin studies '   is to be deleted.  Also the rest of
the text on pg. 14-59 is to be deleted, along with the text concerning the detailed
additional analysis of mortality effects observed in the Martin studies6'11 that
runs from pg. 14-60 to 14-65.  Similarly, the rest of the text on 14-65 and 14-66
(top) on further analysis of the 1975 London and 1975 Pittsburgh episodes is to
be deleted.  The available reports or discussions of the 1975 London episodes do
not allow for more detailed analyses of the type indicated on pg. 14-65; and the
available report by Riggan et al.  (1977)341 on the Pittsburgh episode contains
information only on preliminary analyses that remain to be more definitively
completed, peer-reviewed and published.
                                      -4-

-------
     On pg. 14-70 to 14-71, table 14-16 on qualitative mortality studies is to be



moved to the appendices and referred to in Chapter 14 text only briefly, in

                                                                      I QQ
summary terms.  Also, certain studies, such as those by Buck and Brown


                19                     20
Wicken and Buck,   Burn and Pemberton,    are to be added to qualitative studies


                                                           21 2"?
listed in Table 14-16.  Comments on the Winkelstein studies      and analyses



presented on pg. 14-73 to 14-81 would be especially valuable in order to resolve



whether to retain such detailed discussion of these results as important quantitative



findings or whether to simply list the Winkelstein results in a table of qualitative



findings.



     On pg. 14-90, the summary table (14-21) is to be revised to show the 24 hour



particulate levels at which mortality effects were observed only in terms of the



original units (yg/m  BS; CoH units) in which such data were reported (and not



possible comparable TSP units).  On pg. 14-91, Table 14.22 is to be deleted.



     On pg. 14-93 to 14-95, the Table (14.23) on qualitative studies of air



pollution and acute respiratory disease is to be moved to the Appendices and only



brief summary statements regarding the table kept in the main text of Chapter 14.


                                     177 122 123
Comments on studies by Finklea et al.   '   '    are to be deleted from the



table.



     On pg. 14-96 and 14-97, text revisions are to be made that note the exclusion



from discussion in the April draft of studies carried out as part of the EPA



"CHESS" program.  Also, in that connection, explanatory text will be inserted



stating that:  (1) The manner in which CHESS program study results were reported



and interpreted in summary form in early 1970 publications and in more detail in



the 1974 "Sulfur Oxides Monograph" raised questions regarding possible inconsistencies



in data collection and analyses, as well as interpretation of the reported results;
                                      -5-

-------
(2)  Of particular concern were questions regarding the adequacy of air quality
data measurements (for TSP and SO^, as well as other pollutants) upon which key
quantitative conclusions were based regarding possible air pollution-health
effects relationships; (3)  Many of the outstanding questions regarding the CHESS
studies remain to be clearly resolved and, until such time that they are, the
potential usefulness of such studies is extremely limited in terms of yielding
well-defined information on air pollution-health effects relationships as they
might pertain to development of health effects criteria; (4)  Based on the above
considerations, CHESS program data sets and analyses will not be further discussed
in criteria document drafts, unless questions regarding accuracy of specific data
sets and their analyses have been satisfactorily resolved and reports on them
adequately peer reviewed.
     On pg. 14-102, the last sentence on the page is to be amended to note that,
since measurements of air pollution and pulmonary function reported in the Stebbings
      no                                     p-i /-
et al.   study and the Stebbings and Fogelman    study were not initiated until
after the peak of the 1975 Pittsburgh episode, it is impossible to clearly relate
any health effects observed in those studies to  specific S02 or PM levels. Consequently,
                                                    Op pi C
the rest of the detailed discussion of the Stebbings  '    studies on pg.  14-103
and top, pg. 14-104, is to be deleted.
     Also, on pg. 14-105 and 14-106, all text dealing with the Stebbings and
     1QO
Hayes    report on a 1971-1972 New York "CHESS"  Program panel study is to be
deleted, as per statements made earlier concerning exclusion from discussion of
CHESS Program studies due to unresolved questions regarding their reported results
and interpretations.  Similarly, the detailed text discussing the French et
al.306 New York ARD "CHESS" Program study is to  be deleted from top, pg. 14-109
to top, pg. 14-133, including Tables 14-24 to 14-26 on pg. 14-110 to 14-112.
                                     -6-

-------
     On pg. 14-107 to 14-109, the discussion of the studies71' 205'210 by McCarroll
and associates is to be shortened (and reference to quantitative estimates of
pollutant levels associated with observed health effects deleted).  Consideration
will be given to including brief summaries of those studies in an appropriate
table of qualitative studies.
     On pg. 14-113, the detailed discussion of the Kalpalzanov et al.    study is
to be deleted and its results only briefly summarized in an appropriate table of
qualitative studies.
     On pg. 14-115 to 14-116, the discussions of the Kevany15 and Heinman54
             72 73
and Sterling   '   studies are to be deleted; the results of each are  to be summarized
in an appropriate table of qualitative studies.
     The discussion of the Fletcher et al.    and Angel  et al.   studies on pg.
14-117, is to be moved to the new Section 14.4 on chronic exposure effects,
rather than remaining under the text on acute effects as presently situated.  Note
will be made of difficulties in estimating quantitative levels of SO   or PM
                                                                    /\
associated with observed health effects, and other problems, which argue for
these studies to be included as part of an appropriate table of qualitative
studies.
     The text on the Verma et al.65 study (bottom, pg. 14-120; top, 14-121) is to
be deleted and that study only mentioned briefly in an appropriate table of
qualitative studies.  Also, on pg. 14-121, the discussion of the "Ministry of
               CO
Pensions" study   is to be moved to the new Section 14.4 on chronic effects; note
will be made of problems with air monitoring data used in that study and other
methodological problems which mitigate against useful quantitative information
being extracted for present criteria development purposes.
                                          -7-

-------
     On pg. 14-123, the Shephard et al.327' 328 discussion is to be deleted and
                   Iftfl
the Lebowitz et al.    study results (including top pg. 14-124) briefly summarized
in a table of qualitative studies.
     Table 14-29, on pg. 14-125 is to be revised as follows:   (1) participate
matter measurement data will be expressed only in terms of BS or TSP as originally
reported, with a column being added for BS in the table headings along side the
TSP (yg/m3) heading; (2) "qualitative" studies will be deleted from the table,
including those by McCarroll et al.,205'206 Cassell et al.,208' 209 Greenburg et
al.,196 Stebbings et al.,216 Stebbings and Hayes,190 Heimann,54 and British
                     fi?
Ministry of Pensions.
     On pg. 14-131 to 14-134, certain of the studies included in Table 14-30 as
yielding qualitative information on air pollution-health effects might be appropriately
deleted, except for ones providing data specifically elucidating associations
between health effects and SO  or PM.  Comments on which studies should be retained
                             J\
as meeting such criteria, and which should be deleted as useless for present
purposes, would be helpful.
     The extensive discussion of the Irwig et al.98 and Melia et al.^new ref~ #342^
reports on the British school children study, on pg. 14-139 to 14-149 (top), is
to be deleted.  Essentially no reference in the main body of Chapter 14 is to be
made to either the Irwig et al. or Melia et al. reports in view of the preliminary
nature of the analyses alluded to in the referenced papers and the lack of any
peer-reviewed published reports on "final" or completed analyses of the British
school children study.
     On pg. 14-151 (top), the discussion of the study by Tsunetoshi et al.38 is
to be deleted and the results briefly summarized in a qualitative studies table.
                                    -8-

-------
Similarly, the Suzuki et al.     study discussion on pg. 14-151 (bottom) is to be


deleted and that study summarized in a qualitative studies table, as is also the

                           ?1? ^17     ^1Q           ^10
case for the Toyama et al., l£"3" Tani01* and YoshiiJ|y studies on pg. 14-152.


     On pg. 14-152 to 14-158, all text is to be deleted regarding discussion of

                                                  91 9
the EPA "CHESS" studies reported by Chapman et al.  '  for Utah "CRD" and Chicago


"CRD" prevalence rate data sets.  Also, on pg. 14-158 (bottom) and 14-159 (top)


discussion of the Yoshida et al.176 is to be deleted and results of that study


briefly summarized in a qualitative studies table.


     Comments focusing on the discussion and interpretation of the studies by


Rudnick182 and Douglas and Waller90 on pg. 14-159 to 14-163 would be highly


useful, as would comments on the Lunn et al.  '    studies discussed on pg.  14-

                      1 ft?                    Qfl                 Qfi Q7
163 to 14-165. Rudnick   , Douglas and Waller  , and Lunn et al. °'y/ appear to


to provide at least some reasonably well-defined air quality data by which quantitative


health effects - SO /PM air pollution relationships might be delineated (they
                   J\

have been interpreted by leading experts in such a manner). This, together with


otherwise apparently sound methodological features, argue for these studies being


strongly considered as potential key studies in arriving at final conclusions


regarding the epidemiology data base for SO  and PM.
                                           /\

     On pg. 14-165 to 14-177, all text is to be deleted regarding discussion of


CHESS studies reported by Hammer et al.    and French et al.    (on New York


"LRD" data), French et al.306 (on Utah "LRD" data), and Hammer113'257 (on Southeast


or Birmingham vs. Charlotte "LRD" data).  This is in keeping with statements


presented earlier regarding exclusion of CHESS studies from consideration in view


of questions that remain to be resolved concerning data collection, analyses and


interpretation of results for CHESS Program studies.  Of all the various CHESS
                                        -9-

-------
studies to be deleted at this time, the Hammer113' 257 "Southeast LRD" study
appears to provide the most extensive and thorough data analyses potentially
leading to reliable quantitative estimates of air pollution (SO /PM)-health
                                                               /\
effects relationships. Also, there appears to be a reasonable possiblity of
resolving questions concerning the Hammer study        within the time frame of
finalization of the present document.  Comments on that study would, therefore,
be helpful in determining its possible future consideration for inclusion in the
criteria document as a potentially key quantitative study.
                                                         74-77
     Comments focused on the Van der Lende et al.  studies      discussed on pg.
14-178 would also be quite useful, in view of its  having been interpreted by a
number of experts as yielding important information on quantitative health effects
air pollution (SO /PM) relationships.  Similarly,  comments  would be useful on the
                 /\
        oo                    Q C
Becklake   and Manfreda et al.   studies as potentially finding lack of evidence
of health effects at S02 and TSP levels around 100 yg/m  or less, as discussed on
pg. 14-178 and 14-179.
     On pg. 14-179 (bottom) and pg. 14-180 (top),  the discussion of the Kagawa et
   010  9fiA
al.    '     studies is to be deleted and, at most, briefly  summarized within a
                                                                    87
qualitative studies table.  The same applies for the Zapletal et. al   study
discussed at the top of pg. 14-180.
     Comments would be especially valuable regarding the discussions on pg. 14-
180 to 14-186 regarding the studies by:  Holland et al;101'102 Bennett et al.103;
rolley and Reid112; Ferris115; Mostardi and Leonard177; Mostardi and Martell258;
              215
and Shy et al.    (Cincinnati school children pulmonary function study).  At
least some of these studies appear to provide potentially useful information by
which quantitative health effects - air pollution ,(SO /PM)  relationships might
                                     -10-

-------
be defined, whereas others may be sufficiently flawed methodologically



(e.g. in failure to control for smoking, etc.) so as to be rendered



essentially useless for present criteria development purposes.



     On pg. 14-186 to 14-188, all of the text is to be deleted regarding



the "CHESS" studies reported on by Shy et al.215 (New York pulmonary


                                 ?! ^
function data) and Chapman et al .    (Birmingham and Charlotte pulmonary



function data).



     Comments would be useful regarding the Neri et al .  '   studies,



discussed on pg. 14-189, as well as the other studies discussed on pg.

                                                         OQ

14-190 to 14-195. However, the discussion of Irwig et al.   results, on



pg. 14-193 (bottom), is to be entirely deleted in view of the "preliminary"



nature of the results thus far reported.



     On pg. 14-196 to 14-197, Table 14-40 is to be revised, including:


                                             3                      3
(1) addition of a column heading for BS (yg/m ) along side TSP (yg/m )



and listing of parti cul ate matter measurement data under only one of the



columns according to the original form or units reported for a given


                                                                  1 09
study; and (2) deletion of CHESS Program studies (Goldberg et al . ,



House et al.,108 Nelson et al.,114 Hammer,113'257 Shy et al.,215 Chapman
                                                     99
et al.   ) and qualitative studies (Kerrebijn et al . ,   Yoshida et



al . ,   ) consistent with deletions in text noted above.     The present



Summary and Conclusions section (14.6) of Chapter  14, starting on pg.



14-199, is to be designated as Section 14.5 under  the proposed chapter



reorganization format outlined on the first two pages of the present  -



materials. Reflecting the planned format change, the first paragraph on



pg.  14-199 is to be appropriately revised to note  under points (3) and
                                     -11-

-------
(4) that acute and chronic exposure effects discussions appear under
Sections 14.3 and 14.4, respectively, of the newly reorganized chapter.
Point (5) at the end of the first paragraph is to be deleted.
     On pg. 14-200, the last part of the last sentence of the first
paragraph (text starting with "--not for the purpose...") is to be
deleted as unnecessary. The next paragraph on pg. 14-200 is to be revised
to make reference to Table 14-41 as summarizing the results of key
studies discussed earlier in the chapter as providing valid information
on quantitative relationships between acute exposures to sulfur oxides
or particulate matter and mortality and morbility health effects.
Reference is also to be made to Table 14-42 as containing similar summarization
of key quantitative studies concerning chronic exposure effects.
     Table 14-41, on pg. 14-201 and 14-202, is to be revised as follows:
(1) additional column headings for COH and BS measurement results in
    3                                            3
yg/m  are to be provided along side the TSP (ug/m ) heading; (2) results
for particulate matter measurements will be entered under one of the
three (BS; COH; TSP) columns only, as per the original units or form
reported for a given study; and (3) numerous deletions of entries from
the revised table are to be made.  Such deletions are to include: (a)
the first four sets of entries designated as being for British, Dutch,
Japanese, and USA studies under episodic mortality; and (b) the morbidity
                                      190
study entries for Stebbings and Hayes,    McCc
et al.,208'209 and Stebbings and Fogleman.216
study entries for Stebbings and Hayes,190 McCarroll  et al.,163 Cassell
                                   -12-

-------
     On pg. 14-203, changes analogous to the first two types listed above
for Table 14-41 are to also be made in Table 14-42.  Entries are to be deleted
                                            1 Rfi                         1 K 18
from Table 14-42 for studies by Winkelstein,I0° Zeidberg and colleagues,10"
Hammer et al.,214 Goldberg et al.,109 House et al.,108 Nelson et al.,114
Hammer,113'257, Shy et al.,215 and Chapman et al.213
     From pg. 14-205 to pg. 14-208 (top, before heading for Section 14.6.2),
all text for present Section 14.6.1.1 is to be deleted.  The text under
Section 14.6.2 (pg. 14-208 to 14-214), however, is to remain, as is the text
under Section 14.6.3 (pg. 14-215 to pg. 14-251).
     On pg. 14-245, Figure 14-8 is to be deleted and the differences between
                                                 301     312
evaluations of key studies between Holland et al.    , WHO    and other reviewers
briefly discussed only in new text inserted on pg. 12-244.   Study results  for the
Osaka (1962), Rotterdam (1960's), France (1973), Tokyo (1970), and Southeast
USA (1969-71) entries in the figure will not be discussed.   The mistaken data
entry for "Chicago-(1972)M in the figure actually refers to Mostardi's177'258 studies
in Ohio (1972), and the entry in the key to the right for Apling et al., Waller
(1977-78) London is for Apling et al.; Weatherly and Waller (1977-78) London.
Discussion of differences in the reviewers' evaluations of study results will note
where the particular review "translated" original estimates of health effects-associated
particulate matter levels associated with health effects from original COH or
BS units to approximate corresponding TSP levels.
     Lastly, at the end of Chapter 14, copies of summary tables now appearing
only in Volume I of the document (as Tables 1-19 to 1-22) are to be inserted to
summarize the evaluations of different reviews for key quantitative studies.
                                  -13-

-------
The tables will be the same as present Tables 1-19, 1-20, and 1-21, except
for those modifications discussed for those tables earlier, under present
corrigenda materials for Chapter 1.  Appropriate text will also be inserted
to discuss the reviewers' evaluations summarized in the tables and definite
statements made regarding which studies appear to be generally viewed as
being valid and conclusions that can appropriately be drawn based on those
study results.
                                   -14-

-------
  14.   EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF ATMOSPHERIC  CONCENTRATIONS
             OF SULFUR DIOXIDE AND PARTICULATE MATTER ON HUMAN  HEALTH
14.1  INTRODUCTION
     In the preceding chapters of this volume (Chapters 11,  12,  and  13),
Information was assessed regarding the uptake, deposition,  and absorption  of
sulfur oxides and particulate matter and various health effects  demonstrated
to be associated with these pollutants by means of animal  toxicology and human
clinical studies.  Such studies offer the advantage of being able to study
biological processes specifically associated with particular pollutant
exposures under highly controlled laboratory conditions.
     The animal toxicology studies are particularly valuable in providing  both
qualitative characterization of the full ranges of health effects caused  in
mammalian species by SOp and particulate matter exposures and information  on
the mechanisms of action underlying such effects.  However, considerable
caution must be applied in extrapolating quantitative dose-effect relationships
defined in animal studies to humans.
     Of course, some such definition of quantitative dose-effect relationships
can be more directly ascertained by means of human clinical studies.  Such
studies, however, are also somewhat limited, in terms of the kinds of health
effects potentially characterized by them.  More specifically, only the effects
of short-term (a few hours) exposures or perhaps a few repeated short exposures
are typically investigated in such studies.  Also, the nature of the effects
studied are generally limited to detection of onset of relatively transient
changes in pulmonary or cardiac functions and, at times, related physiological
or biochemical parameters.  In addition, restrictions arising from  human  rights
                                   14-1

-------
considerations often result in limitations that preclude thorough investigation



of health effects experienced by the most sensitive members of the population.



     Community health (epidemiology) studies offer several  advantages that go



beyond what can be determined by animal toxicology or human clinical  studies,



in that health effects of both short- and long-term pollutant exposures (including



the presence of other pollutants) can be studied and sensitive members of



populations at special risk for particular effects identified.   In addition,



epidemiology evaluations are not limited to the study of more or less transient



physiological or biochemical effects but also include investigation of both



acute and chronic disease effects induced by SO  and particulate matter pollution
                                               A


and associated human mortality as well.  Information from epidemiology studies,



then, together with the results from animal and human clinical studies, help



to provide more complete understanding of the health effects of environmental



air pollutants such as sulfur oxides and particulate matter.



     Before proceeding with evaluations of epidemiology studies in this chapter,



certain methodological considerations should be discussed as background for



the critical review that follows.  Epidemiology is the study of the etiology



and natural history of disease in populations.  Epidemiologic studies examine:



(1) the distribution of diseases in populations and their subgroups;  (2) the



interplay of agent, host, and external environment; and (3) epidemics or



changes in the homoeostasis in populations.  As such, epidemiologic studies



are important in understanding air pollution.  They can be  conducted  in clinical



settings or among populations in communities (or subcommunities)  to examine



the relationship between air pollution concentrations and health  effects.



Such relationships may be found to be spurious (accidental),  indirect (occurring



in the same place and/or time), or direct (such as when subclinical or clinical
                                   14-2

-------
disease nearly always follows exposure).   The consistency of a relationship  in


different times and places and the strength of that relationship will  generally


determine the likelihood of the relationship being causal.   The tendency for


certain events to occur together (dose and response or stimuli and response)

                                                                    93*i 937  93ft  94?  9A4
also strengthens the conviction that the relationship may be causal.    '•''


A. B.  Hill added the concepts of the specificity of results and the demonstration


of a biological gradient as other patterns of results highly indicative of


likely causal relationships existing.


     There are, however, complications associated with estimating dose and


measuring effects by means of community health studies.   For example,  certain


competing risks, such as cigarette smoking and occupational exposures  must be


identified and taken into account in experimental design and statistical


analyses of study results.  Other confounding factors, such as socio-economic


status, race, and weather, must also be evaluated.  In all studies, the researcher


accepts the exposures as they occur.  Exposures are not subject to manipulation,


although ambient levels change during the course of a study.  It is always


difficult to evaluate the long-term effect of large fluctuations in the levels


of air pollution around a given mean value compared to small  fluctuations


around the same mean.


     Population studies involve the comparisons of groups of  people residing


in different areas (spatial) or the change in certain measurements in the


groups over time (temporal).  There is no guarantee that the  populations


residing in different areas are anything like each other and  lifelong exposure


is usually not considered.  There are always possible errors  and biases,


effects of response rate, effects of perception,  and various  methodological


problems of both a measurement and a statistical  nature.
                                   14-3

-------
     Many epidemiological studies of the health effects of air pollutants rely



on descriptive methods.  When possible, covariables and confounding variables



are described, and occasionally used in analysis.   Health indices nay use



available data such as mortality statistics.   Analytical approaches are more



likely to involve the collection of a greater amount of data on individuals



and more reliance on statistical analysis.   They usually provide information



on other key variables in addition to the specific dependent and independent



variables (health indices and exposure levels, respectively).   They usually



test specific hypotheses, searching for associations between occurrence of



particular diseases and potential causal agents.  Prospective studies are



those which start with risk or causative factors and proceed to the disease.



They usually employ standardized statistical  measurements and have better



contro,! of other variables.  Retrospective studies (like case-control studies)
      i


start with the disease and examine risk or causative factors.   They encounter



difficulties in (1) ascertaining cases (a group of individuals who meet certain



criteria for the presence of a certain disease process) and controls, (2)



obtaining pertinent records, and (3) obtaining data on and measuring of risk



factors.  Such studies, however, at times lack the best probability estimates



of risk.  Epidemiological studies in the clinical setting, for example, involve



the use of clinical techniques on patient populations to assess the effect  of the


                                  249
environment on cases and controls.


                                                               3t/'z
     Health risks may be evaluated, according to Lowrance (1976),  in four



steps:  identifying health effects; quantifying these effects at various



concentrations of pollutant; estimating the number of people exposed at those



concentrations; and calculating overall health  risks associated with the given



degree of concentration.   In this regard, it  is more difficult to  determine



the health effects of specific amounts of sulfur oxides emitted by specific
                                   14-4

-------
sources, or suspended particulate matter of specific  types  emitted  by  specific



sources than it is to demonstrate a health effect of  pollution  in general.   In



addition, acute, readily detectable effects and chronic  and often delayed



effects due to cumulative exposures must be of concern.   Also,  there are



limits to relating the varieties of effects to combinations of  pollutants,



isolating of the effects of individual  pollutants, and isolating of air



pollution effects from other causal contributing factors.



     Making valid observations of air pollution exposures are probably the



most difficult aspects of community studies.   To make observation even more



difficult, there is lack of consistency in the measurement techniques  used



over time in the United States and in other countries.  (See Chapters  2,  3,



and 5.)  No completely satisfactory methods, for example, have  been devised



for deriving equivalency relationships among data for smoke, CoHs,  or  high-volume



results, although some efforts have been made (see Chapter 3).   Also,  the



specific measure of particulate air pollution (BS, TSP,  CoH, etc.)  most  relevant



to health effects is not yet clearly established.  Few particles greater than



15 urn in aerodynamic equivalent diameter appear to reach the lower  respiratory



tract; but the possible significance of larger particles still  needs  exploration.



The relative importance of individual physical/chemical  characteristics  of



fine and coarse mode aerosols needs further exploration.  (See Chapters  2, 6,



and 11).



     In studying the health effects of particulate matter, one difficulty is



the variety of ways in which particulate pollution has been measured.   Most of



the measurements of particulate matter made in Great  Britain and on the European



continent have used the British Standard Smoke (BS) method.  This  is a nongravi-



metric method, using the light reflectance from  a stained  filter paper.   The



reflectance is calibrated against  a standard Coal Smoke and given  in ug/m .
                                   14-5

-------
In essence it measures the blackness of the spot.   The interpretation  of


standard smoke measurements is influenced by the relative prevalence of black


and white, grey, or other colored particulates.   This method collects  the


smaller particle sizes that can penetrate into and be deposited deeply in  the


lung.  Comparisons have been made in Great Britain between British Standard


Smoke and total suspended particulates (TSP) as measured by the high-volume


sampling methods; and TSP values have been found to generally be consistently

                                                 3
higher than BS values at BS levels below 500 ug/m , reflecting the fact that


high-volume samplers collect particles over a wider range of sizes.  Some  of


these particles are not likely to penetrate into the lung, but can be  deposited


in the upper airways—nose and pharynx—where they can have an effect  either


directly or secondarily when swallowed.  From certain British data and other


analyses discussed in Chapter 3, a correction factor can be applied to "covert"


British Smoke data to total suspended particulates as measured by the  high-volume


method, the measure of particulate pollution in many studies in the United


States.  Other  studies, especially in New York, have measured coefficients of


haze (CoH).  Only limited information currently exists, however, regarding the


relating of this measure to TSP measurements.


      There are  very few pollutants which have been measured over long periods


of time in a great number of cities.  This shortage of data is associated with


two  related problems.  First, to the extent that the variation in the available


air  pollution data does not reflect the variation of all mortality- or morbidity-


inducing pollutants, the estimates of the effect of sulfur  oxides and partic-


ulate matter may be biased.  Ambient air pollution represents  a  complex mix  of


materials, which makes the identification of the causative  agent, or  agents,


difficult.  Thus, sulfur oxides or particulate  matter  levels  may represent


indices of pollutant mixes containing other toxic  agents  more  directly associated


with health effects found to vary with SO  and  particulate  matter air concentrations


                                   14-6

-------
     A third feature of many pollution data sets is significant colinearity.
In general, places which have high particulate levels also tend to have  high
SO- levels.  Although this does not limit our ability to find a "pollution"
effect, it does limit an effort to partition the effect among the various
pollutants being considered.  With coal burning, for example, concentrations
of S02 and particulate matter tend to fluctuate together, making it difficult
to separate the relative contribution of each pollutant to any effects  seen.
     An additional difficulty in relating air quality to health is the  possi-
bility of a lag between an initiating exposure and its effect.   The latency
between the initiating insult and the detection of cancer is often many years
and some health effects of air pollution may be subject to similar delayed
response.   On the other hand, a high concentration of sulfur oxides or  partic-
ulate matter may immediately initiate some responses.  In reality, time lag  is
a complex problem involving the weighted average of exposures in various time
periods.  However, almost all studies use limited data on lagged exposure and
most use only current air quality to proxy the previous exposures.  In  serial
measurement studies, the failure to consider the appropriate lagged exposures
will probably result in biasing the estimated effect toward zero.
     Many observational studies have estimated exposures from data obtained at
monitoring sites used to represent large areas, 2 to 5 km in radius.  Thus,
measurements at these sites may not correspond to exposure for some individuals
in the area respresented.   The estimate of exposure  is even  less representative
for persons working in other areas or significantly  exposed  at work.  In
addition,  most persons spend more time indoors where the air pollution mix can
be quite different.
                                   14-7

-------
     In serial measurement studies, the average exposure in the community may



not equal the ambient air quality at the monitoring site.   However,  if a



change in air quality at the monitoring site corresponds to a proportional



change in the community exposure, the monitored air quality can be used as a



surrogate for actual exposure.   Cross-sectional studies present a different



problem when using data from a central monitoring site to measure exposure.



The relationship between community exposure and central station ambient air



quality may change from community to community.  When many monitoring sites



have been selected to monitor sources, it is possible that the dependence



between community exposure and monitored ambient air quality is a function of



the air quality.



     Many studies have found that meteorological factors help determine ambient



pollutant levels.  Many studies have found that meteorological factors affect



health.  There  is obviously a complex interaction between meteorological



conditions and  air pollutant levels in space and time.  The meteorological



variables which have been shown to be critical include:  temperature, relative



humidity, wind  speed (and direction), precipitation, and the adiabatic lapse



rate.  Also included are barometric pressure, solar radiation, and other



meteorological  indices.  Studies in which the meteorological variables are not



considered along with the pollutant levels or exposures are usually judged to



be lacking in critical information or in environmental factors which may



influence the health indices (as well as the factors which may influence  the



pollutant levels themselves).  Occupational exposure to pollutants can certainly



have a major effect on the host, and possibly on the host's family.   Interactions



may also occur between the occupational pollutant  exposure and the ambient



pollutant exposure.   Thus, studies of acute and/or chronic effects of  the
                                   14-8

-------
S02/TSP complex should consider the occupational  exposure effects  as  well.



Lifelong exposure to other pollutants from any source will  influence  chronic



diseases.   Housing ventilation, filtration, the generation of pollutants  in



Indoor environments, and temperature and humidity conditions 1n those environ-



ments will all have a relative role in the influence on human health.   As



such, they play a significant role in the effects of the SO./TSP complex  on



the health indices.  The status of the host and the host's history and genetic



makeup will influence the ways the pollutants may have an effect and  on what



indices.



     In addition to the SO^/TSP exposure variables, and the health indices



(the independent and dependent variables, respectively), there are many



variables which may act as either covariables or intervening, confounding,  or



spurious variables.  In addition, there are temporal and spatial factors  which



must be considered.  Covariables are those factors which also help determine



occurrence of and variation in the dependent variable or the independent



variables.  Intervening variables are those factors through which an independent



variable may have an effect on a dependent variable.  Confounding variables



are those factors which, because of their direct or indirect relation to



either dependent or independent variables, have a tendency to confound the



picture unless they are taken into account.  Spurious variables are those



factors which happen to be totally unrelated variables that  fluctuate in time



or space in a parallel fashion to either the dependent or independent variable,



and thus may be associated with either one due to the influence of variable



tijne or the variable space (or similar variables).



     It is important to eventually determine some form of quantitative relation



between the exposure dose and the health effect response.  This will  differ
                                   14-9

-------
with regard to type of response and will always have a time component as an



additional dimension.  Some attempts have been made to do this for health


                  245
status as a whole.



     The quantification of dose-response relationships will yield a family of



curves specific for different health effects and specific for factors of age,



sex, etc., as well as for the addition of other environmental variables.  This



hypothetical family of curves might show that a given increase in exposure



amount may increase the frequency of some effects, whereas those same amounts



may not increase  other health effects.  Susceptible populations may not only



have a curve that is higher than that for nonsusceptible populations, but it



may have a different shape.  Extrapolation of dose-response curves is a form



of theoretical model building or hypothesis generation.  Extrapolation does



not provide the empirical evidence of effect at any given level.



     Dose-response curves could be utilized as sets of damage functions for



pollutants to be  applied to the dose estimates for all segments of the popula-



tion.  Data gaps  may require judgments and assumptions to be used in order to



derive estimates  of  relationships occurring within those gaps.  Although only



estimates, they may  be useful to suggest what changes in dosage may lead to a



relative change of effects in the population exposed.  Absolute change estimates



may be more speculative.  Certainly in a qualitative sense, one would continue



to expect decreases  in overall risk for those effects with decreasing pollutant



levels.



     Demographic  and anthropomorphic measures are usually covariables.  Disease



occurs differentially in males and females, and at different ages.  Disease



may occur differentially in different race or ethnic groups  independent of



social status.  Height and weight (body mass) have been  shown to  be highly
                                   14-10

-------
pertinent in terms of functional characteristics such as lung volume and



pulmonary flows.



     Smoking should be a key variable in the examination of the effects of



pollutants on the health indices.  Other behavioral variables which may influence



the status of the host or susceptibility to certain diseases include:   alcohol



consumption, diet, exposures in recreational activities and hobbies, exercise,



other recreation and other activities including vehicular driving.



     Biological factors in the host which will influence the effect of pollu-



tion on the health indices include:  resistance, susceptibility, immunity,



present disease of the type being studied, and co-morbidity.  Often these are



not measured or measurable.  Co-morbidity and present disease, however, should



be known and considered.  Familiar factors, including genetic factors, and



exposure to microbes that can produce acute illness, also play a role in the



status of the host, and thus, the potential pollutant effects.



     Social economic status and cultural factors will also influence the host,



not only in terms of the possibility of an effect of a pollutant on a host,



but also the perception of the effect and the medical care received by the



host.  In comparing different areas, socio-cultural differences are often



critical.



     The MRC questionnaire or variations thereof has come to be the most



commonly utilized tool to derive health indicators of respiratory disease.



Such questionnaires generally include information on demographic variables,



anthropomorphic variables, acute and chronic  respiratory disease history, and



may also seek information on family respiratory history, occupational  exposure


                                     249
histories, and residential histories.     Standardized  questionnaires  have



become the tool of choice.  Some inter-observer variability with the MRC
                                   14-11

-------
questionnaire, however, has been noted; and variations have been noted with
self-administration of the questionnaires.   Nevertheless, comparisons of
interviewer- and self-administered questionnaires have generally found good
agreement,  (c.f. Wiggins, 1974; Lebowitz,  1980).
     Questionnaires to derive information on acute changes (diaries) have been
developed.  The period of recall is considered critical.  Such diaries have
been utilized most effectively in conjunction with medical practices, house
visits, phone calls, and pulmonary function testing.  Frequent monitoring and
follow-up with direct contact (visits or calls) are considered necessary.
Motivated and understanding subjects have improved the amount and quality of
             234 249
the response.    '
     The most commonly used pulmonary function tests in epidemiological studies
are peak flow and spirometry.  The peak expiratory flow rate (PEF or PEFR) is
the maximum flow rate during a maximum expiratory flow volume (MEFV maneuver).
The instrument in general usage is the Wright peak flow meter.  It is used
often  to measure serial changes.  It predominately shows  large changes in
upper  airway function.  It has a great deal of variability and poor ability to
be calibrated.  However, it is a useful adjunct of acute  studies; it is not
                              234 249
otherwise generally suggested.   '
     Spirometry tests normally measure the forced vital capacity (FVC) and the
forced expiratory volume (FEV).  They are the simplest, most repeatable,
valid, and among the most discriminating tests reflecting mechanics of
          234 249
breathing.   '     The subject must be coached through  the MEFV maneuver.
     Other tests have been used occasionally.  These are  more complex and are
used in specialized studies to look at different properties of  lung
mechanics.234'249
                                   14-12

-------
     Observational studies of the health effects of air pollution  are  sometimes



viewed as natural  experiments in which the exposure to pollutants  varies  over



groups or over time.   However, this view overlooks the effects  of  other factors



influencing mortality or morbidity which may also vary over the study  units.



These factors are  typically not subject to control by the investigator.



Ideally, the influence of such variables is minimal and can be  quantified.   In


                                            231
practice, this ideal  is not always achieved.



     Cross-sectional  prospective studies compare health index differences to



air pollution levels  during the same time period across several locations.



Such studies attempt  to relate differences in community health  indices to



differences in air quality across communities.   The adjustment  for concomitant



variables such as  age, personal habits, and occupation is the most sensitive



part of the analysis  of cross-sectional data.  Retrospective studies start



with the disease and  seek risk or causative factors.  They encounter difficulties:



(1) in ascertaining cases (a group of individuals who meet certain criteria



for the presence of a certain disease process) and controls; (2) in terms of



the inadequacy of the records utilized; (3) in obtaining and measuring risk



factors; and (4) in the lack of true probability estimates of risk.  Prospective



studies are those which start with risk or causative factors and proceed to



the disease.  They usually employ standardized statistical measurements and



have better control of other variables.



     Randomization cannot be used in all cases to  avoid  selection effects.



The influence of extraneous factors is sometimes partially controlled by



studying population groups which are as similar as possible  and which are



exposed to similar environmental conditions except for air pollution  level.



Typically, investigators also use some method of  adjustment  to correct observed
                                   14-13

-------
associations between sulfur oxides or particulates and the health measures for
differences between populations or over time in these extraneous factors.  The
adequacy of these adjustments depends entirely on the selection of factors and
their interrelationships.  Moreover, the degree of success in adjusting for
selection effects is unknown.  Therefore, replication and reanalysis of studies
are essential to establish a pattern of association while minimizing selection
effects.
     Although there have been many literature reviews on S0x and particulate
matter  effects>245-248,251,301,304,107, 311, 313,314 thgy do not a]1 su1t the

purposes of an air quality criteria document.  A more exhaustive and less
personal review assessment than appears in some is necessary.  As a starting
point  in the present assessment, important information discussed in Chapter 3
is  summarized regarding  critical appraisal of SCL and particulate matter air
quality measurements employed  in community health epidemiology studies evaluated
 in  this chapter.  Then,  the  ensuing discussion of epidemiology (community
health) studies  is subdivided  into three main subsections:  Section 14.3 deals
with mortality studies;  Section 14.4 discusses studies relating morbidity to
 short-term pollutant exposures; and Section 14.5 discusses morbidity associated
with  long-term studies.  Within each of these chapter subsections, a number of
different  health end points  are discussed.  For example, under the mortality
section, studies of effects  of acute air pollution episodes on deaths  and
death  rates are delineated,  as well as studies on long-term mortality  trends.
Under  both  the long- and short-term morbidity sections,  studies  are discussed
which  deal with health end points such as chronic bronchitis,  respiratory
diseases,  pulmonary function, and aggravation of cardio-pulmonary symptoms.
The main focus of this chapter is to describe the studies  used  and consider
the interpretation of individual study results.
                                   14-14

-------
14.2  AIR QUALITY MEASUREMENT CONSIDERATIONS



     The critical assessment contained in Chapter 3 of this document regarding



practical applications of measurement approaches employed in Great Britain  and



the United States for determinations of air concentrations of oxides of sulfur



and particulate matter are concisely summarized here as background Information



important for the ensuing discussion of community epidemiology studies.   The



information presented in part concerns published information on the relative



specificity, sensitivity, accuracy, precision, and reliability of the methods



discussed when used under optimum conditions in the hands of technically-expert



analysts.  Much more emphasis, however, is placed on evaluation of results



actually obtained in the course of practical applications of the measurement



methods, often by less technically-skilled personnel.  That evaluation draws



mainly upon published commentary on quality control assessments for the different



applications.  Also, the major focus here is on British and American air



measurement approaches most widely used in acquiring S02 and particulate



matter data utilized in published quantitative community health studies of



interest later.



14.2.1  British Approaches                                            .•??,•



14.2.1.1  British SO^ Measurements—As noted earlier, the  lead dioxide gauge



was used extensively in Britain during the years prior to  1960.  However, use



of the hydrogen peroxide method was gradually interspersed with the  lead



dioxide gauge during the course of the 1950s, often  being  coupled  in tandem,



as it were, with the apparatus for smoke measurements.  Much of the  early



(1950s) British epidemiology data discussed later  in this  chapter  has been



related to S0? measurements obtained by the hydrogen peroxide method, especially



where 24-hr S0? values are used.  Nevertheless,  it  is  useful to compare the
                                   14-15

-------
results obtained with the two methods,  since some British air quality data of

historical interest are derived from the lead dioxide method.

     In 1962, as part of the  establishment of the British National  Air Pollution

Survey, a working party was set up to compare the lead dioxide gauge with the

hydrogen peroxide method, which was then chosen as the standard method for use
                                                                        &/
-------
         v>
         tu
         E
         X
         O

         5
         o

         u
   S


   7


 > 6



$ B

 §

 8 4

 *n _
 O **


 r 2
                       REGRESSION LINE

                       95* CONFIDENCE LIMITS
    •  •    :  i s*T\  l   *
\:   :  wf::.   ' ".'-'

                         '
        I i ! ' V  '
               0     100     200    300    400    BOO    600     700


            CONCENTRATION OF SO2 BY THE HYDROGEN PEROXIDE METHOD pg/m3





Figure 14-1  A comparison of lead dioxide and hydrogen  peroxide methods for

            sulfur dioxide showing wide variations  between  simultaneous

            measurements.   The solid line is the  regression line, and the

            dotted lines  are the 95  percent confidence  limits.  From WSL
                                   14-17

-------
     In other words, estimates of SO,, levels derived from lead dioxide

sulfation rate measurements, especially 24-hr estimates,  can only be roughly

compared with S02 estimates obtained by the hydrogen peroxide method at other

geographic sites or at later times at the same location(s).   Also, from the

data in Figure 14-1, comparisons between sulfation rate readings may only be

meaningful when such readings differ by the equivalent of about 180 ug/m  of

SOp.  Some of the types and magnitudes of errors encountered in the British

application of lead dioxide gauges to measure S02 levels  are summarized in

Table 14-1.  As shown in Table 14-1, several problems (e.g., humidity and

temperature effects) result in the lead dioxide method being essentially

useless for 24-hr, measurements and in their otherwise having a rather large

(±180 ug/m  20) error band associated with them.

     Based on some of the above problems, when the National  Survey began in

1961 it was recognized that the lead dioxide method could not provide the

24-hour SOp measurements necessary for correlation with mortality and

morbidity effects investigated by epidemiology studies.  The hydrogen peroxide

method for S02 was, therefore, adopted as being more valid than the old lead

dioxide gauge sulfation method.  Because many of the staff making the

measurements would be the same people who had been servicing particle deposit

gauges and the  lead candles without detailed technical knowledge  of the
                                                          £{/,£•
analyses, however, an Instruction Manual (IM) issued by WSL in  1966 had to be

quite detailed and clearly readable by people with no training  in analytical

techniques.

     As mentioned above, the  lead peroxide method was selected  because  its

sensitivity, reliability and  precision were demonstrated to be  much better

than that obtained in comparison to the  lead dioxide method.  More
                                   14-18

-------
                           TABU M-1.   SUWARY or CVALUATIM or SOURCES. WWHTWK. <•*
                                                       ASSOCIATED WITH BRITISH SOj MEASUREMENTS
   TIM
  period
                     Beasui se»nt
                       o»thod
   Reported
     of erro'
                                Direction and a»gn1t«da of
                                      reported error
                                                                                                                    British SOj data
                    lead Dioxide Humidity (RH)
                                 Teeperature (T)

                                 Wind  spaed (WS)
19H-1MO
 (British National
 Air Pel. Survey)
                    Hydrogen
                     Peroxide
                               Reectlen  rote  Increase* with RH.
                               Rcectlon  rate  Increoses 2X
                                per 5* rise.
                               Reaction  rate  Increases
                                with WS.
                                  (Overall
 Siting of Senate line
  Intake:
  a.  too near boiler chlemyt  50 -  100 pf/ar overostleatlon.
  b.  too near vegetation       50 - .70 percent undorestleatlon.

 Saaplo line Adsorption:
  a.  Good care t cleaning      10 ug/eT vaderestlaetlon.   .
  b.  Averoge care              20-25 ug/n   low froo 50 ug/B .
  c.  Poor car* (Insects,  dirt)  Probable greater underestleatlon.

 Flow Meter Problem*:
  a.  Dally norawl condition*
 b. B-port onlt with only
    one weekly flow roadlng

Allowoble Filter Clean
 leakage
Poor Cleap Care ft Tochnloue
t 3 percent variation.

t S percent variation.


1-2 percent enderoatleatlon.

S-10 percent «ndere*t1oat1en.
                                 Crede • Classware Usage       2-5
                                 laproper Alkalinity Buffering S-10 ug/ai' underestlMtloo.
                                                               40 ug/er low froa 50 pg/e
 C02 In Deelnerallted  In
                                  Ataeipnarlc Aanonl*
                                                                 eonthly Man.
                                                                 tu
                                                                <80
                                                                                     oii on  101 «f
                                                                    er aaeiilef 1n orfean areas.
                                                                    ^/m  low on
                                                                             on  Ind. days t 40

                                                                      lav tvntnly •!•••<• Man In
                                                                country areas.
                                                                        error In d»tor«inat1o«.
THratlon Error:
 a. Moroni-sharp color       »5
    change of Indicator et
    pH 4.5                            .
 b. Gradual color change of  *10 »»/•* error In determination.
    Indicator at pH 4.5              .
 c. Rounding off to 0.1 •!   *5  Kt/"J error 1n eetnrolnetlen.
    of alkali voluot added.
                                 evaporation of reagent:
                                                              <15 vt/m  everestlewtloB,
                                                              'especially In suaer anntnt.
                                                                                                       Variable positive blot, eopoclally In aoaw.
                                                                                                       Variable positive bias, especially In tMswr.

                                                                                                       Variable positive blM. isnder high wind cond.
                                                                                                       Con be s* to i  180 u»V
                                                                                                       OccMlanel (prob. rare) poeltlvo blao.
                                                                                                       Occasional (prob. rare) negative bias.


                                                                                                       Possible general 10 pg/ta3 nogetlve b1a
                                                                                                       Occasional 40-501 negative bias.
                                                                                                       Likely rare 50-90S negative bias.
                                                                                                       •vjgllglble 1a»ect.  fritmit tM av«c1s1en
                                                                                                        of data.
                                                                                                       •SX negative bios en Mgh SO.-tS «qre.
                                                                                                       •9 positive bios on low $0*1$ days.
                                                                      Nagllglble 1se
                                                                       of deu.
                                                                      likely occMle
                                                                                                                     ct.

                                                                                                                     el
                                                                                                                                 od tl* precision

                                                                                                                               nefetiv* bias.
                                                                                                       Negligible   *_v.  .
                                                                                                       Occasional 5-10 pg/er negative blea.   fc
                                                                                                       Occasional negative bios of up to BOX.
                                                                      >» Mfe  net. bias ea> 101 of saewr
                                                                      ~sss9les In ur*>en  area*.
                                                                      Occasional  neq. bias  In coentrv eroes-
                                                                      •p to BO •»/• dally  data k ep to 1001
                                                                      eonthly even In  suaaer.
                                                                                                     Pisie»« t S **/•  precis Ion of *Ma.
                                                                                                             * 10 (Pf/a* precision level. c

                                                                                                      Added t S pa/ej precis la* error.0
                                                                     13-100X pea.  bias  for SO.  data <1M >    .
                                                                     7.5-1M pos.  bias  for SO*  of  100-700 (**•».,
                                                                     J.»-7.5X pos.  bias  for  $0- of 2OO-400 »•/•I*.
                                                                     O.25X pos.  bias  for S0  dlta >400 ug/o  .
Teetteratvre and Pressure:
 a. Corrections • nereis I
 b. large AP at filter
                                                               n tmderettlMtlen.
                                                               101 underestimation.
                                                                                                     eonorel V nog. bias In SO, data.
                                                                                                     Occasional - tlOX negative bias 1n SO, dot*.
*0ata free 1W5-1W0 eott clearly  lopacteel.

^Oate froe 196«-19C7 eatt clearly  Impacted.

e*t <50 ufl/«J -ncertalnty due to these two errors  Is - 7 ug/-3 or 14*.  Thet It. *W of the date ere wltMn 14* end 5X ere >tM In error.

-------
specifically, the British Standard for sulfur dioxide determination by the



hydrogen peroxide method states that replicate determinations can be expected



to be within ±20 ug/m3 for concentrations up to 500 mg/m  and within ±4 percent



for concentrations above 500 ug/m ;  and an OECD Working Parting stated the



accuracy of the method to be ±10% at levels >100 ug/m3.   However, as summarized



in Table 14-1, numerous sources of errors have been encountered in the practical



application of the method in collecting data for the British National Survey



over the past 15-20 years.



     Certain of the sources of error listed in Table 14-1, it can be seen,



resulted in relatively small errors, whereas others produced errors ranging up



to 50-100% in magnitude.  Also, some errors appear to have been restricted to



affecting data from only  limited locations (usually unspecified as to specific



names  of localities) or during only limited time periods.  Many of these types



of errors appear to have  been detected fairly quickly and steps taken to



successfully correct or minimize them.  Still other sources of errors exist



(e.g.,  those from reagent evaporation), which have likely affected essentially



all British National Survey S02 data.  Some of these appear to remain uncorrected



to this date, in some cases more than 10 or 15 years after they were first



detected and brought to the attention of Warren Spring Laboratory officials



responsible for overseeing quality control for the entire National Air Pollution



Survey.  See Chapter 3 for a more detailed discussion of each type of error.



     Taking the above information into account for present purposes, it would



be extremely difficult to determine precisely which errors affected  particular



National Survey data sets employed in British epidemiology and other studies



discussed later in this chapter.  That would  likely require  a thorough examina-



tion,  on a time- and site-specific basis, of  records detailing information  on
                                   14-20

-------
how each pertinent data set was collected and WSL quality control  assessment

reports for the data sets.   Alternatively, in later evaluations of British

epidemiology studies one could accept the following overall  evaluation and set

of conclusions by the WSL (1975) regarding British National  Survey air pollution

data (emphases added):

     The actual degree of accuracy attained in the Survey is not known.
     Input data are scrutinized by WSL staff, and subjected to computer
     checks, and any reflectances, titres, or air flows which are abnor-
     mally high or low or show unusually abrupt changes from one day to
     the next are queried and data known to be invalid are excluded from
     the annual summary tables.  Such checks can however eliminate only
     some of the gross errors.  More information will become available on
     accuracy when current (1974) plans to institute additional quality
     control, e.g., on reagent solutions, are put into operation.
     However, although the accuracy of the Survey data cannot at present
     be quantified, many of the errors discussed in the previous para-
     graphs will cancel out when data are averaged over periods of a few
     months or a year, or for groups of sites.  The remainder tend to
     show up as anomalies when data are compared with past or subsequent
     data at the same site or with data from other sites; anomalies of
     this kind have been commented upon throughout the Reports.  Members
     of Warren Spring Laboratory staff have devoted a large effort over
     the years to site visiting and checking on procedures.   It is their
     experience that the vast majority of the instruments are maintained
     and operated with reasonable care^and accuracy.  The Laboratory is
     therefore confident that the accuracy is sufficient for the type of
     data analyses carried out in the present series of reports.

Presumably, it is the opinion of the WSL  and British epidemiologists that the

accuracy of the survey data is also sufficient to meet the original objectives

of the Survey, ie. to assess  the benefits accruing from the Clean Air Act of

1956, which requires use of the survey air quality data along with community

health endpoint evaluations in order to define quantitative air pollution/health

effects relationships.  That  this presumption is  likely correct is further

attested to by the long history of reliance  on these data by British epidemio-

logists, such as  in the making of statements  regarding such quantitative  relation

ships  in innumerable journal  articles  and reviews  appearing during the  past

twenty years, up  to and Including the  very  recent review  by Holland  et  al.  (1979)
                                    14-21

-------
14.2.1.2  Dally Smoke Measurements of the United Kingdom National Survey—The



general technique for the British Smoke shade (BS) measurement 1s described in



detail in Chapter 2, and a detailed critical assessment of the measurement



procedure is provided in Chapter 3 to allow for evaluation of the precision,



accuracy, and reliability of the measurements.   Also, details of the BS



measurements are provided by an Instruction Manual (IM) issued by (Warren



Spring Laboratory in 1966.  At the start of the National Survey in 1961 (WSL,



1961)  it was recognized:  "The daily instrument, while comparatively simple in



design and operation gives reliable results TT\ good hands* and seemed the best



choice for the National Survey."  WSL circulated the specifications of the



apparatus and methods to all the cooperating organizations as careful, uniform



work was essential if the results from the different sites throughout the



country were to be comparable.  However, WSL found that detailed instructions



were necessary as most of the Local Authority staff making the measurements



had no training in analytical techniques.  These methods were reviewed by an



O.E.C.D. Working Party and a report "Methods of Measuring Air Pollution"



(OECD, 1964) was prepared, which was accepted into the British Standards



Specification 1747, Parts 2 and 3.  The Manual of Instruction (WSL, 1966)



incorporated the improvements in techniques, "but apparatus and procedures are



specified in much greater detail to assist operation by observers with no



technical knowledge."*



     Partly due to the lack of analytical training of survey monitoring site



operators, and other factors as well, various errors were encountered in



carrying out BS measurements for the National Survey.
 'Underline added for present emphasis.
                                   14-22

-------
     Table  14-2  summarizes  information  discussed  in  Chapter  3  on  the  sources,



magnitudes  and directional  biases  of  errors  associated  with  British smoke



measurements  during  the  past  30  to 40 years.   For example, prior  to 1961,  the



use of weights for sealing  purposes led to highly variable errors 1n  BS



measurements  due to  leakage at filter clamps,  and steps were taken to require



screw-down  clamps as standard procedure as part of the  later British  National



Survey work implemented  after 1961.   It is not clear to what extent any  specific



British BS  data  sets from the 1950s may have been affected by  the clamp  leakage



problem, but  one must assume  that  such  errors could  not have often been  very



large or serious and that the WSL  took  appropriate steps to  eliminate or



invalidate  any data  in gross  error as they were detected via their quality



control efforts  in the late 1950s.  Analogously,  there  is evidence that  WSL



did take steps to inform users  of  pre-1961 BS data of errors arising  from  (1)



comparing reflectance on filters to photographs of painted  stains and (2)  use



of reflectance readings  below 25 percent,  where the  stain was  too dark to  use



the Clark-Owens  DSIR curve.  However, it also appears that  only a few investigators



(e.g., Commins and Waller,  1970) took steps to go back  and  correct published



reports based on the affected pre-1961  data and to publish  revised analyses



taking into account  corrections  for the pre-1961  data errors.



     Probably of much greater concern than the pre-1961 BS  measurement errors



are those encountered after the  establishment and initial implementation of



the British National Survey in  1961.   These include  certain errors,  e.g.,  the



"computer error  of  1961-1964,"  which were eventually detected by WSL and



resulted in steps being  taken to correct affected BS data in National Survey



data banks.  It  is  clear, however, that whereas users of the affected data may



have been informed  of such  errors by WSL, virtually none of them  have taken
                                   14-23

-------
             TABLE 14-2.  SUMMARY OF EVALUATION OF SOURCES, MAGNITUDES, AND DIRECTIONAL BIASES OF ERRORS
                                ASSOCIATED WITH BRITISH SMOKE (PARTICULATE) MEASUREMENTS
Time
period
Measurement
method
Reported source
of error
Direction and magnitude
of reported error
Likely general Impact
on published BS data
1944-1950s
Pre-1961
Smoke filter
1961-1964
1964-1980
 Leakage at clamp.
 Weights used to make the
   seal.
Highly variable under-
 estimation of BS levels.
                                             Depending upon observer
                                                and value of R.
Comparing reflectance to
   photographs of painted
   standard stains.
 Reflectance (R) below 25%,  50-100% underestimation.
   stain too dark with use
   of Clark-Owens DSIR curve.
                 Computer not following
                   proper calibration curve.
                Clamp correction factor
                   for other than 1-inch
                   clamp.


                Flow rate - normal 1 day.
                Flow by 8-port with 1
                  reading per week.
                Variability of reading
                   reflectance.
                Averaging reflectance
                  Instead.of averaging
                  mass/cm .
                Use of coarse side of
                  filter facing upstream.
                             <80% underestimation at low
                                R 1f not corrected by WSL
                                (See Moulds.1961) and
                                discussion of clamp size
                                correction factor.

                             Uncertain; derivation
                                cannot be verified.
                                Possible +20%.


                             +3% variation.
                             r!0% underestimation.
                             +10% overestlmation.

                             +2 units of R

                             Highly variable under-
                               estimation due to non-
                               linearity of R.
                               6-15% underestimation.
Probable widespread highly
 variable negative bias.
                              Probable widespread relatively
                                small negative bias.

                              Occasional 50-100% negative
                                bias in some data sets.


                              Negligible for BS <~100 ug/"»3-
                              Increasing negative bias up to 80%
                               as BS values increase over 100
                              Possible underestimate for 2-inch
                                 and 4-Inch clamps
                              Possible overestimate for 1/2-Inch
                                 and 10 rm clamps.
                              Presumed ± 3% precision level.
                              10% negative bias on high BS days.
                              10% positive bias on low BS days.

                              Error Increases with BS level fro»-±10%
                              at 50 ug/KT up to ±20% at 400 ftg/m .
                              Probable small negative bias at low
                              BS levels, could be large at high BS.

                              Occasional negative bias of 6-15%.

-------
                                                        TABLE 14-2  (continued).
       Time
      period
Measurement
  method
Reported source
   of error
Direction and magnitude
   of reported error
Likely general Impact
on published BS data
                                    Reading of wrong side of
                                      stained filter.

                                       Leakage at filter clamp
                                       a. Normal, with good care
                                       b. With Inadequate care.
                                       c. Careless  loading where
                                          uneven stains are
                                          produced.

                                       Use of wrong clamp size
                                       a. Stain too light R>90%.

                                       b. Stain too dark R<25%.
                                              50-75% underestimation.
                                              1-2% underestimation.
                                              2-8% underestimation.
                                              10-20% underestimation.
i
ro
in
                                               Highly variable over-
                                                estimation.
                                               Highly variable under-
                                                 estimation.
                                                          Occasional negative bias
                                                      of 50-75%.


                                                     General 1-2% negative bias.
                                                     Occasional 2-8% negative bias
                                                     Occasional 10-20% negative bi
                                                     Data usage not recommended.

                                                     Data usage not recommended.

-------
steps to (1) alert recipients of publications containing analyses based on the


affected data of the likely inaccuracies or ranges of error Involved;  (2)  to


reanalyze the study results based on the affected data sets;  or (3) to reissue


or publish anew any revised analyses.   In fact,  even some Warren Spring Laboratory


quality control literature prepared and published during the  1960s or  1970s


and still in use may contain incorrect information and recommended standard


procedures for BS measurements based on analyses "contaminated" by computer


errors or other problems summarized in Table 14-2 and discussed in more detail


in Chapter 3.


     In regard to determining which British BS data sets and  related epide-


miology studies are affected by different post-1961 National  Survey errors, it


is again presently very difficult, as was the case with British S02 measurements,


to specify with any confidence the nature and magnitude of specific errors


impacting particular studies.  This would probably require thorough examination


of records and WSL quality control reports concerning each of the pertinent


data sets.  On the other hand one can project that certain data sets and


British epidemiology studies were almost certainly affected by some subset of


BS measurement errors and these are taken into account in evaluating such


studies later this Chapter.  For example, published reports o^ the "Ministry

            fe*-                           %
of Pensions" (1965) and Douglas and Waller (1966) studies contain specific


reference to usage of National Survey data from the 1961-64 period and,


therefore, the results of those studies should be reevaluated  in  light of


measurement errors reported by the WSL for that period.


14.2.2  American Approaches


14.2.2.1  American SO,, Measurements—Turning to American measurement approaches,


different types of measurement methods for a given pollutant were adopted  by
                                   14-26

-------
various local, state, and federal  agencies in establishing or expanding  air



quality monitoring systems that proliferated across the United States  during



the 1950s and 1960s.   Rather than  discuss methods used for S02 measurements by



all of the different American air  monitoring systems,  main emphasis  1s placed



here on the discussion of only certain key American applications  of  measurement



methods for S0x that are of crucial importance for later discussions of  quanti-



tative relationships between health effects and atmospheric levels of sulfur



dioxide.  These include mainly applications of SO^ measurement methods as



employed in the EPA "CHESS Program" as the single largest attempt to define



quantitative relationships between air pollution and health effects.



     In regard to sulfur oxides measurement approaches used in the United  States,



lead dioxide or other "sulfation rate" measurement methods were,  as  in Britain,



widely employed prior to the early 1960s for assessing SO- air levels.  However,



probably to a somewhat greater extent than in Britain, sulfation rate measurement



techniques continued to be used later into the mid or late 1960s by  some



monitoring programs in the United States or in connection with certain community



health epidemiology studies, as discussed later in this chapter.   As shortcomings



of the "sulfation" methods became more widely recognized, however, their use



was generally abandoned and more specific methods for the measurement of SOp



or other sulfur oxide compounds were adopted, as was done in Britain. The



hydrogen peroxide acidimetric method (see OECD, 1965) selected for use in the



British National Air Pollution Survey, however, was not very widely adopted in



the United States for S02 measurements.  Rather, versions of West-Gaeke (1956)



colorimetric procedures were much more widely used in the USA.  Conductivity



measurements for S02 (Adams et al., 1971). based on an acidimetric method



adaptation often used in automatic instruments and most suitable  for  measuring
                                   14-27

-------
periods of around 24 hours, later began to be applied in the operation of some
American air monitoring networks in the 1970s.
     The West-Gaeke method was the method mainly employed in the EPA "CHESS
Program" for determining SOp air levels for inclusion in analyses of community
health end point data in "CHESS" epidemiology studies.   The application of
that method in the CHESS Program was accordingly most thoroughly discussed in
Chapter 3.  The types of errors in measurement associated with CHESS SOp data
are summarized in Table 14-3, along with notation of some factors affecting
earlier sulfation methods.  Much of the information on the former subject is
                                                          .  /j
derived from a 1976 Congressional Investigative Report (IR; which contained a
thorough evaluation of EPA CHESS Program air quality measurements and other
aspects of the Program.
      Looking at the types of errors associated with earlier American use of
sulfation rate lead dioxide methods, similar effects of temperature, humidity,
etc. ,  as affected analogous British SOp methods are seen to apply here to
American data as well.
      Turning to American applications of SOp measurements since the widespread
abandonment of sulfur dioxide sulfation rate methods in the mid to late 1960s,
several different types of errors were identified as being associated with EPA
CHESS  Program SOp measurements via a thorough evaluation of the CHESS Program,
                      irt
as reported in the IR (1976).  As can be seen, the magnitudes of some errors
in CHESS SOp measurements spanned about the same range as those seen for
British National Survey SOp measurements and, at times, derived from analogous
sources of error, e.g., evaporation or other loss of reagents.  In the case of
the American CHESS Program data, however, the specific overall impact of the
various detected errors on particular CHESS data sets appears to have been
                                               /»?
more definitively defined by the work of the IR (1976); more specifically, it
                                   14-28

-------
       1944-1968
                                       TABLE 14-3.  SUMMARY OF EVALUATION OF SOURCES. MAGNITUDES, AND DIRECTIONAL BIASES OF ERRORS
                                                              ASSOCIATED WITH AMERICAN SO. MEASUREMENTS
T1M
period
Measurement^
method
Reported source
of error
Direction and Magnitude
of reported error
Likely general Impact on American SO. data
Lead dioxide.
Humidity (RH).
Temperature (T).

Wlndspeed (WS).

Saturation of Reagent
 (sulfatlon plate mainly).
                                                                      Reaction rate Increases with RH.
                                                                      Reaction rate Increases 2X per 5°
                                                                       rise.
                                                                      Reaction rate Increases with WS.

                                                                      Variable underestimation beyond
                                                                       pt. where 15X of PbO, on plate
                                                                       reacted.            J
Variable positive bias, especially 1n summer.
Variable positive bias, especially In sumer.

Variable positive bias, especially In summer.

Possible large negative bias, especially for 30-
 day samples for summer Monthly readings.
 t
ro
vo
       1969-1975
        (EPA CHESS
        PROGRAM)
West-Gaeke
 Pararosanallne.
                                         (Overall Errors).
                   Spillage of reagent
                    during shlpnent.

                   T1*e delay for reagent-
                    50. complex.
                                         Concentration dependence
                                          of sampling method.
                             18X of total volume SOX of tine;
                              occasional total loss

                             SO, losses of 1.0, 5, 25, and
                              75X at 20, 30, 40, and 50°C,
                              respectively.

                             Underestimation of unspecified
                              Magnitude at dally SO, >200
                                                                                     Generally wide ± error band associated with data.
                                                                                      Possible negative bias up to >100X. mainly 1n
                                                                                      summer, with 30-day reading.
Half of SO
 mean of
0, data likely negatively biased by
17X; some up to 100X.
Usually small (
-------
appears that the CHESS data generally tended to be somewhat negatively biased
in comparison to other local or state S0? data from monitoring sites proximal
                                                                  in
to the CHESS sites, with the local and state data judged by the IR (1976) to
be reasonably accurate and reliable.  The specific magnitude of the negative
bias for particular years of CHESS data is summarized in Table 14-3, and
appears to have been around 30-40% in some circumstances and up to around 100%
in other cases.
14.2.2.2  American High-Volume TSP Sampling Measurements
     As discussed earlier, the hi-volume TSP sampler, since its development in
the  early 1950s, has been the instrument most commonly used in United States
for  measurement of atmospheric particulate matter; and high-volume TSP readings
have most typically been used in American epidemiology study evaluations of
associated  air pollution-health effects relationships.  In contrast, other
particulate matter measurement approaches (e.g., the coefficient of  haze
method)  saw only relatively limited application during the 1950s and early
1960s  in  certain American  locations and were infrequently used in estimating
 quantitative relationships  between  airborne particulate matter and health or
welfare  effects.   Accordingly, major emphasis is placed below on the critical
appraisal of certain  key applications of hi-volume TSP measurements  in the
United States.  As before,  in discussing American applications for measurement
of oxides of sulfur,  the present  summarization focuses most heavily  on evaluation
of applications of TSP measurement  methods employed  as part of the  EPA "CHESS
Program," as the single most extensive and comprehensive  use  of  such methods
as part  of  American community health epidemiology studies.  Much of  the  information
is derived  from the 1976 Congressional Investigative Report  (IR), which  included
a thorough  analysis of EPA  CHESS  Program TSP measurements and comments  regarding
certain  local  or state TSP  measurements.
                                    14-30

-------
     The  main sources,  directions and magnitudes of errors identified as


possibly  affecting American TSP measurements are summarized in Table 14-4.   In


addition  to various sources of minor errors inherent to the basic TSP sampling


method, certain other nuances of procedures included in the Federal Reference


Method (40 CFR 50, Appendix B) may have resulted in the introduction of an


additional slight negative bias in TSP data obtained by American researchers.


This, more specifically, pertains to the manner in which flow rate calculations


are made  upon which final TSP concentration determinations are based.


     The  Federal Reference procedure calls for the averaging of the initial


and final recorded airflow rates.  However, as described in Appendix 3-A of


Chapter 3, the uncontrolled flow rate drops more rapidly at the start of the


run than  at the end of the run.  Therefore, a linear approximation leads to an

                   0^^^                           (ia&tet&Zlter &~£d£?d£*j£s*'
overestimate of the/^flgw rate, which will reduce the jnea^uped value.  Consequently,


all TSP data computed in this manner have a slight negative bias which  is


likely usually of the order of 5 percent; on occassion, however, under  circumstances

                                               3
where the flow rate may have fallen below 40 ft /min, larger errors  (up to


approximately 15 percent) may have been introduced.  Assuming that monitoring


site operators in the United States adhere to the recommended Federal Reference


Method procedures, then this type of bias is likely inherent in essentially


all American TSP data collected without flow rate control or recording.


Despite such problems, it can be seen that the maximum  range of uncertainty


derived from the various errors associated with American TSP measurements  is


generally less than 20 percent in either a positive or  negative direction  on a


random (±) basis.
                                   14-31

-------
       Time
      period
                   TABLE 14-4.  SUMMARY OF EVALUATION OF SOURCES, MAGNITUDES, AND DIRECTIONAL BIASES OF ERRORS
                                  ASSOCIATED WITH AMERICAN TOTAL SUSPENDED PARTICULATE (TSP) MEASUREMENTS
  Measurement
    method
  Reported source
     of error
Direction and Magnitude
   of reported error
Likely general Impact
on published TSP data
    1954-1980
Staplex HI Vol TSP
 i
oo
ro
Tim* Off (Due to power
  failure).
Weighing error.

Flow Measurement (with
  control).

Flow Measurement (without
  control)
a. Constant TSP—Average
    of flows.
   1. Low TSP level.
   2. High TSP level.
b. Rising TSP-Average of
   flows.
c. Falling TSP-Average of
   flows.
Aerosol evaporation on
  standing.
Condensation of water vapor.
Foreign bodies on filter
  (Insects).

Windblown dust Into filter
  during off-mode.

Wind speed effect on pene-
  tration of dust Into the
  HI-Vol shelter.
Wind direction effect due to
 HI-Vol Asymmetry
Artifact formation, NO,
  SO'                3
                                                                     Variable underestimation.

                                                                     ±2X random variation.
                                                                     12X random variation.
                                                   2X underestimation.
                                                   5-10X underestimation.
                                                   10-20X underestimation

                                                   10-20X overestlmatlon.

                                                   1-2X underestimation.

                                                   5X overestlmatlon.
                                                   Generally small over-
                                                    estimation.
                                                   Generally small over-
                                                    estimation.
                                                   Less penetration at high
                                                    wlndspeed.

                                                   Higher penetration when
                                                    normal to sides.
                                                   5-10 ug/m  overestlmatlon.
                              Negligible Impact, rare negative bla*.

                              Negligible Impact.
                              Negligible Impact.
                              Negligible Impact.
                              Possible 5-lot negative bias.
                              Possible 10-20X negative bias.

                              Possible 10-20* positive bias.

                              Probable negligible Impact.

                              Possible 5X positive bias.
                              Possible 5* positive bias.

                              Occasional (rare) positive bias.

                              Occasional (rare) negative bias.


                              Probable Increase 1n random  (i) error.

                              Occasional positive bias.

-------
                                                           TABLE 14-4 (continued).
       T1M
      ptrlod
  Measurement
    Method1'
  Reported source
     of error
Direction and Magnitude
   of reported error
        Likely general Impact
        on published TSP data
    1969-1975
     (EPA CHESS
     PrograM).
Fed.  Reference
 Method Standard
 HI-Vol Sampler
Loss of sampling Material
 In field.
                                       Loss of sampling Material
                                        1n Mailing.
                                       Evaporation of organic sub-
                                        stances.


                                       Vlndflow velocity and
                                        asytmetry.
                                       (Overall errors).
No specific estimate of
 Magnitude of error; but
 would be underestlMatlon.

Reported 4-25X apparent
 loss; MBX. likely due to
 crustal (sand, etc.)
 fall-off froM selected
 Utah saMplIng sites.
No specific estlMate of error
 Magnitude, but not likely to
 exceed 5X underestlMatlon.

No specific estlMate of error
 Magnitude; but Most likely to
 Increase randoM variation or
 SMall underestlMatlon.
Probable slight negative bias
 In Utah winter data.  No known iMpact
 on other CHESS TSP data.
Probable general small <10X negative bias;
 occasional 25% negative bias.
                                                                                      Probable slight negative bias
                                                                                       of <5X for TSP data fro* urban/
                                                                                       Industrial areas.
                                                                                      Negligible iMpact or slight
                                                                                      negative bias.
                                                                                      Generally <10X negative bias;
                                                                                      occasional 10 to 3OX negative bias.
 i   .
u>   As suMMarlzed by Congressional Investigative Report (IR).

-------
     Errors in addition to general TSP measurement errors reported by the 1976

Congressional Committee Investigative Report (IR, 1976) to affect CHESS Program

TSP measurements during 1969-1975 are broken out and listed seperately in

Table 3-5.  Some of those errors (e.g., loss of sample materials 1n filter

removal from the field monitoring apparatus) were reported by the IR (1976) as

likely affecting only very restricted CHESS data sets.  Others, e.g., errors

due to loss of sample in mailing, appear to have been more widespread and

presumably impacted on many CHESS data sets.  It is interesting to note,

however, that the IR (1976) concluded that the net effect of all of the errors

was to introduce, in general, a slight negative bias of 10 to 30 percent into

CHESS TSP data, which is not much beyond the range of different types of

errors (e.g., linear flow corrections) more generally associated with American

applications of TSP measurements.  Section IV C 3 of the IR (1976) further

concluded that:

     "...the TSP data were by far the best quality data taken in the
     CHESS monitoring program.  Differences measured between High and Low
     sites are probably reasonable estimates of the differences of TSP
     exposures as received by populations in these areas."


  It appears reasonable to concur with the IR (1976) and, accordingly, to

accept CHESS TSP measurements as reasonable estimates of TSP exposures of

CHESS Program community health study populations, taking into account that
                                                  J^
such data may by biased low by no more than 10 or. at mojt. 30 percent.

14.3  AIR POLLUTION AND MORTALITY

14.3.1  Introduction

     Mortality represents the ultimate end point of many disease  processes.

Estimates of mortality rates are generally fairly accurate  in most places  for

most time periods.  On the other hand, mortality rate  is not necessarily a
                                   14-34

-------
sensitive indicator of the effect of pollution at any given place  or time,
since it may be related to various lengths and types of exposures.   Also,
recorded cause of death may or may not be accurate,  necessitating  additional
care in assessing reports of pollution-associated increases in cause-specific
mortality.   Daily mortality varies greatly and its relationship to fluctuations
in ambient air levels may be fortuitous or may represent a trend that started
anywhere in the past (days, weeks, or years earlier).  Despite the above
problems, numerous studies have attempted to determine possible relationships
between air pollution, including elevated levels of SO  and particulate matter,
and documented increases in mortality rates.
     Studies of mortality tend to fall into three broad categories:   (1)
episode studies examining the effects of very high pollution levels lasting,
at most, for a few days; (2) studies in which short-term fluctuations in
pollution and mortality are monitored over more extended time-periods for a
particular population, and (3) cross-sectional studies in which mortality and
pollution are compared across different geographic areas.  The earliest mortality
studies had limited estimates of pollution, and the  numbers of deaths were
compared with those from other periods of time with  the hope that similar
conditions prevailed except for air pollution.  Often the differences are
large enough to be convincing in spite of the lack of complete information on
other pertinent data.
     Short-term effects studies are usually limited  to a well-defined population
that 1s followed through time.  Since the period of  time is relatively short,
it is usually safe to assume that the population has remained  constant with
respect to age and composition.  These studies are  very  sensitive to temporal
                                   14-35

-------
variables such as influenza cycles, ambient temperature and other meteorologic



factors, season, day of the week, and even holidays.  Confidence can be best



placed in those studies of this type where the contributions of such factors



are either controlled for or otherwise properly adjusted for or taken Into



account.



     Long-term studies usually compare mortality rates over long periods of



time such as one to twenty years.  The comparisons are usually cross-sectional,



that is, between geographic areas.  Temporal factors are less important, but



the demographic characteristics of the study areas are critical.  Among the



more important  factors are age, race or ethnic differences, sex, socioeconomic



status,  in-out  migration, smoking habits, and general health care.  The location



of monitoring sites in each area is also extremely important in long-term



studies.   If the monitors in some geographic areas are in industrial locations



while  the  monitors  in other areas are in residential locations, the differences



that are ascribed to ambient air pollution may actually represent other



differences between industrial and residential locations.



14.3.2  Acute Episodes



     Detailed study of the human health effects associated with episodes of



severe air pollution spans a period of less than 50 years.  The earliest



reliable documentation of such episodes describes an incident in  the Meuse



Valley of  Belgium in 1930.I



     An intense  fog covered the Meuse Valley from Liege to Huy  '     from



December 1 to 5, 1930, and was accompanied by an anticyclonic high  pressure



area with  low winds and  large amounts of fine particulate matter.   Sixty



deaths associated with the fog occurred among residents of the  Valley  on
                                    14-36

-------
December 4  and  5.   The people  who  died  were  sick for only  a short  time.



Although there  were no other immediate  deaths,  several  persons  affected  by  the



fog died much  later from complications  associated with  fog-induced Injuries.



The death rate  in  the  area was 10.5 times normal.   The  illnesses abated  rapidly



when the fog dispersed.


                                                                  149
     A similar  but smaller event occurred in Donora, Pennsylvania.     Donora



was blanketed  by a dense fog during late October 1948,  which adversely affected



43 percent  of  the  population.   Twenty persons died during  or shortly after  the



fog, and 10 percent of the population was classified as being severely affected.



No pollution measurements were made during the incident but the investigators



concluded that  no  single chemical  agent was  responsible.   Sulfur dioxide,  its



oxidation products and particulate matter were undoubtedly significant



contaminants.   During  subsequent inversion periods, presumably not as severe



as the one  in October  1948, daily averages of sulfur dioxide as high as  0.4



ppm (~1140  |jg/m )  were recorded.


                                                                          2 202-204
     A pollution episode also occurred on December 5 to 9, 1952 in London.  '



Monitoring  sites near  the center of the fog averaged 1.98 mg/m  British  Smoke



(BS) with an average maximum of 2.65 mg/m ;  the maximum BS reported was  4.46



mg/m  for a 48 hr  sample.  The corresponding mean values for S02 were 0.91



ppm, 1.26 ppm and  1.34 ppm.  Four thousand excess deaths were noted during the



fog.  As shown in  Figure 14-2, the death rate began to rise within 24 hours of



the beginning of the pollution episode and fell abruptly to slightly elevated



levels when the fog abated.  Most deaths occurred among people with pre-existing



disease, including bronchitis (tenfold increase in  deaths) and coronary heart



disease (threefold increase).   It has been noted that  influenza present in



London at the time may have also influenced the reported death rate.
                                   14-37

-------
         /  ?  J  4  5  6  7  6  9  10  II  12 a 14  15



                           DECEMBER 1952





Figure 14-2.   Daily air pollution and deaths, London, 1952203
                              14-38

-------
                                                      11-14
     Excess mortality in London during lesser episodes      was  assessed  by



various statistical techniques for comparing observed and expected mortality.



The expected mortality rates were estimated from the mean number of deaths



occurring during the same dates over a number of years,  from observed deaths



during previous or subsequent weeks, or by deviation from 15-day moving



averages of daily mortality.  Aerometric data obtained for the various studies



are not entirely comparable; thus the study results only allow for crude



comparison.  It has also been noted that the published concentration levels



may not be representative of the acutual exposures of all of the affected


           312
population.



     The information on mortality and maximum 24-hr pollution measurements  for



BS and SO,, are presented in Table 14-5.  The maximum 24-hr concentrations of



S02 during the 1952 and 1962 episodes were almost identical, and 1962 maximum



TSP measurements were 75 percent of the 1952 maximum, but far more deaths



occurred in 1952.  This raises questions concerning the influence of factors



other than pollutant levels.  The maximum smoke concentration recorded in 1952



was the highest ever observed and yet is believed to have underestimated the



actual concentration, because the filter became completely saturated and



additional deposition had little effect on the intensity of the black spot



produced on the instrument's filter tape.  In 1962, publicity about the



hazards of episodic conditions may have motivated the population, particularly



the elderly, to avoid exposure as much as possible.  Interpretation of the



other data in Table 14-5, however, argue against this possibility.   In 1956,



the memory of the  1952 episode should still  have been clear and,  therefore, at



least as many precautions should have been taken.   However, more  excess  deaths



occurred in 1956 than in 1962, even though concentrations  were  less  than those
                                   14-39

-------
   TABLE  14-5.   EXCESS  DEATHS  AND POLLUTANT CONCENTRATIONS  DURING SEVERE
               AIR  POLLUTION  EPISODES IN LONDON (1948-75)2,3,219-221,301
                                                  Maximum 24-hr pollutant
                                                  concentration, pg/m3
               Duration,         Estimated         Smoke        S02
  Date           days         excess  deaths         (BS)  (H202 titration)


Nov.  1948         6                750             2780       2150
Dec.  1952         4               4000             4460       3830
Jan.  1956         4               1000             2830       1430
Dec.  1957         4                750             2417       3335
Jan.  1959         6                250             1723       1850
Dec.  1962         5                700             3144       3834
Dec.  1975         2              100-200            546        994
                                14-40

-------
measured in 1962.   Thus,  the influence of publicity on minimizing exposure  is
only one possibility.   A  second possibility is that influenza in 1952  may have
increased mortality.   A third possibility is that the composition of air
pollution changed  between 1952 and 1962 as a result of the 1956 British  Clean
Air Act.  The act  limited the combustion of high-volatile coal  for domestic
heating and thereby affected the amount of tars in the atmosphere.   Such
alterations in the composition of air pollutants could have delayed or altered
the atmospheric transformation of S02 to more toxic materials.
     Regardless of whether any of the above explanations apply, one clear
conclusion from the major London episodes is that increases in mortality are
associated with severe increases in air pollution.  During the most severe
episodes, maximum  24-hour concentrations exceeded 1400 ug/m  (0.5 ppm) for  S02
and 1700 ug/m  for smoke  (BS).  A less severe episode in 1975, resulting in
               •
100-200 estimated  excess  deaths, had maximum 24-hour concentrations of about
994 ug/rn  (0.35 ppm) for S02 and about 546 ug/ni  for smoke ..-.     jt has
been suggested    that mortality levels during this episode may have been
affected by a concurrently occurring physician's strike in London; but the
strike referred to actually occurred the week before the air pollution episode.
Thus, one would have to assert that it was the return of the physicians to
work that may have contributed to the observed increases in mortality as an
alternative to the induction of mortality by the elevations in air pollution.
                                     Q
     One study, by Gore and Shaddick,  has associated sharp increases in
mortality with four milder episodes of high air pollution between  1954 and
1956 in London.  Using a 7-day moving average of deaths, the authors concluded
that significant increases in the number of deaths occurred when 24-hour mean
BS concentrations exceeded 2000 ug/m  and the 24-hour mean S02 concentration
was at least 1150 ug/m3 (0.4 ppm).
                                   14-41

-------
     The data from the London air pollution episodes do not clearly delineate
the effects of specific pollutants acting alone or in combination.   However,
during these periods characterized by heavy fog, low wind speed and high
humidity, the conditions for the formation of secondary pollutants may have
been better than usual.  One of these conditions could be the presence of
impurities in the particulate matter that could serve as catalysts for the
reactions that form secondary pollutants, such as the transformation of sulfates
from sulfur dioxide (SO^).  Holland et al. (1979)    draw attention to iron as
an  impurity in coal as possibly being involved in catalyzing atmospheric
conversions of certain sulfur compounds to more toxic forms.  The concentrations
of  sulfates were not recorded, but according to current knowledge they could
have likely been very  significant components of the pollution, related both to
the particulate matter and the precursor SOp.  In addition, the effects of low
temperatures may have  been important.
     Episodes of acute air pollution have also occurred in the United States,
but no  single event has reached the proportions of the major London episodes.
Studies  have been consistent, however, in showing that increases in total
mortality, and in some cases cause-specific mortality and morbidity, were
associated with the major episode in Donora in 1948 and, also, with episodes
in  New  York City.   "     In these studies, increases in mortality have generally
been related to 24-hour mean S02 concentrations above 1000 pg/m3 (Table 14-6),
together with measured particulate matter above 5.0 coefficient of haze units
(CoHs).  Ingram and Golden154 estimated that 5.0 to 6.0 CoHs was approximately
equivalent to 570 to 720 ug/m3 of BS as monitored in England.
     The estimates of excess mortality reported from the five New York episodes
were derived by comparing daily deaths during periods of high air pollution
                                   14-42

-------
                             TABLE 14-6.   ACUTE AIR POLLUTION EPISODES IN THE  UNITED  STATES
24 Hour
pollutant concentrations*

Location
Donora, Pa.

Detroit
New York City


New York City
»-•
•f New York City
5 New York City
New York City

Date
Oct. 1948

Sept. 1952
Nov. 1953


Dec. 1962
Jan 1963
Jan-Feb 1963
Feb. -Mar. 1964

Reference
(149)

(230)
(151)


(150)
(150)
(153)
(153)
Estimated
excess deaths
20

t infant mort.
200


90
7
" f
405-647C
50
S02, max particulates,
ug/m3a
max:
>1140 (0.4 ppm)
2620 (1.0 ppm)
1000 - 1500
Max (1 hour)
2288 (0.86 ppm)
1890 (0.72 ppm)
1830 (0.7 ppm)
1570 (0.6 ppm)
1570 (0.6 ppm)
CoHsb

___

5.0


6.5
6.0
7.0
5.0
ug/m3 TSP

— — —
>200
570


800
720
880
570
^Conversions:         ,
 1 ppm S02 = 2620 ug/m

b5-6 CoH = 370-720 ug/m3 TSP

clnfluenza outbreak also present

-------
with daily deaths for the same period in the years immediately before or



following the episode   '    or by calculating daily deviations from a 15-day



moving average of daily deaths.     The number of deaths in New York City was



reviewed for excess mortality in relation to the air pollution episode of



November 1953 by Greenburg et al.     Excess deaths were related to elevated



concentrations of sulfur dioxide and suspended particles.  Average daily smoke



shade  (particulate matter) measured in Central Park was  in excess of 5.0 CoH



units  (568 ug/m3 TSP), while the S02 rose during the episode from the typical


                                               3            3
New York City 24 hr average of between 400 ug/m  to 532  ug/m  (0.15 to 0.20



ppm) to 24 hour averages of 1000 to 1500, and reached a  maximum level of 2288



ug/m  (0.86  ppm), which was probably a half-hour value.  For this episode,



 there was  a  lag effect and excess deaths were distributed among all age groups.



 The number of deaths, although not showing the marked rise seen in some of the



 London episodes, was  above average for comparable periods before and immediately



 after the  incident.   For the period November 15 to 24, 1953, the average



 number of  deaths per  day was 244, whereas during the 3 years preceding and



 following  1953, the average was  224 deaths per day for the same calendar



 period.



      A later New York City episode (1962) was also studied by Greenburg et



 al.,   but  they did  not discern any excess mortality.   McCarroll and  Bradley



 and McCarroll,    however, did find evidence of excess mortality arising  from



 acute episodes  in New York City  in November and December of 1962, January and



 February of  1963, and February and March of 1964.  In their studies, those



workers compared 24-hour average levels of various pollutants with  New York



City mortality  figures, employing daily deviations from  15-day  moving  averages.



 Pertinent  air quality measurements were performed  at  a  single  station  in  lower



Manhattan, and  fluctuations in the values at  this  station  were  known to correlate
                                    14-44

-------
well with those at another station 6.5 miles away.   Excess deaths during the
                               v

first episode peaked on December 1, 1962 one day after the daily average for


sulfur dioxide concentrations peaked at 1886 ug/m3 (0.72 ppm) and smoke shade


levels peaked at 6.5 CoH units (800 ug/m  TSP) during a period of atmospheric


inversion and low ground-wind speed.  The increased death rates were shared by


the 45 to 64 age group and those over 65.  A later episode, occuring around


January 7, 1963, was associated with an SO. concentration above 1834 ug/m


(0.7 ppm) and a smoke shade value of 6.0 CoH units (720 ug/m  TSP).   Some days


did not have excess mortality.  During another episode between January 29 and


February 13, 1963 a peak death rate was apparently superimposed upon an elevated


death rate average due to the presence of influenza virus in the community;


daily pollutant levels averaged about 1570 ug/m  (0.6 ppm) for SO. and 6.0 for


CoH units (720 ug/m  TSP).  A fourth episode of excess mortality (April 1963)


did not show sharp increases  in air pollution.  A fifth episode (February to


March 1964) again showed simultaneous increases in air pollution and mortality.


S02 was over 1570 ug/m  (0.6  ppm) and TSP was 570 ug/m  (5 CoH).


     Severe air pollution also encompassed the New York City area during


the Thanksgiving weekend, November  23 to 25, 1966.  The maximum 24-hour average


of hourly SO. values, as measured by electroconductivity, was 1,340 ug/m   (0.51


ppm) on November 23, and 1,230 and  1,020 ug/m  (0.47 and 0.41 ppm) on  the  24th

                                                          3
and 25th.  The maximum hourly concentration was 2,670 ug/m   (1.02 ppm).  Smoke


shade values were above 5 CoHs  (570 ug/m  TSP) on the 3 days.  The average


number of daily deaths during the 7 days of the air pollution episode  was  261


compared with the expected value of 237  for control periods  in 6  surrounding


years.229
                                   14-45

-------
               230
     In Detroit    a rise in infant mortality and deaths in cancer patients



occurred over a 3-day period in September, 1952, accompanied by a rise in the



3-day mean suspended particulate matter above 200 ug/m  and an Instantaneous



S02 maximum of 2,620 ug/m  (1.0 ppm).  This is not believed to be related to



cold temperatures that often characterized the London episodes.



     Direct, precise comparisons of the pollution data from the London and



United States episodes, it has been asserted,    cannot be made because of



differences in the methods used for measuring air pollution concentrations.



However,  even rough comparisons accomplished by interconversion of BS, CoH,



and  TSP  (by means of the  approaches discussed in Chapter 3) suggest that the



pollution must have been  much greater in London.  This is consistent with the



 respective health findings indicating that, in a population of approximately



 the  same size, the estimated number of excess deaths was much higher in London.



 than in  New York.  Of  course, these differences may have also been caused by a



 number of factors, including the accuracy with which the air measurements used



 reflected exposure for the total population, and the fact that the concomitantly



 occurring pollutants may  have been quite different and might have acted together



 to increase the  impact on human health.  It is known also that acute episodes



 of excessive mortality have  not been associated with all days of  high  pollution



 in New York or London.152'163



      Investigations in Rotterdam (Brasser et al.302; Joosting303; Biersteker315)
 indicate  that  a  positive association exists between air pollution  and  total



 mortality as shown  in Table 14-7.  Biersteker315 found excess  mortality to be



 associated with  24  hour smoke and S02 levels of approximately  500  ug/m3 (OECD

                    2

 smoke)  and 1000  ug/m  (sulfur dioxide method), respectively.   Brasser  et



 al.     found similar relationships when the S02 value of  500 ug/m3 per 24
                                   14-46

-------
                                         TABLE 14-7.   OTHER ACUTE AIR POLLUTION EPISODES
24 Hour mean
pollutant concentrations
Location
Osaka
Rotterdam
Date
Dec. 1962
varies
Reference
100
232
Estimated
excess deaths
60
varies
S°2/3a
ug/m3
262
300-500
TSP
(ug/m3)
1000
d
     JParticulates to S02 ratio of 1:3-1:4 (303)
-fc.
I

-------
hours is surpassed for a few days.   This effect may begin to occur at lower


concentrations, somewhere between 300 and 500 ug/m3 S02 (0.11 to 0.19 ppm) per


24 hours, based on S0? measurements made with the hydrogen peroxide titrimetric


method.232'302  The Rotterdam episodes of January to February 1959 and December


1962 have also been discussed by Joosting.     Particulate levels are generally


low  in  Rotterdam.  On comparing particulate and S02 concentrations, Joosting


has  characterized the ratio of particulates to S02 as low (1:1), moderate


(1:1.5  to 1:2), and high (1:3 to 1:4).  Rotterdam is in the last category,


whereas London is in the first.


     Watanabe100  (Table 14-7) found 60 excess deaths (about 20 percent) associated


with a  1962  air pollution episode  in Osaka, Japan, in which the 24-hour mean


SOp  concentration exceeded 260 ug/m  (0.1 ppm) together with concentrations of

                          3
TSP  greater  than  1000 ug/m  , both  measured at a central station.  Low temperatures

                                                   312
may  have been partly responsible for these effects.


     When a  marked  increase in air pollution is associated with a sudden


dramatic rise in  the death rate or illness rate that lasts for a few days  and


both return  to normal shortly thereafter  (as documented in the above studies),


a causal relationship is strongly  suggested.  Sudden changes in weather,


however, which may  have caused the air pollution  incidents, must also be

                                                                . pop
considered as another possible cause of the death rate increase.     On the


other  hand,  the consistency of the above  associations between S02 and particulate


matter  elevations and increases in mortality render  it extremely  unlikely that


weather changes alone provide an adequate explanation for all such  observations.


This view is further reinforced by (1) the fact that at  least some  episodes


(e.g.,  the 1952 Detroit one) were  not accompanied by sharp  falls  in temperature;


and  (2) other weather changes of similar  magnitudes  to those  accompanying the
                                    14-48

-------
above pollution episodes  are not usually associated  with  such  dramatic



increases  in mortality in the absence of greatly increased  levels  of  S0?,



particulate matter,  or other pollutants.



143.3  Mortality Associated with Short-term Variations  in  Pollution



     A number of investigators have reported on relationships  in the



United States between mortality and daily variations in  air pollution during



non-episodic periods.155-160,170,171




     Schimmel and Greenburg    used more than 500,000 death certificates  for



New York City in a study of daily mortality from January 1, 1963 to December  31,



1968.  The study attempted to relate fluctuations in mortality to  daily S02



and smoke shade, after adjusting for weather and other temporal  factors,  and



recognized the problems of auto- and cross-correlation.   The authors  concluded:



"...that with a high degree of probability a certain portion of deaths  would



not have occurred at the time they did, in the absence of air pollution."  By



using their fully adjusted model, their estimate of excess deaths  was 18.2 per



day.  Pollution estimates only came from a single station (Harlem), where SO-



averaged 0.17 ppm (450 ug/m ) for the study, while smoke shade averaged 2.1


                   3

CoH units (203 ug/m  TSP).  The authors attributed approximately 20 percent of



the excess deaths to SO- and 80 percent to smoke shade, but it has been noted



that this represents stretching interpretation of the epidemiologic data to a



point of precision beyond that allowed by existing techniques.     Schimmel


             155
and Greenburg    also performed cause-specific analyses for ten different



cause categories.  Estimated excess deaths were high in both the respiratory



disease category and the coronary heart disease category.  The linear  regression



model of Schimmel and Greenburg assumes that excess deaths rise in proportion



to the increase of the S0? or smoke shade levels over the  range of values they



studied.
                                   14-49

-------
     Schimmel  and Murawski    '     expanded the death certificate data to



include information through 1972.   Using a revised model, they revised their



estimate of premature deaths to be 2.8 percent (about 7 deaths per day) and



stated that the lower estimates were "...explained by a fuller correction for



seasonal trends and temperature effects."  They found a colinearity of temperature



and SOp, but a curvilinear term for temperature may be more appropriate due to



the known increase in mortality at extreme temperatures.   They estimated the



percent excesses attributed to SOp and to smoke shade.  Based on separate



analyses for the years 1963 to 1966, 1967 to 1969, and 1970 to 1972 the authors



concluded that the reduction in SOp levels had not resulted in decreased



estimated premature deaths due to SOp.  They further stated that "the SOp



association with mortality is not really a measurement of SOp effects but,



rather, SOp is to be viewed as an index of the effects of the more volatile



components of combustion activity."


             187
     Schimmel    has presented additional data and analyses for the 14-year



period  of 1963 to 1976, leading to results and conclusions similar to those



derived from the earlier papers by Schimmel and Murawski.   '


                    184~5§§ 301 312
     Several reviews    "   •   •*" have been critical of the findings and



interpretations reported in the above Schimmel papers.1        Some of the



same criticism may also apply to certain other studies of the short-term



effects of air pollution on mortality.  With particular reference to the



Schimmel papers, various reviewers noted that large standard errors for reported



S02 effects, and others, complicate interpretation of the Schimmel findings.



Also, it was pointed out,     it is not particularly surprising that some weak,



but statistically significant, relationships were found  (especially in the



earlier Schimmel papers) in view of the enormous numbers of regression analyses
                                   14-50

-------
carried out and the consequent likelihood that at least a few statistically



significant associations would be found by chance alone.   Conversely,  it was


     18^
noted  ? that,  because of considerations not taken into account In SchirmneVs



later papers,  one cannot rule out a possible significant contribution  of SO,,



to mortality levels observed in New York City—although Schimmel  and his

                                         &foity£<*' «e*~

colleagues failad to find any significant^assrociations between
S02 levels and decreasing- mortality rates over the same time- span.   One factor



that may strongly limit the potential for Schimmel 's statistical  approach (to



convincingly demonstrate significant associations, or lack thereof, between



various air pollution parameters and mortality) was his use of air quality



data from a single monitoring site in New York City.  Thus, the crucial air



quality measurement data imputs, upon which virtually all of the rest of his



analyses very heavily depend, may not have adequately represented exposures


                                                312
for the entire New York City population studied.


            158
     Hodgson    used multiple regression methods to examine the relationship



between deaths and air pollution concentrations in New York City.  He concluded



that much of the variation in deaths could be explained by the ambient concen-



trations of S0? or particulate matter (as measured in CoHs) but the monthly



average data used provided no useful quantitative information.


                                                            159
     Multiple regression analyses were used also by Buechley    to relate



daily deaths in the New York/New Jersey metropolitan area  from 1962 to 1966  to



concentrations of S0? measured at a single monitoring station.  For this



analysis, the data were adjusted for season, temperature,  day of week, and an



Influenza epidemic.  Beuchley's results have been interpreted to  indicate  that



on days on which the 24-hour mean SO- concentration exceeded 500 ug/m  (0.19



ppm), deaths were 2 percent higher than expected;    on  days when  the  24-hour
                                   14-51

-------
mean S0? concentration was 30 ug/m  (0.01 ppm) or less, deaths were 1.5 percent


less than expected (see Figure 14-3).   The authors indicated that measurement


of particulate matter (CoHs) did as well as S02 in predicting deaths, but no


data were given.  Extension of the analysis through 1972    gave Indications


of the  importance of temperature and influenza regarding short-term variations


in the  number of deaths.  The extended analysis again  indicated the association



between pollution and deaths but gave no additional information on the relative



significance of SOp or  particulate matter.


      Lebowitz    studied  relationships between air pollution exposure and


mortality in New York (1962 to 1965), Philadelphia (1963 to 1964), and Los Angeles


 (1962 to 1965), and Lebowitz et al.    performed similar studies in Tokyo


 (1966 to 1969).  These  investigators developed a model in which higher air


 pollution concentrations  (one standard deviation above season mean) were


 treated as stimuli; deaths, using various  lag periods  were treated as responses


 to these stimuli.  Although no definitive  levels were  reported, significant


 relationships  between periods of heavy pollution and increases in the number


 of deaths were found  in each area studied.  New York winter pollutant averages


 were 484 ug/m3 (.182  ppm) S02 and 150 ug/m3 TSP (2.12  CoH).   Philadelphia


 winter average TSP was  100 |jg/m  (1.6 CoH).   Los Angeles winter average  S02



 was 390 pg/m   (.148 ppm).  Adverse temperature and humidity changes  were shown


 to be very important  as well, but did not  account  for  all mortality  increases


 more directly  attributable to or closely associated with  increases  in  air


 pollution.



      A number  of reports  have investigated relationships  between  mortality and

                                                                                5-14
 air pollution  in England  during periods with  no unusual  air pollution  episodes.



 For most of these studies, 15-day moving  averages  were constructed and the


 effects of pollution were assessed  in terms of  daily  deviations  from these
                                    14-52

-------
                                                     47 D«y»
42


£ «i
u



t-
DC
0
£
_l -1

LU
CC -2
-


-



-












232
Days
-








120
Days j

-" - •








13U
Days










210
Days

-






Days











275
Days

""
-



1B4










203







99
Jays









114
Day*








.
-







-.

— —
— "
  10
              30      60  BO    140  200  300 400 SOO 650 1.000 UOO
Figure 14-3.   Residual Mortality as a Function of S0? for the       ic.q
               New York - New Jersey Metropolitan area, 1962 to  1966
                           14-53

-------
baselines.   Increases in daily deaths during the winter of 1958-59 were found



to be associated with concentrations of BS >750 ug/m3 and SOp >660 ug/m  (0.25



ppm).    Increases in daily deaths were not associated with pollutants at


                                                   14
lower concentrations.  Similar studies in Sheffield   were not as consistent.



Increases in deaths were associated with very high concentrations of pollutants,



but  random variations in the number of deaths were so large that firm conclusions



could not be drawn.



     Among the most  important British studies bearing on acute health effects



of  sulfur oxides and particulates at levels near present 24 hour air quality



standards are those  of Martin and Bradley   and Martin.   The first of these



studies  related daily mortality from all causes and from bronchitis and pneumonia



to  the  level of S0?  and smoke in London during the winter of 1958 to 1959.



The authors  found  a  considerable number of coincident peaks in pollution level



and daily mortality.  The correlation of mortality from all causes with pollutants



measured on  the log  scale was 0.613 for smoke (BS) and 0.520 for S0~.  Neither



temperature  nor humidity was significantly correlated with mortality.



      Though  the authors emphasized the relationship between change in pollution



 level  and change  in  number of deaths, an influenza epidemic occurring during



part of  the  study  may have influenced part of their results.  The authors,



however, provided  the number of deaths, smoke levels, and S02 levels from



November 1,  1958 to  February 28, 1959 in the published report on the study.   A



further  analysis of  these data was performed by Ware et al.304 but excludes



the  month of February, in which an epidemic of Type A  influenza also had  a



significant  influence on daily mortality.  For the remaining 92 days,  the



deviation of daily mortality from the 15-day moving average  (truncated  at each



end  of the series) was computed, and the average of these deviations  is given



for  intervals for  smoke level in Table 14-8 and S02 level in Table 14-9.
                                   14-54

-------
TABLE 14-8.   MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING  AVERAGE,
      BY LEVEL OF SMOKE (LONDON, NOVEMBER 1,  1958 - JANUARY 31,  1959)
              Smoke level,        Number            Mean
                ug/m  BS          of Days         Deviation
                100-199               6            -17.84
                200-299              14            -11.63
                300-399              16            -10.31
                400-499              19             -5.57
                500-599               9             18.46
                600-699               6             18.80
                700-799               7              5.31
                800-1199             10             17.17
                 1200+                5             31.37
 TABLE 14-9.  MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING AVERAGE,
      BY LEVEL OF S02 (LONDON, NOVEMBER 1, 1958 - JANUARY 31, 1959)

SO, level ,
3
ug/m BS
100-199
200-299
300-399
400-499
500+
Number
of Days
16
28
22
12
9
Mean
Deviation
-11.38
-10.78
8.50
13.45
21.25
                                 14-55

-------
     These tables suggest 500-600 ug/m  BS and 300-400 ug/m3 S02 as levels

above which increased mortality is seen, although this is not intended to

suggest a threshold for response.   In fact, the data suggest a gradient of

mortality over the entire range of air quality seen.  Although temperature and

humidity were not correlated with daily mortality, both pollution level and

daily mortality increased throughout the period of study, and the possibility

of other extraneous seasonal variables contributing to this association cannot

be ignored.  On the other hand, it has been suggested    that the use of

15-day  moving averages may underestimate the magnitude of effects associated

with some  episodes of high air pollution and, thusly, even more marked increases

 in mortality might be attributable to the increases in S02 and particulate

matter.

      A  similar  analysis was carried out by Martin for the winter of 1959-60.

This winter had fewer incidents of high pollution.  The significant positive

 correlation between mortality and pollution was, however, still present although

 the  coefficients  were somewhat lower than in the previous year.  Tables 14-10

 and  Table 14-11 show Martin's results combining high pollution days from  1958

 to  1959 and 1959  to 1960, after excluding days on which pollution  had  fallen

 from a  previously higher  level.  The mean deviation was positive in every

group.   Bronchitis mortality was also significantly, though  less strongly,

correlated with pollution level, but pneumonia mortality was  not correlated

with pollution.

      Holland et al. (1979) discuss the  above findings on mortality as  follows

(ejnphasis  added):

           The nearest approach to an episode of high pollution in  London
      in the last  10 years has been one  lasting about  two days,  on  December
      15-16, 1975.  On that occasion, the  24-hour  average concentration of
      smokg (BS)  rose to 546 ug/m  , and  that of sulfur dioxide to 994
      ug/m  .  A  comparison of the crude  weekly totals  of  deaths  for the
                                    14-56

-------
TABLE 14-10.   MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING AVERAGE,
                 BY LEVEL OF SMOKE (LONDON, 1958 to 1960)

Smoke level ,
pg/m BS
500-599
600-699
700-799
800-1199
1200+
Number
of Days
9
6
9
8
7
Mean
Deviation
5.2
13.0
9.2
15.6
40.0
TABLE 14-11.  MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING AVERAGE,
                   BY LEVEL OF S02 (LONDON, 1958 to 1960)
               S05 level,         Number            Mean
                     3
                 pg/m             of Days         Deviation
                400-499               9              9.0
                500-599               6             11.6
                600-799               9             16.0
                800-899               6             19.2
                  900+                5             39.6
                                  14-57

-------
weeks around that time shows an excess of 100 to 200 in the week of
the fog; but, as in a number of the other episodes, there was also a
fall in temperature that may have been a contributory factor (11,
12).  Relationships between short-term changes in mortality and low
temperatures have been recognized for many years, having been demonstrated
in  London data as far back as the nineteenth century (13, 14).
     In addition to studies of the major episodes of high pollution,
attention has also been paid to day-to-day variations 1n mortality
in  London since 1952.  Gore and Shaddick (15) calculated seven-day
moving averages of deaths in the inner area (County of London) only,
over winter periods from 1954 to 1956, and they found sharp increases
in  association with four foggy periods.  Their own assessment was
that the  increases in deaths were particularly marked when pollution
(as 24-hour averages) exceeded 2000 ug/m  smoke (BS), with 0.4 ppm
(1149 ug/m  ) sulfur dioxide.  This was a very conservative judgment,
and there were increases in deaths in their series with^smoke and
sulfur  dioxide concentrations of the order of 1000 ug/m  and 750
ug/m  ,  respectively.  Such changes may, in part, have been attributable
to  other  associated environmental conditions, such as cold weather
(that  is, within minimum temperatures falling below freezing point),
but, ajs  i_n  other studies of the kind, there i_s m> satisfactory way
of  distinguishing  the effects o_f these factors.  It is important in
trying  to elucidate the influence of temperature independent of
other  meteorologic variables to compare like with like.  Thus, cold
Januarys  should be compared with warm Januarys, and cold Julys with
warm Julys.  Most  work has shown an association between respiratory
disease and cold weather (e.g., see reference 16).
     The  main  series  of studies on day-to-day variations in deaths
 in  Greater  London  is  that by Martin and colleagues.  In most of
 their  studies, 15-day moving averages have been calculated and the
 short-term  effects of pollution have been assessed in terms of
 deviation from these.  (The moving average for each day refers to
 the average number of deaths for the day in question, together with
 seven  days  on  each side of it.)  The general seasonal trends and the
 direct effects of  epidemics (notably of influenza) are eliminated  in
this way, although there is a risk of underestimating the magnitude
of  effects  associated with some episodes of high pollution.   In  the
winter of 1958-1959,  when there were many days with high pollution,
Martin and  Bradley (17) reported a marked association between daily
deviations  in  deaths, and concentrations of smoke or sulfur dioxide.
These  increases in deaths were consistently related to day-to-day
 increases in concentrations of the pollutants, and the authors
originally  assessed their results in terms of the increments  in
pollution only.  They also showed that there were significant correlations
between deviations in deaths and the actual concentrations of pollutants
on  the  same day.   No  correlation technique such as this, however,
can show  the full  impact of pollution.  The effects are  sometimes
dalayed by  about one  day, but since there is no uniformity  in any
such lag  effects during a winter season, it cannot be  dealt with
simply  by introducing a one (or more) day lag between  the  pollution
and mortality  figures.
                               14-58

-------
          Martin and Bradley displayed their results in detail  in tabular
     form, so  that days with elevated pollution could be linked with
     changes  in  mortality in the most appropriate way.   Subsequently,
     increases in deaths (of 20 or more on a total of the order of 200-400
     per day)  were considered to be associated with 24-hour mean concen-
     trations  of smoke  (BS)  >750 ug/m  and S02 >0.25 ppm (710 ug/m )
     (18).  It was not  possible then, by this technique, to detect
     variations  in daily deaths at lower concentrations, and this finding
     has not  been contradicted HI any way by subsequent events.   Indeed,
     with a general  decline  in pollution levels in London such that
     24-hour  (BS} smoke concentrations are now seldom,  if ever, as high
     as 750 ug/m , there jjs  still ITO evidence o_f associations of any
     day-to-day  variation jjn mortality with relatively minor peaks i_n
     pollution.

                                           301
     Not mentioned by Holland et al.  (1979)    in their above analysis  is the

fact that Martin and his colleagues reported that they found no significant

association between excess mortality and temperature.  As stated by Martin and

Bradley   in  discussing their findings for the winter of 1958 to 1959  (emphasis

added):

          Temperature is the climatic factor most frequently considered
     to have  an  association  with fog mortality.  Russell (1924, 1926)
     drew attention to  the importance of cold weather as a factor in
     increasing  mortality rates during fogs, but his investigations were
     based on weekly means and his results are not, therefore, applicable
     to the immediate effects of individual incidents.   By itself, unless
     well below  freezing point, temperature appears to have comparatively
     little immediate effect on winter mortality and this i_s exemplified
     by the low  correlation  coeficient (-0.030) which was found during
     the winter  of 1958-59.   A range of 30-38°F j_s characteristic £f most
     winter fogs and temperatures consistently below 30°F are the exception.
     At the other extreme several fogs each associated with a mortality
     peak were found in November and December.  1958, with temperatures
     substantially over 38°F.  As yet details have not been collected of
     a sufficient number of  incidents to estimate mathematically the
     effect of temperature on fog mortality, but apart from the exceptional
     incidents with very low temperatures H appears on present information
     to have  a comparatively minor influence.

See Appendix 14-B for more detailed review of literature on associations

between mortality and temperature.

     Also overlooked by Holland et al. (1979)    in their above analysis  is

the fact that other tests (beside correlation techniques) of possible associations
                                   14-59

-------
between mortality, S02 and participate matter levels and temperature changes
can be utilized to assess results reported by Martin and colleagues.  The
report by Martin and Bradley   presents a daily mortality-BS-S02 data set in
tabular form.  That detailed presentation of data allows for the validity of
some of the above blanket statements by Holland et al.    to be evaluated
by means of certain nonparametric statistical tests.
Timing of Observations
     The mortality data  from Martin and Bradley are reported on the calendar
 day  of the date of death, that is 0001-2400.  The S02 and smoke data for the
 given day are  an  average for seven Greater London stations obtained from the
 24-hr  collection  values  recorded from the bubblers and filters which were
 turned off at  0900 the same day.  The meteorological observations  for London
 (Croydon) give the maximum temperature between 0900 to 2100.  The  assignment
 of the minimum temperature is  less certain.  As stated in the footnote  of the
 meteorological observations table "Minimum temperature night period 21-9 h.
 and are  entered to day of reading."
      If  strictly  interpreted,  the recorded daily minima may not be independent
 since  the temperature at 2400  may be the minimum on day 1 and the  temperature
 at 0100  may  also  be the  minimum on day 2.  That is, some of the minima  in the
 table  could  be 1  or 2 hours apart and other minima values could be 46 to 47
 hours  apart.   With this  timing uncertainty in mind, we can model  these  data as
 follows.
     The recorded minimum temperature recorded on day 1 influences the  pollution
 level recorded over the  time period 0900, day 1 to 0900, day  2.   Because
 mortality from relatively low  pollution  levels would  take a period of  time  to
 occur, we expect  the mortality on day 3  to be influenced by the  pollution
                                    14-60

-------
recorded on Day 2.  Such a delay is not unreasonable since there is likely to

be a finite time from the stimulus which may lower resistance to a preexisting

low grade infection until the crisis stage is reached or for other fatal

effects to be manifested.  In addition, respiratory patients in hospitals

might be placed in oxygen tents, with heroic measures taken to keep them alive

from day 2 to day 3.

     A careful inspection of the mortality and temperature tables lead us to

the period December 8 to December 24, 1958 for the detailed study.   This

choice was made because of the fact that daily mortality rates tended to

steadily increase over the winter period, November 1958 to February 1959.

This upward trend may have been caused by a combination of several  of the

following factors:

1.   Decreasing Temperatures :  The monthly mean minima are shown in Table

     14-12 with the corresponding average for the years 1931 to 1950.  Note

     that while temperatures in November and December were warmer than normal,

     those in January and February were somewhat colder than normal.

                                 TABLE 14-12.
                 MINIMA TEMPERATURE DATA FOR LONDON (Croydon)

Month
November 1958
December 1958
January 1959
February 1959
i
2. Presence of Influenza in
1958 to 1959
mean minima
40.6
38.1
31.5
34.7
London
1931 to 1950
average minima
40.1
37.0
36.1
35.7

     Martin and Bradley report that an influenza epidemic occurred  during  this

winter period.  The peak in mortality and peak in pollution occurred  almost  on
                                   14-61

-------
the same days in February 1959; however, this may not have been happenstance



but indicitive of a true pollution effect of exacerbation of the preexisting



disease.



3.   Cumulative Dosage Effect



     A repeated dosage of pollution to a susceptible individual may serve to



lower the bodily resistance to such a point that an insult which might have



produced mild discomfort in November could produce a pulmonary crisis in



February.  This would result in gradually increasing mortality trends over the



course  of the winter, likely peaking in February along with peak pollution



levels  and influenza effects.



     By choosing December 1958, which was relatively warm, we avoid possible



temperature  complications, the influence of the later influenza outbreak, and



the  "sampling without replacement" problem as potential alternative explanations



for  mortality effects varying as a function of S02 and particulate matter



pollution levels.



     The pollution  levels and minimum temperatures given in Table 14-13 were



all  in  the range where Holland et al.    stated that no discernible mortality



 (20  or  more  on  a total of the order of 200-400 per day) effect should be



observed (that  is,  when BS < 760 ug/m , S02 < 0.18 ppm, T minimum > 33°F).



     In order to establish the robustness of these pollution data during this



period,  the  day-to-day variation is evaluated by a sign-test.  If we assume



that SO,, and BS are independent of each other, then during the 17-day period,



the  16  day-to-day changes should occur randomly.  Therefore, one could expect



8 days  when  S02 and BS rise or fall together and 8 days when they do not rise



and  fall together.  As shown in Table 14-13, there are only 2  days  of opposite
                                   14-62

-------
   TABLE 14-13.   POLLUTION AND TEMPERATURE DATA  FOR  LONDON, DECEMBER 1958
Date
December
8th
9th
10th
llth
12th
13th
14th
15th
16th
17th
18th
19th
20th
21st
22nd
23rd
24th
Total deaths
(all causes)
307
305
288
285
308
291
289
334
343
319
307
284
297
256
297
311
296
Smoke BS
(ug/m3)
720
290
400
440
430
340
540
760
670
560
560
300
150
190
430
520
430
Minimum
S09 temperature
(ppm) (°F)
0.175
0.117
0.112
0.113
0.118
0.078
0.105
0.162
0.134
0.122
0.121
0.058
0.042
0.054
0.084
0.128
0.106
37
36
35
36
38
36
33
36
39
40
42
46
50
45
39
38
39
Heating
degrees
(60-T min)*
23
24
25
24
22
24
27
24
21
20
18
14
10
15
21
22
21
*Heating degrees  are expressed in terms of 60°F—the minimum
 temperature (°F) recorded for a given day at London (Croydon).
 Tljis assumes that residential space heating is utilized proportionally
 in relation to decreases in outside ambient temperature below 60°F.
                                    14-63

-------
variation (Dec. 9-10 and Dec. 11-12).  The chi-square test with 1-degree of


freedom is 2 (6)2/8 = 9 (P = 0.003), so one rejects the null-hypothesis of no


association and accepts the alternate hypothesis of BS - S02 association.  The


averaging of air quality data from 7 monitoring stations apparently removes


the routine or expected experimental errors, and the average is robust as


expected.  One can also perform the same test on smoke (Day 2) vs temperature


as heating degrees (Day 1) data, and SOp (Day 2) vs minimum temperature as


heating degrees (Day 1).  Because of the one-day offset, we have 15 variations


with  null expectations of 7.5 each.  For BS there are only 2 days with opposite

                                                                          2
variation, so  that the chi-square test with 1-degree of freedom is 2 (5.5) /7.5 = 8


(P =  0.005) which demonstrates the close association of smoke (BS) with heating


degrees.  Repeating the evaluation, but for SOp and temperature (heating


degrees), there are 4 days with opposite trend so that the chi-square with


1-degree  of freedom is 2  (3.5) 77.5 = 3.26 (P = 0.07) which is on the edge of


statistical significance  and highly suggestive of an association between S02


and temperature.


      These evaluations show  how the sign test can demonstrate an association


in  cases  where one expects,  from prior knowledge, an association to exist.


Mortality Association with Temperature and Pollution


      Because temperature  is  assumed to be offset from mortality by 2 days, we


have  only 14 day-to-day changes and an expectation of 7 similar changes  and 7


dissimilar changes if mortality Day 3 is independent of the minimum tempera-


ture  Day  1.  The data set gives a total of 4 opposite sign changes, so  that


the chi-square test with  1 degree of freedom is 2 (3)2/7 = 2.57  (P = 0.13).


Note,  if  we test mortality Day 2 with temperature Day 1; P £ 0.50.  Thus,


temperature does not appear  to be statistically significantly  related to
                                   14-64

-------
mortality during the December, 1958,  period studied.   Performing similar



computations with both BS and SOp on  Day 2 and mortality on Day 3,  however,



there are 15 possible changes and only 3 were in the  opposite direction,

                                                                o

leading to a chi-square test with 1-degree of freedom of 2 (4.5) 77.5 =5.4



(P = 0.02).   Thus, it appears that mortality may be significantly associated



with increases in S02 and particulate matter at levels (190 - 520 ug/m  BS;



150 - 375 Mg/m3 S02) below those stated by Holland et al.301 to be  the lower



limits where mortality occurs.  Furthermore, such mortality effects appear to



have occurred in the absence of any significant influence by temperature,



which was always above freezing and averaged approximately 39°F (minimum)



during the December period studied.



     Similar thorough revaluations are being carried out for mortality data



from the 1975 London episode, when 100-200 excess deaths occurred and pollution



peaked for only 2 days, and also from a 1975 Pittsburgh episode, when 20



excess deaths were reported.  Apparently, Holland et  al.    overlooked the



possible mortality effect in Pittsburgh, Pennsylvania, which was noted at the


              82                              301
end of a paper   cited by them (Holland et al.    reference 5-21).   These



mortality effects associated with the  Pittsburgh episode were described by


                    12
Riggan et al. (1976)   and were also reported in a companion paper presented


                                                                    341
at the 1977 Puerto Rico epidemiology symposium (Riggan et al., 1977)    attended



by several of the authors of the Holland report.     It is not implausible



that these excess deaths in Pittsburgh were related to the pollution  levels,



because these pollution levels were similar to those found in London  from



December 8-24, 1958.  There exists another insidious similarity between the



London episodes and the Pittsburgh episode in 1975.  As Holland et al.  (1979)



aptly pointed out on page 556 of their report, sulfuric acid might be a
                                   14-65

-------
component of crucial importance.   The catalytic reaction of sulfur dioxide to
sulfuric acid on moist particulate materials might have been occurring in
London where iron is present as an impurity in coal (as noted by Holland et
al.310), and also in Pittsburgh where ferric oxide is likely present as "an
                                                                   342
impurity" associated with steel making operations (see Sugden, 1967   ).
Consequently, more credence must be placed in the possibility that mortality
in air pollution episodes can and has occurred even under present day air
quality  conditions in the United States and Britain.
                          222
      Glasser and Greenburg    carried out an analysis of daily mortality in
New  York City during the 5 year period 1960 to 1964, using only data from the
months  October  through March.  Deaths were analyzed both as deviations from a
15-day  moving average and as deviations from the 5-year average for each day.
 Results from the two analyses were said to be qualitatively similar.  Twenty-
 four hour average pollution data were based on hourly SO^ and bihourly smoke
 shade (CoH) readings.  The  results are adequately summarized by the unadjusted
 analysis, which is  given in Table 14-14 and 14-15.  This analysis suggests a
 mortality effect for smoke  shade above 3.0-4.0 CoH  (350-400 ug/m  TSP) and S02
 above 786 ug/m  with very distinct increases above  5 CoH (568 ug/m  TSP)  and
 786  pg/m  S02.   In  cross-tabulation of daily mortality by S0? and smoke  shade
 level,  S02 appeared to be more strongly related to  mortality and was  used as
 an index of pollution in some  analyses.   In a multiple regression analysis
with temperature and rainfall, S02 was more strongly associated with  mortality
than either weather variable.  This association persisted  in analyses of
bimonthly periods.  Although the observations are dependent, Glasser  and
Greenburg computed  standard errors for the mean deviations  by assuming
independence.   Most of these standard errors were near 2.0, though  the entry
18.80 in Table  14-14 had a  standard error of 4.3.
                                   14-66

-------
        TABLE  14-14.   AVERAGE  DEVIATION  OF  DAILY MORTALITY  FROM NORMAL,
BY LEVEL OF  SMOKE  SHADE  (CoH),  (NEW  YORK, 1960  to  1964, OCTOBER THROUGH MARCH)

Smoke shade
level, CoH
<1.0
1.0-1.9
2.0-2.9
3.0-3.9
4.0-4.9
5.0-5.9
6.0+
Number
of days
26
160
318
239
83
19
9
Mean
deviation
-2.79
-1.55
-2.37
1.48
2.52
18.80
17.18
        TABLE 14-15.   AVERAGE DEVIATION OF DAILY MORTALITY FROM  NORMAL,
        BY LEVEL OF S02 (NEW YORK,  1960 to 1964, OCTOBER THROUGH MARCH)

SO, level ,

(jg/m
<262
262-524
524-786
786-1048
>1048
Number

of days
112
311
172
66
80
Mean

deviation
-3.49
-3.08
1.78
9.42
11.86
                                   14-67

-------
     To analyze possible mortality effects of even lower levels of pollution,
even the 15-day moving average method is not sufficiently sensitive.  Some
authors have argued that more sophisticated adjustment techniques are necessary
to ensure that seasonal and temperature effects are eliminated 1n adjusted
analyses.
     Kevany et al.   used partial correlation analysis to develop a relation-
ship between SO,,  and smoke pollution in Dublin, Ireland, and specific mortality
data derived from death certificates between 1970 and 1973.  Some forms of
mortality were reported to be occasionally correlated with SO. levels of 100
to  150 ug/m  .  The findings, however, were internally inconsistant  and based
on  truncated distributions of pollutant concentration estimates.
      In summary,  the results of  the above studies of mortality associated with
 short-term  variations  in  air pollution collectively provide further evidence
 for associations  between  excess  mortality and marked elevations  in  atmospheric
 concentrations of S0?  and particulate matter.  Again, however, as in the case
 of the earlier discussion regarding acute pollution episode mortality effects,
 it must be  noted  that  in  assessing various published results or  the data sets
 and analyses upon which the  results are based, it is often difficult to
 differentiate  precisely the  relative contributions to the  observed  excess
 mortality rates  of:   (1)  S02 or  particulate  matter, acting alone or in
 combination;  and  (2)  the  possible effects of covarying  changes  in temperature,
 other meteorological  parameters  or concurrent  outbreaks  of influenza or  other
 diseases.
      Nevertheless, based  on  several methodologically  sound studies  which have
 taken the latter  factors  into  account,  it appears to  be possible to derive
 credible,  albeit  rough, quantitative estimates of particulate  matter and SO.
 concentrations associated with the occurence of  increased mortality in
                                    14-68

-------
disparate geographic areas.   Thus,  for example,  the studies  of  Martin  and



Bradley   and Martin  strongly point toward notable increases  in  mortality  in



London having occurred in association with repeated short-term  exposures to



particulate matter levels exceeding approximately 500-600 ug/m  BS  and S0?



levels of 300 to 500 ug/m .   Careful further analysis  of their  data, as detailed



above, suggests possible significant mortality effects at even  lower levels  of



BS and SO^, in the absence of significant temperature  effects.  In  addition,


                                     222
analysis of the Glasser and Greenburg    study points  toward increased mortality



in New York City, occurring in association with particulate  matter  levels


                                       3                               3
rising above approximately 350-400 ug/m  TSP) and S02  above  524-786 ug/m  .



14.3.4  Cross-Sectional Studies of Mortality



     Numerous qualitative studies have been performed  comparing mortality  in



areas of lowest-to-highest pollution concentrations.   Most of these studies do



not account for cigarette smoking,  occupation, social  status,  and/or mobility



differences between areas, thus making it difficult to define accurately  any



quantitative relationships between mortality and air pollution parameters.



Many such studies are summarized in Table 14-16.  These are  followed  by a



discussion in more detail of other studies yielding better quantitative



information bearing on the present discussion.


                   199
     Buck and Brown    found a gradient of mortality from chronic respiratory



illness from 1955 to 1959 that coincided with areas of lowest-to-highest



pollution in 1962 in middle class areas.  The pollution concentrations and



mortality were from different years.  This study did not find a significant



relationship between smoking and mortality from lung cancer but the authors



estimated that increased mortality occurred with levels of over 200 ug/m  BS


            •3

and 200 ug/m  S0?.  Controlling for regional smoking and socio-economic
                                   14-69

-------
     TABLE  14-16.
                  QUALITATIVE ASSOCIATION OF GEOGRAPHIC DIFFERENCES  IN  MORTALITY
                  WITH RESEDENCE IN AREAS OF HEAVY AIR POLLUTION
Pemberton-aqd
 Goldberg^"
Stocks
      138,164-167
      224-225
Gorham
Gore  and Shaddick
    -in   • ii.2ZD
  and  Hewitt
Haastrom et al.
 Zeidberg et al
 Sprague et al.
16
 17
 Lepper  et  al.
              227
 Jacobs aa
  Landoc
                    1950-1952 bronchitis mortality
                     rates in men 45 years of  age
                     and older  in county boroughs
                     of England and Wales
                     Bronchitis mortality,  1950-1953,
                      in  urban and  rural  areas  of
                      Britian, with adjustments  for
                      population  density  and  social
                      index

                     1950-1954 deaths,  53 counties
                      of  England, Scotland, and
                      Wales

                     Mortality in London, 1954-1958
                      and in 1950-1952,  respectively
                     1949-1960 deaths for each cause
                       in Nashville, Tenn. , categor-
                       ized by census tract into 3
                       degrees of air pollution and
                       3 econimic classes  (levels
                       not accurately determined)
                     1964/1965 mortality rates in
                      Chicago census tracts strati —
                      fied by socioeconomic class and
                      S02 concentration
                     1968/1970 mortality rates
                      in Charleston, S.C. ,
                      industrial  vs. non-indus-
                      trial  areas
Sulfur oxide concentrations
 (sulfation rates) were con-
 sistently correlated with
 bronchitis death rates in the
 35 county boroughs analyzed

Significant correlation of mor-
 tality from bronchitis and
 pneumonia among men, and from
 bronchitis among females, with
 smoke density

Bronchitis mortality was strongly
 correlated with acidity of
 winter precipitation

Duration of residence in London
 significantly correlated with
 bronchitis mortality, after
 adjusting for social class

Within the middle social class,
 total respiratory disease
 mortality, but not  bronchitis
 and emphysema mortality, were
 significantly assoicated with
 sulfation rates  and social index.
 White infant mortality  rates
 were significantly  related to
 sulfation rates

Increased  respiratory disease
 death rates  in areas of inter-
 mediate and  high SOp concen-
 tration,  within  a  socioeconomic
 status, without  a  consistent
 mortality gradient between the
 areas of  intermediate and high
 SO-  concentration

Higher total  and  heart disease
 mortality rates  in industrial
 area
                                          14-70

-------
Morris et al.
            24
Collins et al.
             287
Beaker et al.
            323
Toyama
     330
Lindeberg
        321
1960-72 mortality rates
 compared to 1959-60 air
 pollution levels

Death rates in children 0-14
 years of age, 1958-1964,
 1n relation to social and air
 pollution indices in 83 county
 boroughs of England and Wales
Thanksgiving 1966 Fog,
 New York
Mortality in districts
 of Tokyo
Deaths in Oslo winters
Mortality higher in smokers
 with lower air pollution
 exposures

Partial correlation analysis
 suggested that Indices of
 domestic and Industrial
 pollution account for a
 differences in mortality
 from bronchopneumonia and
 all respiratory diseases among
 children 0-1 year of age

Complaints of cough, phlegm,
 wheezing, breathlessness, eye
 irritation increased with in-
 creasing air pollution

Bronchitis mortatliy associated
 with dustfall (but not cardio-
 vascular, pneumonia or cancer
 mortality)

Average deaths per week, 1958-65
 winter, correlated with pollution
                                        14-71

-------
differences did not remove the high correlation between air pollution and
bronchitis mortality.      That is, although Buck and Brown    did not find a



relationship between smoking and lung cancer and bronchitis mortality,    the



variation in smoking between regions was too small  to differentiate the observed


   .  . ..   ....        247,307
mortality differences.    '



     Wicken and Buck   compared deaths from lung cancer and bronchitis (1952



to 1962) in areas of contrasting air pollution (1963) in northeast England.



Differences in death rates  were associated with differences in exposure to



pollutants with high areas  having annual BS of 160  ug/m  (250 ug/m  TSP) and



S02 of  115 ug/m . Because adjustments in analyses were made for smoking, age,



and social class, this study is generally considered to be a methodologically


            304
sound  study.


                       20
     Burn and Pemberton   studied total mortality and mortality from lung



cancer  and bronchitis in three areas of differing pollutant concentrations in



Salford, England.  Total mortality showed a gradient in the standardized



mortality ratio of between 90 and 106 with gradients in winter and summer for



S02 (340 to 715 and 450 to 680 ug/m , respectively) and British Smoke (145 to



255 and 170 to 270 ug/m,  respectively).  Since cigarette smoking, social



status  and mobility were not examined, questions have been raised regarding


                                            248 301
the validity of these reported associations.    '


                        228
     Watanabe and Kaneko    studied 1965/1966 mortality rates in the Osaka,



area of Japan, stratified into 3 areas by degree of air pollution.  Moving



averages and lags in mortality were utilized.  A stepwise increase in total



mortality and deaths from circulatory disease was seen in areas of greater
pollution independent of temperature effects.  The levels  in the highest area




                                          >2
were 300 ug/m3 TSP and 215 to 266 ug/m3 SO, (0.08 to 0.10 ppm).
                                   14-72

-------
                        21-23
     Winkelstein et al.,      studied total  and cause-specific  mortality  in



Buffalo and Erie County, New York,  for the years 1959 to 1961,  in relation to



the air pollution levels.   A network of 21 sampling stations  provided  data on



TSP, settleable solids,  and oxides  of sulfur for the period July 1961  to  June



1963.  Four areas were designated on the basis of the isopleth  concentrations



of particulate matter, with the 2-year geometric mean concentrations of TSP  in



the four areas being <80,  80 to 100, 100 to 135, and >135 pg/m3.   Each area



was also divided into five economic groups.   Chronic respiratory disease



mortality for white males  50 to 69  years old was about three  times higher in



the high-pollution areas than in the low-pollution areas.   The  positive association



between TSP concentrations and total or chronic respiratory disease mortality



persisted across all economic groups.  There was a positive association between



stomach cancer and 2-year geometric mean TSP in excess of 80  ug/m .   Deaths



from cirrhosis of the liver also showed a positive association  with TSP con-



centration for both white men and white women 50 years and older.  Average



annual death rates, as they related to TSP concentration and  economic  level,



are shown in Table 14-17.   Multiple probit analysis indicates the independent



effect of particulate matter on mortality.



     Questions have been raised   '    concerning the validity  of the above


           21-23
Winkelstein      findings, because the study did not include  smoking,  occupation



or mobility data.  However, these variables correlate significantly with



economic levels, which were controlled for in the analyses, somewhat minimizing



such shortcomings.     In addition, Winkelstein    conducted  a follow-up



survey of smoking in adult women in Buffalo in 1963.  He attempted to determine



the potential influence of smoking by residence.  Among non-smoking women over



age 44, productive cough was positively correlated with residential suspended



particulate concentrations.  Smokers with 5 or more years residence also had
                                   14-73

-------
          TABLE 14-17.   AVERAGE ANNUAL DEATH RATES PER 1000 POPULATION
         FROM ALL CAUSES ACCORDING TO ECONOMIC AND PARTICULATE LEVELS, AND
       AGE:   WHITE MALES, 50-69 YEARS OF AGE, BUFFALO AND ENVIRONS, 1959-1961
Particulate level
Economic
level
1 (low)
2
3
4
5 (high)
Total
1 (low)
—
24
(3663)
--
20
(6625)
17
(6335)
20
(16623)
2
36
(530)*
27
(9720)
24
(7684)
22
(7881)
21
(6394)
24
(32209)
3
41
(5281)
30
(6968)
26
(3954)
27
(2639)
20
(574)
31
(19416)
4 (high)
52
(1954)
36
(3185)
33
(1298)
--
--
40
(6437)
Total
43
(7765)
29
(23536)
25
(12936)
22
(17145)
19
(13303)
26
(74685)
                                21
    Source:  Winkelstein, et al.

   *Population sizes given in parentheses


    ANALYSIS TABLE USING ASYMPTOTIC CHI-SQUARES ESTIMATED BY PROBIT ANALYSIS
Effect
Participates
Linear effect
Nonlinear effect
Economic effects
Interactions
Asymptotic
chi-square
76.55
72.55
4.00
392.34
4.23
Degrees
of freedom
3
1
2
4
8
P-value
<.001
<.001
.135
<.001
.836
Source:   V.  Hasselblad (personal communication)
                                   14-74

-------
          TABLE  14-18.   AVERAGE  ANNUAL DEATH RATES PER 1000 POPULATION
                     FROM ALL CAUSES ACCORDING TO ECONOMIC,
                           PARTICULATE AND SO  LEVELS
Economic
level
1 (low)
2
3
4
5 (high)

Part, low
S0x low
36
(530)*
26
(13,383)
24
(7,684)
21
(13,771)
19
(11,428)
Pol lution
Part, low
SO high
x s
(0)
(0)
(0)
19
(735)
16
(1,301)
Levels
Part, high
SO low
46
(4,413)
33
(2,245)
28
(4,189)
27
(2,639)
20
(574)

Part, high
SO high
J{
41
(2,822)
32
(7,908)
26
(1,063)
(0)
(0)
                            188
 Source:   Winkelstein et al.

*Population sizes given in parentheses

     ANALYSIS TABLE USING ASYMPTOTIC CHI-SQUARES ESTIMATED BY PROBIT ANALYSIS
Effect
SO -particulate interaction
SO adjusted for participates
Participates adjusted for S0x
Economic
Other interactions
Asymptotic
chi-square
.55
3.26
43.36
406.84
4.95
Degrees
of freedom
1
1
1
4
7
P-value
.458
.071
<.001
<.001
.666
Source:   V.  Hasselblad (personal communication)
                                     14-75

-------
positive correlations with residential TSP; both findings were independent of



socio-economic factors.305'307  This indicates the likely existence of effects



on health of residential pollution independent of smoking.   Nevertheless, the



specific contribution of smoking to mortality effects observed in his early



studies21'23 could not be definitively determined, by this approach.



     It has also been conjectured,    (without presentation of convincing



supporting data), that Winkelstein's   original findings might be simply



accounted for by higher mortality rates in high pollution areas being due to



greater proportions of residents in the high pollution areas coincidentally



also falling higher in the 50-69 age range studied than those in the low



pollution areas.  This would, however, have to be an extraordinary coincidence



indeed for the same pattern of age bias to follow precisely the same dose-response



relationship patterns observed for pollution-mortality relationships shown in



Tables 14-17 and 14-18.  Winkelstein also evaluated the possibility that



census tract population size (and thus density) could be positively correlated



with both air pollution levels and mortality rates.  The total death rate for



white men ages 50 to 69 were computed for each of the four air pollution



levels in each group; it did not appear that the observed association of air



pollution and mortality was related to population size.


                188
     Winkelstein    reanalyzed the same mortality data using two particulate



levels and two oxides of sulfur (SO )levels.  The areas were split at 100
                                   /\

    3                                      2
ug/m  for particulate matter and 0.45 mg/cm -30 days for S02>  The mortality



rates (Table 14-18) show increases for particulate matter independent of



economic level; tests of significance calculated as in Table 14-17 show  that



particles explain a highly significant increase in mortality.  Probit analysis



indicates that SO  adjusted for particulate matter had only borderline significance
                 /\


while particulate matter adjusted for SO  was  highly significant.  The relative
                                   14-76

-------
risk ratio of the high-particulate areas to the low-particulate (and low SO )



areas was between 1.15 and 1.29, for the economic levels (except for the


                                     189
highest economic level).   Winkelstein    performed a similar analysis for



women (similar to Table 14-17).   The same pattern of increasing mortality



rates across participate categories was found.   The number of occupationally



exposed women can be assumed to be small at that time (1960) such that industrial



exposure was not the primary cause of increased mortality.



     Taking into account all of the above analyses and information concerning



the Winklestein studies, it would appear that his finding on associations



between variations in mortality and geographic areas in terms of relative



levels of particulate matter or sulfur oxides are likely valid and cannot be



explained away in terms of possible confounding or covarying factors alone.



On the other hand, caution must be exercised in regard to uncritical, full



acceptance of the specific quantitative dose-response relationships implied by



the summarization of pertinent air quality data appearing in the published



Winkelstein reports without closer examination and analysis of the original



air quality data.



     More specifically, conversion of Winkelsteins' air quality data from



2-year geometric means to annual arithmetic means is especially important  in



order to allow for more direct comparison of his findings with results which



have more typically been reported in relation to annual average TSP concen-



trations expressed as arithmetic means.  Conversion to arithmetic means of the



specific geometric means that served as the basis for Winkelstein's original



TSP pollution level groupings results in the values listed  in the third vertical



column of Table 14-19.  Similarly, conversion to arithmetic means of the


                                                                           21-23
geometric means for pertinent SO  air quality data reported by Winkelstein
                                /\


yields results as indicated in the third column of Table 14-20.
                                   14-77

-------
             TABLE 14-19.   COMPARISON OF ARITHMETIC AND GEOMETRIC
                MEANS OF TSP DATA - BUFFALO STUDY, 1961-1963


 TSP Measurement          2-Year             2-Year            With Flow
Original Grouping     Geometric Mean     Arithmetic Mean*   Rate Correction
< 80 pg/m 75
76
78
80**
80-100 87
89
89
90
93
95
100-135 106
110
111
124
125
132
135
> 135 142
152
178
205
87
83
87
91
100
100
102
103
105
109
119
122
125
146
146
156
154
163
180
203
249

£ 100


115-125





~ 140-175




£ 180-285


                                 21
*Modified from Winkelstein (1967)   by E.  Davis, personal communication to D.  Mage
**In the original analysis, this station was included in the grouping
< 80 ug/m , 2-year geometric mean.
                                   14-78

-------
            TABLE 14-20.  COMPARISON OF ARITHMETIC  AND  GEOMETRIC  MEANS  OF
                  OXIDES OF SULFUR DATA -  BUFFALO STUDY,  1961-1963*
 TSP Measurement
Original Grouping
2-yr geometric mean
   Oxides of Sulfur
     (mg/crri )**
2-Yr. Geometric Mean
   Oxides of.Sulfur
      (mg/cm )
2-Yr. Arithmetic Mean
 Estimated §02
Level (ug/m"
< 80 ug/m 0.198
0.219
0.257
0.256
80-100 0.219
0.278
0.209
0.237
0.339
0.262
100-135 0.242
0.429
0.326
0.337
0.359
0.307
0.461
> 135 0.328
0.169
0.530
1.250
0.237
0.256
0.290
0.289
0.252
0.299
0.241
0.259
0.385
0.297
0.359
0.455
0.423
0.375
0.421
0.417
0.509
0.349
0.327
0.566
1.315
19
20
23
23
20
24
19
21
31
24
29
36
34
30
34
33
41
28
26
45
105
*Based  on data from Winkelstein  (1967).
                                       21
                                                'i
**Actually SO  values  shown  here  represent mg/cm  readings per 30 days.

***Values stated here  are  likely  underestimations of actual SO. concentrations due
   to probable errors  in measurement associated with use of "sDlfation rate"
   analytical technique, as  discussed briefly in accompanying text and in more
   detail in Chapter 3.
                                       14-79

-------
     In addition to the above considerations,  certain sources of measurement



error that would likely have affected the precision of the quantitative estimates


                                              ?1~?3
of TSP and SO  levels employed by Winkelstein,      have come to light in
             J\


recent years.  For example (as also discussed  in Chapter 3),  underestimation



of TSP concentrations likely occurred due to probable overestimation of flow



rates during sampling periods.  This arises from the standard procedure,



employed by Americans, in taking an average of the flow rate  readings obtained



at the start and end of a sampling period, rather than obtaining continuous



readings during the period and more accurately determining the flow rate by



integrating the area under the curve defined by the decreasing flow rate



readings over the sampling period.   Precise estimation of the size of likely



resulting errors associated with specific American hi-vol TSP estimates determined



in the above manner is of course impossible but probably would not be more



than about 15 percent (see Appendix A of Chapter 3).  Applying a 15 percent



maximum correction to the "arithmetic mean" TSP estimates in  Table 14-19



results in annual average TSP values designated as being obtained "with flow



rate correction" in that table.



     Analogously, it must be noted that the "sulfation" method used in deter-


                                                            21-23
mining the oxides of sulfur SO  data reported  by Winkelstein      is not



specific for sulfur dioxide (S02).   Also only  approximate estimates can be



made of the proportion of S02 contributing to  the reported SO  data, as per



the values shown in the fourth column of Table 14-20.  The interpretation is



further complicated because the basic SO  and, therefore, these derived SO,
                                        ^                                 £


estimates likely were affected by the sensitivity of the sulfation  technique



to variations in temperature and humidity.  Thus, unless the  latter were well



controlled within the monitoring sites, the net outcome would  likely be that
                                   14-80

-------
the values  shown in Table 14-20 somewhat  underestimate  the  actual  oxides  of
sulfur air  levels  (see  Chapters 2  and  3  for  a  more  detailed discussion  of the
sulfation method).   Regardless  of  the  precise  actual  levels of  either overall
oxides of sulfur or S02 as a subset,  however,  the matter of their  possible
contribution  to mortality (either  alone  or in  combination with  TSP)  is  more  or
less moot because  no statistically significant SO  effects  or SO -particulates
                                                 f\              XX
interactions  are demonstrated by the  probit  analysis  in Table 14-18.
                     25
     Lave and Seskin,    in another often-quoted study,  obtained a  positive
association for both men and women between bronchitis mortality in England and
smoke (BS)  measurements.   The positive association  persisted when  socioeconomic
                                                                             or
factors were  included in a multiple regression analysis.  These investigators
then compared bi-weekly concentrations of air  pollutants in 114 SMSAs  in  the
United States during 1964 with deaths from bronchitis.   Regression analyses
showed significant positive relationships between mortality and suspended
particulate matter, even after adjustment for  climate and the type of home
heating (both associated independently with mortality).
     The bi-weekly high-volume TSP concentrations during the period covered by
the analyses  ranged from 45 to 268 ug/m , with a mean of 118 ug/m .   This
would suggest that biweekly mean TSP concentrations of 120 ug/m  or higher
                                                                   27
would be associated with excess bronchitis deaths.   Lave and Seskin   subsequently
published  results of a time series analysis of air monitoring data from 25
SMSAs as they related to bronchitis mortality, lung cancer mortality, and
infant mortality during the years 1960 and 1969.  In this analysis, each type
of mortality was related to air pollution concentration  as indicated by the
annual mean concentration of TSP or sulfate.
                                   14-81

-------
     Again, TSP readings and suspended sulfate readings >120 >10 exceeded the
mean pollutant concentrations and, on the regression scale, were associated
with increased mortality.   The time series analysis indicates that TSP has
about three times the explanatory power in the regression than does sulfate
and almost five times the explanatory power of SO^.   Nitrates and N02 were not
significant in this analysis.  The authors state that S02 and the nitrogen
compounds may be important acting together with the particulate matter.
     Many questions can be raised about these study results.  Cigarette smoking
was not considered in the analysis.  There may also have been problems arising
from nonuniform distributions of samples or from other variables not included
in the analysis.  Air pollution was measured only twice monthly at one or more
monitoring stations in each of 114 metropolitan areas.  The regressions also
included some possible confounding by sex distributions, age distributions and
socioeconomic levels.  Although this was an attempt to specify effects of
SO /TSP, effects of other pollutants cannot be subtracted.   The greater effects
  /N
of smoking were not included, nor were the effects of other exposures.
Potentially confounding are the choice of residential area related to the co-
and intervening variables and other community differences not measured.  The
method is unable to relate pollution levels in cities to actual exposure of
individuals to air pollution attributed to the area of residence, especially
                                          251
given the mobility of the U.S. population.     Time series analysis also may
have systematic biases.  Seasonal variation was not controlled.  Problems with
geographic comparisons of mortality include:  lack of information on  covariables,
intervening variables and confounding factors; lack of specific exposure
histories and of specific causes of death; errors of  omission  and commission
in assigning deaths to places; inability to pinpoint  effects of specific
                                   14-82

-------
pollutants  or to characterize dose-response relationships;  Inability to



generalize.   Considering all  of the above problems with the Lave and Seskin



analyses, their reported findings and conclusions cannot be accepted as being



accurate or useful  for present health criteria development  purposes.



     Four regression analyses are also reported by Lipfert.    >253  The first



of these arises from analysis of 1969 mortality data from 60 U.S.  cities using



a model  much like one of Lave and Seskin1s; very similar coefficients are



obtained.   The first two models differ only in that the first uses mortality



data from 60 SMSAs  while the second uses mortality data from 60 U.S.  cities.



The coefficient of  sulfate (S04)is larger in~the second regression using



smaller geographic  areas.   The third model differs from the second in that



more cities are included and age of housing and birth rate  are added as



independent variables, while smoking is added in the fourth.  Though the



coefficient of TSP changes very little, the coefficient of sulfate is negative



in these regressions.



     A regression analysis of 60 U.S. cities in 1970 was performed by Crocker


      254
et al.     In addition to variables used by other investigators, this model



includes variables  for climate, education, availability of medical care and



nutritional habits.  Although Crocker uses SO- and not SO. as a pollution



variable, neither pollutant contributes  significantly to the regression.  They



report a correlation between SOp and SO. of 0.74.



     In evaluating regression analysis studies further, it should be noted



that the contribution of air pollutants  to mortality can be summarized by



"elasticity".  Elasticity is a dimensionless number that represents  the expected



percent change in the dependent variable, mortality, associated with a 100



percent increase from the mean value in  each of  the independent variables.
                                   14-83

-------
Elasticity is computed by multiplying each air pollutant regression coefficient



by the average value of that pollutant in the data set, adding these quantities



for all pollutants, and dividing by the average mortality over study units.



So long as the set of pollution variables chosen contains variables expressing



the association of air pollution with mortality, elasticity is relatively



insensitive to subset selection from a set of highly colinear pollutant



variables.  Thus, elasticites can be viewed, at least approximately, as



measuring the total mortality effect of all pollutants included.



     Elasticities for the nine regression analyses summarized above are as

                                                    pec

follows.  The simplest model used by Lave and Seskin    for the analysis of



the 1960 data had the largest elasticity (0.09).  As other variables were



added,  such as home heating fuel in the second regression, elasticity declined



(0.03).  When occupation was added to the model for the first regression,



elasticity declined to 0.05.  The first two Lipfert regressions use population



density, percent above age 65, percent nonwhite and percent with income below



$3000  as independent variables.  Their elasticities were 0.10 and 0.09, respec-



tively.  When birth rate and age of homes are added to the third or cigarette



smoking to the fourth, elasticity declines to 0.06 and 0.004, respectively.  The



effect of cigarette smoking is especially notable.  Finally, in the analysis


                 254
by Crocker et al.    using several other independent variables, the elasticity



is nearly zero (0.004).  These variables included measures of medical  care,



diet,  climate and cigarette smoking and could easily be defended as critically



important in any analysis controlling for other factors influencing mortality.



     Though several authors have argued that the omission  of smoking only adds


                        254
to error, Crocker et al.    report a correlation of 0.23  between cigarette



consumption and sulfur dioxide in the six cities  in their study.   Certainly
                                   14-84

-------
the two variables are not causally related,  but both may reflect  other



characteristics  of the population.


                         255
     Schwing and McDonald    report on a study of 46 SMSAs  (1959  to  1961)  in



which 23 explanatory variables were used,  including climate,  socioeconomic,



occupational and smoking variables and eight air pollutants.   This study



differs from others in that the investigators included all  23 variables  in



their models.  To counter the effects of severe colinearity,  the  authors  used



two methods of analysis:   ridge regression and constrained  least  squares,  as



opposed to ordinary least squares.   (The previously reported  studies all  used



ordinary least squares.)



     Ridge regression is a numerical method for stabilizing estimates from



data that have several colinear variables.  While the method  does achieve



stability, it does so by selecting an arbitrary constant that has the effect



of shrinking each estimated coefficient toward zero.  Though  ridge regression



leads to smaller standard errors for the estimated coefficients,  these coefficients



are no longer interpretable as partial regression coefficients, that is,



measures of the  effects of changes in a single variable while other variables



are held fixed.   As emphasized throughout this chapter, colinear data sets are



fundamentally insufficient to allow assignment of mortality effects to individual



members of a group of colinear independent variables.


                         255
     Schwing and McDonald    also used constrained  least squares, constraining



the air pollution coefficients to positive values.  This may be unreasonable



when eight air pollutants are studied simultaneously; for instance, respirable



sulfate as a fraction of total sulfate is not constant over different levels



of air quality (see Chapter 5).  Schwing  and McDonald report an elasticity of



0.022 from ridge regression and an elasticity of  0.045 from constrained  least
                                   14-85

-------
squares.   These values are still an order of magnitude larger than that reported



by Crocker et al.  (0.004).254  While Crocker et al.  did not include data on



occupation, Schwing and McDonald did not include medical  care.



     While Lave and Seskin256 found associations between  air quality and both


                                                   254
cardiovascular and cancer mortality, Crocker et al.     found neither association.



Crocker et al. found an association between particulate level and pneumonia



mortality, while Lave and Seskin did not.  In most analyses that can be compared,



Crocker et al. estimated air pollution effects smaller than those of Lave and



Seskin.  This difference may be explained largely by the  use of additional



independent variables in the models of Crocker et al.



     In general, the regression analyses of cause-specific mortality show



inconsistencies across studies which highlight the sensitivities of these



analyses to the selection of independent variables.   The  colinearity of air



pollution variables, and other variables related to mortality, limits the



information to be gained from observational studies on the mortality effects



of pollutants at low concentrations.



     In summary, many of the cross-sectional mortality studies reviewed above



either yielded only qualitative findings concerning air pollution mortality



relationships or, alternatively, suffer from methodological deficiencies which



make it impossible to accept their published findings regarding pertinent



quantitative dose-response relationships.  Still, on the other hand, at least


                                                         TO 1QQ                 21"23
some of the studies, such as those by Buck and associates   '    and Winkelstein,



have yielded quantitative results not convincingly attributable to potentially



confounding or covarying factors and appear to be of use, when appropriately



interpreted in light of certain methodological considerations, in  arriving  at



quantitative estimates of air concentrations of TSP or SO   associated with



increased mortality.
                                   14-86

-------
14.3.5  Lung Cancer Mortality



     Exposure to materials found in the ambient air may be associated with



increases in lung cancer under some circumstances.   Cigarette smoking is the



uajor known cause of lung cancer, and occupational  studies indicate that



significantly high risks of lung cancer are associated with exposure to ionizing



radiation, fibers, or specific metals.  The interactions between smoking,



occupations, and ambient air exposure are not well  understood.



     A number of studies have reported on differences in lung cancer rates in



urban and rural areas.          Higher rates are consistently found in urban


                                                                          lift
areas even after removing the effects of cigarette smoking.  Doll and Hill



found increased lung cancer deaths for urban dwellers that might have resulted



from increased air pollution.  They reported that the effect of living in an



urban area was insignificant compared with the effect of smoking cigarettes.



The assumption is that the major difference has to do with the ambient air



pollutant exposures.  This may not be the case, as there are many other factors



that differentiate urban and rural areas, such as:   number of pollutants;



meteorological conditions; occupational and other exposures; and social and



cultural backgrounds.  Unless all the differences between  urban and rural



communities are controlled for, such comparisons run the risk of being fortuitous



The relationships of community size or population density, as indicators  of



varying potential environmental stresses also show a consistent relationship



to lung cancer rates.         Again, the impact is considerably  less than  is



the effect of smoking, and may be related to other urban-rural differences.


                       142-144
     Some investigators        have compared lung cancer rates for  immigrants



from a specific country with rates for native born living  in both countries.



Most of the data suggest that risk for the immigrant, controlling for  smoking,
                                   14-87

-------
is intermediate to the risk in the  native  and  adopted  countries.   Considering



the long latent period for the development of  many  cancers,  this  suggests  that



in some immigrants the effect of early  exposure  may develop  after emigrating.



However, migration involves a time  element,  a  change in  place,  and differential



host characteristics.   These studies  assume that the populations  in the  native



and adopted countries  and factors other than pollutant exposures  are similar.



Such assumptions are difficult to appraise,  but  are more often  incorrect than



correct.


            T26
     Waller,    after  reviewing evidence from  Britain, concluded  that air



pollution either alone or in combination with  other factors, may  contribute



in a minor way to the  development of lung cancer   He also pointed out the



difficulties in assessing relationships between  air pollution exposure and the



development of any chronic condition during a  period of  rapidly changing



concentrations of air pollution.  For example, during the period  1954 to 1965,



the annual mean and peak concentrations of smoke in London decreased signifi-



cantly, as did the concentrations of potential carcinogens such as polycyclic


                      119
aromatic hydrocarbons,    though no significant  reduction in SO-  was recorded.


                    197
     Wynder and Gori    reviewed information relating cancer to environmental



factors.  They concluded that individuals were able to control  many of the



factors related to cancer risk and  thus individual  lifestyles were far more



important risk factors for cancer than was air pollution.



     Corn    estimated relative dose of toxic materials inhaled  from various



sources and concluded that the impact of the maximum quantity of  air pollution



permitted by the ambient air quality standard was  insignificant  compared with



that of smoking one pack of cigarettes per day.



     Benzo(a)pyrene is a known co-carcinogen and is the one  constituent of



particulate matter most commonly monitored in ambient air as an  index of
                                   14-88

-------
potential carcinogenic hazard.   Increases in total  pollution exposure (dustfall,



SOp, trace elements, and polycyclic hydrocarbons) have been shown to be associated



in Japan with increased lung cancer rates in smokers but not in non-smokers.



Smoking also has been shown to increase the risk of lung cancer among asbestos


       145                    146
workers    and uranium miners.      There is, however, no evidence that the



concentrations of materials in the ambient air are sufficient to stimulate



similar smoking-associated increases.


                                                    1?5
     A 1977 report from an international study group    concluded that, although



data are not consistent and are affected by various types of indoor pollution,



the products of fossil fuel combustion (probably acting together with cigarette



smoke) are very likely responsible in large urban areas for approximately 5 to



10 cases of lung cancer per 100,000 males per year.  On the other hand, from


                                                      307 308 312
the above discussion, and as noted by other reviewers,   '    '     insufficient



qualitative or quantitative epidemiologic data presently exists to define



clear associations between cancer effects and exposures to atmospheric con-



centrations of either sulfur dioxide or particulate matter.



14.3.6  Summary for Mortality Studies



     In the above discussion, numerous studies on associations between mortality



and acute, short-term, or chronic exposures to particulate matter and sulfur



oxides were critically evaluated.  Many were evaluated as being flawed



methodologically or their results likely explainable in terms of confounding



or covarying factors to an extent that said findings are taken here as not



being useful in helping to develop quantitative health criteria for the effects



of atmospheric particulate matter and sulfur oxides.  Several other studies,



however, were evaluated as being useful for such a purpose and are briefly



summarized in Tables 14-21 and 14-22.  Note that the values  listed in  those



tables for 24-hr and annual average air concentrations, respectively,  at
                                   14-89

-------
             TABLE 14.21.   SUMMARY OF EVIDENCE FOR MORTALITY EFFECTS OF ACUTE  EXPOSURE TO  PARTICULATE MATTER AND SO,
                                                         (NON-EPISODIC)
24 Hour average pollutant
levels at which effects appear
Type
Daily
Daily
Daily
of study
Mortality
Mortality
Mortality
Reference
Martin
and Bradley11
Martin6
Glasser and
Greenburg222
Effects observed
Increases in daily
mortality
Increases in daily total
mortality above the 15-day
moving average
Increases in daily
mortality
TSP (ug/m3)
500-600
(300-500)*
500-600
350-400
S02 (ug/m3)
300-400
(200-300)*
400-500
524-786

o   *From  supplemental  analysis  given in this chapter.

-------
              TABLE 14.22.  SUMMARY OF EVIDENCE OF MORTALITY EFFECTS OF CHRONIC EXPOSURE TO PARTICULATE MATTER AND  SO,
I
V£>

Annual average pollutant
levels at which effects appear
Type of study
Geographic Comparison
Geographic Comparison
(214 areas)
Geographic Comparison
Geographic Comparison
Geographic Comparison
Reference
Watanabe and
Kaneko228
Buck and Brown199
Wicken and Buck19
Winkelstein188
Burn and
Pemberton20
Effects observed
Increased mortality
Increased mortality
Increased chronic bronchitis
mortality
Increased mortality
Increased chronic bronchitis
and lung cancer
TSP (ug/m3)
300
200 BS
(300 TSP)**
160 BS
(260 TSP)**
125-140 TSP*
680 BS (winter)
270 BS (summer)
(350 TSP)**
so2 (Mg/m3)
215-266
200
115
not significant
715 (winter)
270 (summer)

   * Two-year arithmetic mean with maximum possible flow correction, from Table 14.19.
   **Estimated TSP from 100 BS = 200 TSP and 250 BS = 333 TSP (Holland et al. ).

-------
which effects appear represent the best estimate of TSP or S02 levels present
and associated with mortality effects demonstrated by particular studies,
taking into account various considerations discussed in the preceeding text
and Chapter 3.  Thus, some of the estimates listed in the tables may differ
markedly from those appearing in the published versions of the listed studies.
14.4 MORBIDITY ASSOCIATED WITH SHORT-TERM POLLUTION EXPOSURES
14.4.1  Introduction
     Morbidity studies of short-term air pollution exposures are much less
common in the epidemiologic literature than morbidity studies of long-term air
pollution exposures.  This reflects the dual complications of the difficulty
of having adequate estimates of pollution exposure as well as the statistical
analytical problems of the health data being collected.  For ease of discussion
the studies to be discussed in this section are divided into six categories:
     • Episodic morbidity
     • Chronic heart and lung symptoms and patients
     • Acute respiratory disease
     • Aggravation of asthmatic symptoms
     • Hospitalization-clinic admissions
     •  Absences data
     • Pulmonary function
     Difficulties in either the analysis or interpretation of these classes  of
studies will be addressed separately as they appear in this section.  Qualita-
tive studies are described only in summary form (Table 14-23).  The key con-
clusions derived from such studies are that:  (1) clear relationships or
associations exist between various health effects and  elevated  levels of  S0?
and particulate matter, although the data in the  studies  do not allow for very
                                   14-92

-------
               TABLE 14-23
        QUALITATIVE STUDIES OF AIR POLLUTION AND ACUTE
            RESPIRATORY DISEASE
   Study
         Characteristics
      Findings
Angel et al.
           69
Attack rates of minor respiratory
 illness among 85 London workers,
 examined every 3 weeks, October
 1962-May 1963.
Attack rates were associated
 with weekly average smoke
 and S02 concentrations.
Levy et al.
          70
Schoettlin and
 Landau288
Zeidberg et al.289
Cowan  et al.290
Greenberg et al.291
Wei 11 et al.292
 Carroll293
Hospital admissions for respira-
 tory disease in Hamilton,
 Ontario, correlated with
 sulfur oxide/particulate air
 pollution index.

137 asthmatics reporting attacks
 on daily occurrence of asthma,
 September-December, 1956, in
 Los Angeles Basin.

Study during 1 year of 49 adults
 and 34 children with asthma in
 Nashville, Tenn.
History of asthma, and skin tests
 of University of Minnesota
 students, in relation to dust
 from nearby grain elevator.

New York City hospital emergency
 room visits for asthma  in
 month of September.
Retrospective  study  of  emergency
 room visits to  New  Orleans
 Charity Hospital.
Increased hospital admissions on
 heavy pollution days, except at
 one hospital far removed from
 major pollution sources.
Significantly more asthma on days
 of heavier oxidant pollution.
 No adjustment was made for
 variations in temperature or season

Doubling of asthma attack rates
 in persons living in more
 polluted neighborhoods.  No
 adjustment for demographic or
 social factors.

Significant association between
 grain-dust exposure and
 asthma attacks.
Emergency room visits  strongly
 associated with onset of cold
 weather but  not with  degrees of
 air pollution during  the one
 month of study.

Periodic "epidemics" of  asthma
 in New Orleans could  not be
 traced to any common  pollutant
 exposure.
                                            14-93

-------
                               TABLE 14-23 (continued)
    Study
         Characteristics
      Findings
Phelps294
 Meyer295
Glasser et al.296
Chiaramonte
 et al.297
Derrick57
Rao298
Goldstein and
 Black58
"Tokyo-Yokohama asthma" in
 American servicemen stationed
 in Japan after World War II.
Emergency room visits in seven
 New York city hospitals during
 the November 1966 air pollution
 episode.

Emergency room visits at a
 Brooklyn hospital during a
 November 1966 air pollution
 episode.
Nighttime emergency room visits
 for asthma in Brisbane,
 Australia.

Pediatric emergency room visits
 for asthma at Kings County
 Hospital, Brooklyn, October
 1970-March 1971.
Emergency room visits for
 asthma at a hospital in
 Harlem and in Brooklyn,
 September-December 1970 and
 September-December 1971.
Disease primarily 1n smokers
 attributed to allergic response
 to atmospheric substances that
 could not be characterized.
 Patients Improved after leaving
 the area and were immediately
 affected on return.  Some had
 long-term effects afterwards.

Increased emergency room visits
 for asthma in three of seven
 hospitals studied.
Statistically significant
 increase in emergency room
 visits for asthma and for
 all respiratory diseases, con-
 tinuing to 3 days after the
 peak air pollution concen-
 trations.

Negative correlation between
 asthma visits with degrees
 of smoke shade.

Negative correlation of asthma
 visits with degrees of smoke
 shade.  Lack of temperature
 adjustments.  Considerable
 distance of hospital district
 from air monitoring stations.

Temperature adjusted asthma
 rates positively  correlated with
 S02 values in Brooklyn but
 not in Harlem.  In 1971 period,
 50-90% increase in asthma
 visits on 12 days of heaviest
 pollution.
                                        14-94

-------
                              TABLE 14-23  (continued)
    Study
         Characteristics
      Findings
Finklea et al.117
Finklea
et al.122  123
Incidence of acute respiratory
 disease, determined at 2-week
 intervals, in parents of
 nursery schoolchildren residing
 in Chicago, December 1969-
 November 1970.
Daily diaries kept by 50
 asthmatics in each of three
 New York City area communi-
 ties, October 1970-May 1971.
Acute lower respiratory
 illness rates were signifi-
 cantly lower among families
 living in neighborhoods
 where air pollution had been
 substantially decreased.
 Rates were adjusted for social
 class, smoking, residential
 mobility, and season of year.
 Cannot quantitate pollutant
 exposures.

Temperature-adjusted attack
 rates significantly correlated
 with total particulates in two
 of the communities.  Increase
 in relative risk from days of
 light to heavy pollution was
 relatively small.  High turnover
 in reporting panels.
'Reference  251
                                        14-95

-------
precise quantitation of the specific air concentrations  at which the  health

effects occur; (2) the particular health effects observed with elevated S02

and particulate matter air levels range from temporary pulmonary function

decrements and biochemical changes to rather serious acute respiratory diseases

and exacerbation of preexisting disease processes;  and (3) particular population

subgroups (e.g., the elderly, infirm, and children) are at special  risk for

manifestation of deleterious health effects associated with short-term S02 and

particulate matter exposures.

     Included in the further discussion below of quantitative studies of morbidity

associated with short-term exposures to airborne sulfur oxides and particulate

matter is a series of studies conducted by the U.S. Environmental Protection

Agency, most of which were the result of research conducted under the Community

Health and Environmental Surveillance (CHESS) Program,* an integrated set of
 *The matter of misinterpretation or overinterpretation of data or results of
 analyses of data collected as part of the CHESS Program contributed to
 considerable controversy regarding the validity and accuracy of results
 of early CHESS studies, as interpreted and reported in a 1974 EPA
 monograph entitled "Health Consequences of Sulfur Oxides:  A Report from
 CHESS" 1970-71, U.S. EPA Document No. EPA-650/1-74-004 (May 1974).  The
 controversy eventually led to the 1974 "CHESS Monograph" becoming the subject
 of U.S. Congressional oversight hearings in 1976.  Subcommittees of the U.S.
 House of Representatives Committee on Science and Technology produced a report
 on the Monograph, other aspects of the CHESS Program, and EPA's air pollution
 research programs generally--a report entitled "The Environmental Protection
 Agency's Research Program with Primary Emphasis on the Community Health and
 Surveillance System (CHESS):  An Investigative Report."  Of primary importance
 for the present discussion, that report, widely referred to either as the
 "Brown Committee Report" or the "Investigative Report" (IR), contained various
 comments regarding sources of error in CHESS Program air quality and health
 effects data and quality control problems associated with such data collection
 and analysis.  The I.R. also contained various recommendations to be imple-
 mented by the Administrator of EPA pursuant to Section 10 of the Environmental
 Research, Development, and Demonstration Authorization Act of 1978
 ("ERDDAA," P.L. 95-155, 91 Stat. 1257, November 8, 1977). ERDDAA also requires
 that EPA and the Agency's Science Advisory Board  report  to Congress on the
 implementation of the IR recommendations.
                                   14-96

-------
epidemiologic  studies  performed between 1969  and  1975.   The  health  status  of

volunteer participants was  either ascertained during single  contacts  or  followed

for time periods  of up to nine months.   These health measures  were  coordinated

with air pollution observations from the residential neighborhoods  of the

study participants.  Areas  selected for study were chosen to represent pairs

or larger groups  exhibiting a substantial  pollution exposure range.

     Approximately ten CHESS Program studies  are  cited and discussed  in  the

remainder of this chapter.113,117,122.123,212,213,214,215,297,306  Jhe rationale

for inclusion  here of  these studies, and qualifications regarding their  use,

are set forth  in  Appendix A of this chapter.   Generally the studies cited have

been included  on  the same basis as other non-CHESS studies,  ie.  in light of

their potential  usefulness in yielding information on quantitative relation-

ships between  health effects and air concentrations of sulfur oxides  and

particulate matter.  We have attempted to limit the discussion to studies

which have undergone peer review and have been published in the open scientific

literature apart  from internal EPA reports.

     Although the 1974 CHESS Monograph itself is  not cited or relied upon  in

this chapter,  these considerations reflect the spirit of recommendation 3(b)
^(continued)

     One recommendation of the IR was that an addendum to the 1974 sulfur oxides
monograph be published, to be used in part to qualify the usefulness of the
CHESS studies, and to apprise the public of the controversy surrounding
CHESS.  An addendum has been published, and is available from EPA, as
announced in the Federal Register of April 2, 1980, 45 F.R. 21702.  The addendum
is incorporated by reference in this document in partial qualification of the
CHESS studies cited herein, and is part of the public file (or docket) established
for revision of this criteria document.  The addendum contains the full text of
the IR, reports to Congress by EPA on its implementation of the  IR recommendations,
and a report to Congress by EPA's Science Advisory Board on the  same subject.
                                   14-97

-------
of the IR (1976) that the 1974 Monograph not be used as  a source of specific



quantitative data or interpretations thereof to serve as the basis for regu-



latory decisions without explicit qualifications being provided.



14.4.2  Episodes



     Several British studies have been published on health effects associated



with short-term exposures to sulfur oxides and particulate matter which appear



to provide useful information on quantitative dose-effect relationships.


                        59
     Waller and Lawther,   for example, reported that when smoke (BS) con-



centrations in London increased ten-fold during the course of 2 hours, there



was a deterioration in the clinical condition of some patients with bronchitis



or asthma.  On this day, peak smoke (BS) concentration may have reached 6500



ug/m  .  S02 also increased [maximum about 2860 ug/m  (1.0 ppm)] but H^SO. did



not, on the basis of washings from impactor slides.  Most of the mass of



particulate matter was determined by microscopic studies to consist of particles



less than 1 urn in diameter.


            52
     Lawther   studied associations between daily variations in smoke and S0?



pollution and the self-indicated health status in 29 British patients with



chronic bronchitis.  Patients maintained diaries on which their daily condition



was indicated in relation to their usual condition.  The alternatives were



"better," "same," "worse," and "much worse."  During the month  of January



1954, an episode of relatively high pollution resulted  in a sharp increase  in



the number of patients whose condition worsened as 24-hour  smoke  (BS)  increased



to about 400 pg/m  (470 ug/m  TSP) and 24-hour S02 increased to about 450

    o

ug/m  (0.15 ppm).  Figure 14-4 shows graphically the effects of high pollution



levels observed in the 29 bronchitic patients studied in January  1954.
                                   14-98

-------
    wt or
    aeon
    woasc

    tCTTCO
t

4

0

4

I
!
u
--MN
u
                               OS

                               O4

                               OS

                               02

                               Ol

                               o
                    I?    It    19    2O    21
                                     22
Figure 14-4.
 EffectrOnj-Bronchitic Patients of High Pollution Levels (January
 1954).  '    (The figure represents the  effect on bronchitic
 patients of increased pollution levels;  patients stated whether
 they regarded their condition as "worse" or "better".)
                             14-99

-------
     In the winter of 1955,  the study was extended to include  180 patients  in
the London area.   The prevalence of illness was related more closely to pollution
than to temperature or humidity during the winter months,  and the relationship
disappeared when the levels  of pollution decreased in the  spring.  Actual
numerical data are not given in the report, but inspection of the figures
indicate that prevalence increased with increases in smoke (BS) to about 350
ug/m3 (425 ug/m3 TSP) and increases in S02 to about 300 ug/m .   The data suggest
that during the winter months, SO,, was associated more closely with variations
in  health status; however, in the spring of the year, when pollution concentrations
were no  longer associated with health status, SO,, continued to occur in intermittent
peak concentrations as high as those associated with increased illness during
the winter.  However, the association between pollution and illness decreased
when smoke  (BS) concentrations fell to a fairly consistent 24-hour concentration
of  less  than 250 ug/m  (325 ug/m  TSP).  The few short higher peaks in smoke
(BS) after  this time had little effect on illness status.   These investigators
state that  the results are not indicative of causal relationships, but suggest
that the measurements of smoke (BS) and S0? are at least indicators of whatever
is  the cause.
     A later report by Lawther et al.   gave the results of further extension
of  these studies  into the winters of 1959-60 and 1964-65.   The techniques used
were similar except that the patients now reported on  health status in  rela-
tion to  the previous day rather than in relation to  usual conditions.   These
studies  supported the results  in previous years  in that the worsening  of
health status was associated clearly with  increases  in air  pollution.   The
author stated that, although exact relationships between  the  responses  of
patients and the concentrations of smoke  and SO^  could not  be  determined,  the
minimum  pollution leading to any significant response  was  about  500 ug/m
                                    14-100

-------
(0.17 ppm)  SOp,  together with about  250  ug/m   smoke  (BS).   Inspection  of  the



information provided  in  the  report,  however,  could  lead  to  the  conclusion that



this is  a conservative estimate.   Some  less consistent,  but significant effect


                                                           3        247
may have been occurring  with S02  concentrations  of  250 ug/m  or more.      As



in the earlier studies,  the  results  appear to relate more  closely  during  the



first part of the winter and, in  some instances,  there was  little  response to



higher concentrations of pollution near the end  of  the winter.   Although  the



concentrations of smoke  and  SOp closely correlate,  examination  of  the  data



again suggests that often higher  concentrations  of  SOp near the end of the



winter,  occurring with generally  lower concentrations of smoke, produced  less



response in the study subjects than did the  same concentrations of SOp earlier



in the winter, when smoke was higher.  There  was some evidence  for a loss of



interest by participants.  When the association  between  exacerbations  and SO-



pollution concentrations were compared in the two winters, the  impression was



of a slightly reduced and less consistent, but definite effect  during the



second winter.  The declines in concentrations were from 342 ug/m  BS to 129
ug/rn  BS (225 ug/ni  TSP) and from 299 ug/ni  to 264 ug/ni  S02.     Lawther



et al. also emphasized that these responses may reflect the effects of brief



exposures to maximum concentrations several times greater than the 24-hour



average.



     These studies among chronic bronchitis patients in London continued into



the 1970s as the frequency of periods of high pollution declined.  There were

                                                                       pen

no sharp increases reported in illness scores in the winter  of 1969-70,    nor



in the winter of 1974-75. 251
  ^


     Fry et al.    reported that home visits for respiratory  throat disorders



increased from a normal level of about 85 to 150 per day for their clinic



patients during the air pollution episode in 1962.  However,  this  rate represented
                                   14-101

-------
only 2.4 illnesses per 1000 patients,  with no deaths.   In the  1952  episode  of



comparable length, the illness rate was 9.5 per 1000 patients,  and  there  were



two deaths.   Perhaps their most significant of their observation was  that



their bronchitis patients were affected but their asthmatic patients  were not.


                     196
     Greenburg et al.     found during  a New York episode that  visits  to emergency



rooms for cardiac or respiratory illness increased as CoHs approached 3.0 (260


    3                                                       3
ug/m ) and 24-hour S0? concentrations  reached about 715 ug/m  (0.25 ppm)  as



air quality improved if the high levels of pollution had any immediate effect.



However,  lung function deteriorated slightly over the study period  as air



quality returned to more usual conditions, and therefore no immediate effect



could clearly be attributed to the air pollution levels observed although it



could not be ruled out the post-episode lung function deterioration might



reflect prolonged continuing effects of the pollution episode.



     Results also obtained at Rotterdam have shown that when the S0?  con-


                                                   3            3
centration rose for 3 to 4 days from about 300 ug/m  to 500 ug/m  (0.11 ppm to



0.19 ppm), the number of admissions into hospitals for respiratory  tract


                                                   30?
"irritation" rose, especially in older individuals.     In one episode in


             312
December 1962    p. 69, local hospital admissions increased for cardrovascular



diseases for those 50 and older land mortality may have increased).  Smoke was



about 500 ug/m3 (24 hour) and S02 was  about 1000 ug/m3.


                     82
     Stebbings et al.    reported on the effects of an episode of high pollution



in Pittsburgh on pulmonary function measurements in schoolchildren.  Forced



expiratory volume and forced vital capacity were measured in 270 fourth,



fifth,  and sixth grade children attending six schools.  Four of the  schools



were in the high-pollution area in which 24-hour TSP levels had exceeded 700


    3                                     3
ug/m  and S02 levels had exceeded 300 ug/m  (0.1 ppm).  Measurements of air



pollution and pulmonary function were not initiated until after the  peak of
                                   14-102

-------
the episode had passed,  but it was speculated that lung function would  improve



as air quality improved  if the high levels of pollution had any immediate



effect.   However,  lung function deteriorated slightly over the study period  as



air quality returned to  more usual conditions, and therefore no Immediate



effect could clearly be  attributed to the pollution levels observed, although



it could not be ruled out the post-episode lung function deterioration  might



reflect prolonged  continuing effects of the pollution episode.


                            216
     Stebbings and Fogleman,    also reported on pulmonary function test



results on 224 parochial schoolchildren during and after the Pittsburgh air



pollution episode  of November 1975, then reanalyzed to determine whether a



small subgroup of  susceptible children could be defined.  Individual regressions



of FEV y5 and FVC  on time over the six-day study period were calculated, and



the distributions  of individual slopes for the four exposed and two control



schools were compared.  Excesses of strong upward trends in the exposed areas



would suggest effects of suspended particulate air pollution by indicating



significant improvement following the episode.  A highly statistically significant



excess of strong upward trends in the FVC among exposed students was observed,



and was consistent by sex and by school within sex.  Approximately 10 to 15



percent of the students appear susceptible to an average impairment of about



20 percent of the  FVC.  The findings are  limited by the small  number of subjects



with strong post-episode upward trends in the FVC, and  by  lack of validation



or replication of  the study design, but do suggest that episode  levels of



suspended particulates induce lung damage, and that this may occur  only in a



small susceptible  subgroup.  Children with low baseline pulmonary  function



values, a history  of asthma, or with acute respiratory  symptoms  immediately



following the episode were not found to be especially  susceptible  to these
                                   14-103

-------
effects of suspended participates.   No effect of day-of-week,  learning,  or



other potential intervening effects (including regression toward the mean)



were noted.



     Carnow et al.    conducted a study specifically designed to Investigate



dose-effect relationships between air pollution and morbidity from respiratory



disease in patients during the late 1960s  with chronic bronchitis, as they



related to air pollution exposure in Chicago.  Patients, maintained daily



calendars  of symptoms, grading the severty of their illness from 0 to 4.  SCL



measurements were obtained from eight continuous monitors and from 20 additional



stations where 24-hour mean measurements were obtained 3 days a week.  From



the  data and the  square mile grid covering the city, an index of exposure was



developed  for patients based on the locations in which they spent most of



their  daytime and nighttime hours.   In patients over 55 years of age with



grades  3 and 4 bronchitis, increases in symptoms were associated with higher



SOp  levels on the same day or on the previous day.  Increased symptom rates



were reported when the 24-hour SO,, concentrations were 143 to 257 ug/m  (0.05



to 0.09 ppm).  However, the failure to include data on TSP levels, on



occupational exposures, or on smoking habits detracts from the value of this


study.307


                   173
     Burrows et al.    related the occurrence of symptoms recorded daily  by



patients with chronic bronchitis to continuous monitoring data for gaseous



pollutants.  No relationships were found, except for hydrocarbons, when data



were adjusted for season and daily temperature.  It was  concluded  that  24-hour



concentrations of SOp played no major role  in producing  symptoms  in  people



with CRD but temperature probably did.  This  study was  performed  in  similar
                                   14-104

-------
patients in the same city and at about the same time as Carnow's,  and the  two
appear to cancel  each other.
                        190
     Stebbings and Hayes    report on a study in New York during 1971-1972.
The authors studied the relationship between daily fluctuations in air pollution
levels and the aggravation of symptoms in over 300 elderly panelists in the
New York City Metropolitan area in 1971-72.   Candidates for the study were
interviewed and questionnair information was used to classify them as well,
heart, lung, or heart-lung panelists.  Eligible candidates had to reside
within 1.5 miles  of a monitoring site and had to be 60 years of age or more.
Panelists were included in one of four groups identified as "well"; "lung"
(with respiratory symptoms); "heart" (with cardiac symptoms); and "heart-lung"
(with both respiratory and cardiac symptoms).  The study lasted 34 weeks
during which time each panelist was asked to submit weekly diaries through the
mail indicating the days on which their symptoms were worse or better than
usual.  Panelists who submitted diaries for fewer than 11 weeks were excluded
from the analyses, of which there were many.  Symptoms about which information
was requested differed for each panel but together included the presence of
angina or chest pain, wheezing, cough and phlegm, shortness of breath and feet
swelling.  Panelists also gave information on the presence of cough, colds or
sore throat, doctor visits and hospitalizations.
     Air monitoring consisted of measuring 24-hour mean  levels of  SOp (West-Gaeke),
TSP, RSP, SS, SN, and NOp (Jacobs-Hochheiser method);  the quantitative data
for S02 and NOp for individual days may be  less than  reliable.  Weather data
used in the study included maximum and minimum daily  temperatures  and 24-hour
relative humidity.
                                   14-105

-------
      This report contained a discussion of  the  method  then  available  for
 analyzing the data collected and the probable effect of  its inadequacies.   The
 authors concluded, however, that despite the qualification  and  limitations  of
 the methodology, the proportion of the  respondents  suffering more  symptoms  on
 high pollution days than on low pollution days  was  sufficiently high  that the
 relationships could be detected in the  panels as  a  whole.
      Exacerbation of symptoms in the "well" panel was  associated with elevated
 levels of SCL, RSP, SS, and SN; a similar but weaker pattern was found for  the
 "lung" panel.  Symptoms in the "heart"  panel related only to SN and TSP.
 Temperature showed a positive relationship  to symptom  rates in  the "heart"
 panel, but consistent relationships between temperature  and symptoms  were not
 found  in the "well," "lung," or "heart-lung" panels.   The data  suggested  no
 threshold for the effects, and no lesser susceptibility  in  the  well panelist
 than in the elderly panelist with chronic illness.  The  high and low  ranges of
 24-hour pollution concentrations from which the observations were  developed
 were TSP, <60 and >200 ug/m3; RSP, <30  and  >60  ug/m3;  SS, <6 and >12  ug/m3;
                   3                            "3
 SN, <2 and >8 ug/m ; and S02, <40 and >100  pg/m .   The range for minimum
 temperatures was between <20 and >50°F.
 14.4.4  Panel Studies of Acute Respiratory  Disease  (ARD)
      In addition to methodological problems similar to those mentioned for
 chronic respiratory disease studies, lack of information on specific  agents,
/
'and exposure to them, may pose a problem in correct classification of acute
 respiratory diseases.  Respiratory tract illnesses, especially in childhood,
 are critical  as both pathogenic and natural history events.  Assessment by
 questionnaire alone is difficult to validate and such  history may be  inconsistent.
 On the  other hand, definitions and criteria utilized  in determining the presence
                                    14-106

-------
and nature of acute respiratory illness are important,  but not as  critical,  in



that any changes in symptomatology from a baseline (or  lack of symptoms)  may



indicate an acute event,  although this does not imply that criteria  (symptom,



duration and severity dependent) should not be utilized.



     For acute conditions,  the mode of assessment is more difficult  than  for



chronic conditions in that  almost continuous monitoring is required.   The use



of daily dairies is one mode of assessment, although not lacking in  criticism.



Symptom information in daily dairies often suffers from errors of  omission and



from the likelihood that the subjects would complete the dairy at  the  end of



the period of requested recall, which is likely to produce errors  of commission.



Frequent interviews have been shown to minimize these errors.   Gaps  in information



are the most difficult problem in evaluating acute respiratory illness occurrence



in individuals.   Meteorological factors are important,  perhaps more  important



than the pollutants.   Other covariables and intervening variables  of importance



include smoking, alcohol  consumption, occupational exposures,  housing, family



size, and structure.   Although acute respiratory illnesses may be  better



indicators of effects of pollutants, temporal analysis  of such effects may



produce conflicting findings related to covariables, intervening variables,



the presence of endemic and epidemic infections, reporting biases, and the


                                                     249
environmental interactions  of pollutants and weather.



     McCarroll et al.   studied daily symptoms (from weekly interviews) of



over 1800 individuals in three New York City housing projects between 1962 to



1965.  This represents 35,400 person-weeks of data.  They found that cough



frequency was related to SOp concentration but not particulate matter.  In a

                                one

further report,  McCarroll et al.    showed several period of  increased S02



with associated increases in respiratory and irritation  symptoms.   One episode
                                   14-107

-------
(December 1962) saw a shart increase from 0.1 ppm to over 0.2  ppm in  2  days



accompanied by increased symptoms.   During another episode S0? increased



slowly from 0.05 ppm to about 0.14 ppm over a 3-week period (October  1963)



with increased symptoms.  A third episode occurred in March 1964, with  levels



exceeding 0.3 ppm and increased symptoms (although there was some lag in



symptoms), and corresponding increases in school  absenteeism.

                             pnr

     McCarroll and colleagues    also demonstrated increased prevalence rates



for common colds and cough in children and adults in 6-month periods  surrounding



winter and summer controlling for smoking.   However, these were often inconsistent



with S0~.  Summer particulates (CoH) were positively correlated with  respiratory



symptoms with some increase in prevalence rates for days with CoH above 1.50



significant for children.  With inclusion of meteorological variables in

                    on?
multiple regression,    the incidence rate of common colds was found  significantly



independently related to S02 in some seasons.  The prevalence rate of the



common cold was significantly related to CoH and meteorological variables,

                                                                   one
especially in the spring of 1964 (R = 0.93), and "epidemic period."


                   ?08 ?09
     Cassell et al.   '    showed two contrasting trends in the relationship



of pollutants to acute respiratory illness in winters, storms and air pollution



episodes, the former of which usually hiding the effect of the latter in most


         207
analyses.     Separated, the air pollutants  (CO, COH, SOp) measured within a



quarter-mile of subjects correlated significantly with common cold incidence



and prevalence rates in winter (after controlling for weather variables).  The



winters during this study had mean daily S02 levels of 0.17 ppm  or greater,


                                                                            207
mean daily COH of 2.20 or greater, and mean  daily CO of 2.94 ppm  or greater.

                                                                                  210
Individuals sensitive to the effects of air  pollution and weather were  delineated.



The young (under 10) reacted the greatest to high air pollution  combined with
                                   14-108

-------
low temperature.   Reactions in sensitive individuals were also of greater

duration and severity.   The reporting of acute illness varied proportionately

with social  status but  did not change the relationships mentioned;  the  different

social  status groups *eing followed equivalently and simultaneously.

     French  et al.   conducted an ARD study in the New York communites of

Bronx,  Queens, and Riverhead in 1970-1971.   Telephone interviewer made  biweekly

calls to mothers  of families enrolled in the study to inquire whether any

family member had developed upper or lower respiratory illness in the 2 weeks

and, if so,  whether a doctor had been consulted and on how many days  activity

was restricted.   If an  individual was reported to have both upper and lower

respiratory  symptoms, the illness was classified as lower respiratory disease.

The major response variables were the number of respiratory illnesses per

hundred person-weeks of observation (the attack rate) and an arbitrary  severity

score, which reflected  physician visits, fever, and restricted activity.

Selected interviews were repeated a few days after the initial call and

concordant results were obtained in over 90 percent of those previously

reporting ARD and 98 percent of those previously denying ARD; this shows

reproducibility but not validity of reported illness.  Total and lower  respiratory

illness attack rates in Riverhead tended to be lower than in either Queens or

Bronx, is consistent with the pollution gradient.  Based on NYC DAR levels in
                                                                      3
1970, this would indicate more morbidity in areas with S02 of 160 ug/m   (Queens)
                   O                                         O
or more and  82 pg/m  TSP or more (Queens) compared to 39 (jg/m  TSP in (Riverhead).

See Appendix A for further discussion regarding the results and their

interpretation from this EPA CHESS Program study.

     French  et al.    also reported on an ARD study in families of nursery

school  children in Chicago for one year (12/69-11/70).  A census was obtained
                                   14-109

-------
on families agreeing to participate using a standardized questionnaire.
Migration, crowding and education were obtained and compared between areas.
Telephone interviews by trained interviewers were made fortnightly to the
mother or guardian concerning new respiratory illnesses and their symptoms,
and any medical consultation.  Lower respiratory illnesses (LRI's) were
limited to chest colds with a persistant productive cough, croup,
bronchiolitis, or pneumonia.  A sample of replies were compared to physicians'
records to validate reports. There were 2705 fathers, mothers and children
(ages 112) participating. Areas of relative pollution were grouped into two
categories (see Table 14-24).  All families resided within 1 1/2 miles of an air
monitoring station.  There was an increased attack rate of ARD in all family
members with 3 or more years residence in that area.   Except for children
under 3, all family members in the high pollution areas had an excess risk of
acute LRI (Table 14-25).  Upper respiratory illness (URI) rates were higher in
all family member in the high pollution areas.  These higher ARD rates were
still significant after adjusting for family smoking (Table 14-26); The pollution
effect was independently significant.  See Appendix A for further discussion
regarding the results of this EPA CHESS study and their interpretation.
 TABLE 14-24.  CHICAGO MEAN ANNUAL LEVELS OF POLLUTANTS IN AREAS, 12/69-11/70


LOW
HIGH
so2 (ug/m3)
57
106
TSP (ug/m3)
111
151
SS (ug/m3)
14.5
16.0
                                   14-110

-------
TABLE 14-25 -Acute Reipintory Illneii Among Families Living
Two Metropolit»n Areas
r«mlly
Jt£ment
Chica|o
Fathers
Mothers
Older
tiblings
Nursery
sxhool
Children
Younger
tiblmgs
New York
Fathers
Mothers
School
children
Preschool
Children
Community
Pollution
[ipoiurt
Intermediate
Highest
Intermediate
Highest
Intermeddle
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Low
Intermediate (pooled)
Lo*
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
family
Cfcinftd
AUdreu
Dunnf
Previous
JSyr
No
No
Yes
Ye i
No
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
Ko
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
ln»oH»in|
Upper
Tract
1.00(2.59)'
1.21
1.27
1.20
1.00(3.96)
•l.*6
14
.24
.00(4.09)
.37
.14
.17
.00(7.57)
.12
.05
.21
.00(7.65)
.27
.16
.65
1.00(1.77)
0.95
0.8S
065
1.00(2.51)
091
1.04
0.63
1.00(2.60)
1.09
093
094
1.00(2.71)
1.26
1*£
1.19
ht»ehnn|
Lower
Tract
1.00(042)
2.29
1.10
0.90
.00(0 64)
.45
.53
.22
.00(0.63)
44
0.81
0.82
1.00(1.63)
1.30
1.25
1.53
1.00(2.64)
0.93
0.90
1.00
.00(1.66)
.39
.27
.35
ooa.Boi
.56
.67
.12
.00(325)
.23
.08
.21
.00(547)
.25
0.73
1.21
in
All Acirtt
ReipirJlory
hlnen
1.00(301)
1.36
1.2S
1 14
1.00(4 60;
1.46
1.19
1.28
1.00(4.73)
130
1.09
1.25
1.00(970)
1.15
1.09
1.24
1.00UO<9)
1.18
1.09
1.43
1.00(3.431
1 16
0.95
089
.00(4.31)
.18
.30
.20
.00(606!
.16
.00
.18
.00(8. IB.1
.25
0.98
1.15
'Figures In parentheses indicate base nte per 100 person weeks ot risk.
                                 14-111

-------
TA
BLE 14-26 -Smoking
( family Segment
t
Mothers
Old;'
Nurvery school
Students
Younger
siblings
tie* Ys'k
fathers
Mothers
School
Children
Preschool
Children
•adjusted. Acute Respiratory
Community
Air Pollution
Exposure
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Low
Pooled
Intermediate
Low
Pooled
Intermediate
Low
Pooled
Intermediate
Low
Pooled
Intermediate
Disease Attack Rates*
Relative Risk of Acutt
Respiratory Illnet:
1.00(280)
1.33
1.00(476)
1.25
1.00(7.04)
1.18
1.00(035)
1.02
1.00 (9 <1)
137
1 00(1.58)
1.4}
1.000.72)
1.55
1.00(397)
1.09
1.00(6.12)
1.10
metropolitan Chicago
                              14-112

-------
     All  ARD diary studies experienced attrition over time and some
methodological  problems plagued them.   It is likely,  however,  that families
exposed to high levels of urban pollution experienced higher ARD attack rates
than did those  less exposed.
     A couple of studies have investigated relationships between the incidence
of acute respiratory disease and very high air pollution concentrations.
     Kalpazanov et al.   studied by regression analyses the relationship
between the daily number of newly reported cases of influenza during an
epidemic in Sofia, Bulgaria, and specific meteorologic or air pollution
factors.   The number of new cases was taken from the  official  registration.
Sundays and Mondays were eliminated since it was shown that many Sunday
illnesses were  not recorded until Monday.  Aerometric samples were collected
daily from 8:00 a.m. until noon in the city center.  Correlation coefficients
were developed  for each factor for the day on which the illness was reported,
for the previous day, and for 2 days prior to the reporting of the illnesses.
Results indicated that the same-day measurements of air temperature,
visibility, S02, oxidants, cloudiness, and wind velocity all related to the
number of illnesses reported.  Oxidants, however, showed a negative
correlation.  On the day prior to the reporting of illnesses, only S0? was
related significantly (r = 0.6); 2 days prior to the reporting, nitric oxides,
formaldehyde, and oxidants were associated, oxidants again with a  negative
correlation.  The authors compared these results with those of an  earlier 1972
influenza epidemic also in Sofia   in which almost the  same protocol was
followed.  In 1972, but not in 1974-75, dust was associated with  illness
reporting; a possible explanation of this was the much  lower dust  measurements
in 1974-75.  Nitric oxides were also lower  in 1974-75,  while SOp was about
three times higher.
                                   14-113

-------
14.4.4  Aggravation of Asthmatic Symptoms



     Cohen et al.    studied attack rates in 20 asthmatics over a period of 7



months and showed significant correlations between reported attack rates and



temperature as well as between reported attack rates and 24-hour mean air



pollution levels after the effect of temperature had been removed from the



analysis.  Temperature showed by far the strongest association with attack



rates in multiple regression analyses.   However, SO^, TSP, SS, SN, and soiling



index (CoHs) each explained a significant portion of the residual after the



effect of temperature had been removed.   After temperature and any one pollutant



had been removed, none of the other pollutants explained a significant amount



of the variation in attack rates.  Thus, the overall effect of air pollution



can be attributed to no specific pollutant.  Significant 24-hour concentrations


                                3               3
were assessed as:  TSP, 150 ug/m ; S0?, 200 ug/m  (0.07 ppm); suspended sulfates


       3                                 3
20 ug/m  ; or suspended nitrates, 2.0 ug/m .



     Kurata et al.   found no associations between weekly mean concentrations



of S02, N02, 03, or CO and asthma symptoms.  In this multifactorial study,



weekly mean concentrations of SO,, averaged less than 280 ug/m  (0.10 ppm), but

                                        3

occasional weekly highs reached 500 ug/m  (0.17 ppm).  It may be, however,



that asthma attacks would relate much more closely with daily means or daily



peaks than with weekly mean concentrations of pollution.



     Many studies of asthma failed to evaluate many relevant factors, including



medication (steroids), humidity, exercise, daily temperature changes, other



pollutants, pollen, emotional factors, and exposure to smokers at home or



work.



14.4.5  Hospital/Clinical Admission Studies and Absence Studies



     Visits to the emergency room provide a health outcome measure of a more



severe type than is generally provided by physician visits.  Emergency  room



records are frequently more complete, especially as to the acute episode,  than



                                   14-114

-------
are physician records.   For these reasons, such disease outcomes have been



utilized in several  studies of the acute health effects of air pollution.



Frequently, these studies have examined cause-specific reasons for the visits,



such as asthma.   Most of these studies have been temporal  in nature,  although



some have compared of visits to hospitals in different regions of the city.



Data organization and analyses are usually similar to analyses of daily mortality.



     Unfortunately,  emergency room visits have the same problems with denominators



and reference populations as do other types of visits or medical records.



Also, it is difficult to relate spatio-temporal exposures to specific health



events or to the perceptions of those who come into the emergency room.



Finally, with the increased use of the emergency room as a family practice



center, fewer visits are associated with any acute exposure or attack.



     Although hospital  admissions have some of the same problems associated



with emergency room visits, more information is generally available from the



records.  Hospital studies are limited, however, in terms of the finite number



of people that can be admitted.



     During the winter of 1972 or 1973, Kevany   studied 2364 admissions to



study hospitals.  Data for cardiovascular disease and respiratory disease



admission rates showed very low (r <.30) but significant correlations for both



sexes between heart diseases and smoke or S0?.  Insufficient exposure data



were provided.


            54
     Heimann   studied the effect of short-term variations  in pollutant levels



on the frequency of clinic visits for Boston patients with  chronic respiratory



disease.  These studies were conducted during  periods of higher pollution in



1965 and 1966.  Although indicated associations were  less than  in New York



during episodes, there was a positive association between pollution  levels  and
                                   14-115

-------
clinic visits even though the maximum 24-hour geometric means from 20 stations



were 226 ug/m3 for high-volume TSP, 350 ug/m3 (0.12 ppm) for S02>  and 2.2 for



CoHs.


                    17 T\
     Sterling et al.   '    used data from a medical  insurance group to obtain



information on relationships between air pollution  and hospital  admission for



"relevant diseases" among about 10,000 individuals  in California.   Daily



pollution concentrations were given as the mean of  the maximum and minimum



values of measurements taken at eight stations, 5 to 10 weeks apart, from



March to October.  After allowing for the confounding effects of day-of-week,



deviation of stay, higher relevant admission rates  occurred on those days



among the highest third of sulfur dioxide pollution than on those days among



the  lowest third.  The sulfur dioxide concentration mean for was about 45



ug/m (0.015 ppm); concentrations on the highest pollution day were not reported)



They also correlated with NO^, OX, TSP, but not with temperature or humidity.



Correlations were low and SOp/TSP concentrations were low.  Consequently, one



of the other pollutants with which illness rates were associated (CO, N0?, or



03)  may have been more significant.  The indicated association for S0? may



have been caused by the interrelationships between pollutants.  It is difficult



to state to what extent either SO  or TSP were causally involved in producing



the  health effects observed.

                                                                               p
     Illness data were obtained in many of the early s;evere pollution episodes. '



This information did little more than confirm the mortality results, though



there was some evidence that the increase in illness was  not as large in



percentage terms as the increase in deaths, and the effects were not so sudden.



Martin  examined hospital admissions for the winters of 1958 to 1959 and 1959



to 1960 and found, after adjustment for day of the week and correction for



15-day moving average, significant correlations for both
                                   14-116

-------
cardiovascular and respiratory conditions with smoke and sulfur dioxide.   The
average deviations by group are shown in Tables 14-27 and 14-28 and show more
irregularity than the mortality data.
                    274                 69
     Fletcher et al.     and Angel  et al.    followed 1,136 working wen aged  30
to 59 in West London by surveys at 6-month intervals.   The surveys included
collection and measurement of morning sputum volume and FEV.as  well as data
from respiratory symptom questionnaires.  Expected patterns of  decline in lung
function with age occurred, and this was most rapid in cigarette smokers with
low lung function to start with.   Another finding was a decrease in sputum
volume in men with constant smoking habits most consistently in the winter
samples.  During six years of study, there was a decrease in mean sputum
volume during the first morning hour from about 1.5 ml to about 0.75 ml,
associated with a decrease in smoke (annual) from 140 ug/m  (234 ug/m  TSP)  to
       3
60 ug/m .   Possible changes in cigarette tars, and in methods of smoking could
                            251
have influenced this result.      During the winter of 1962 to 1963, they
intensively monitored a subsample of 87 men.  The incidence and prevalence of
respiratory illnesses were associated with both BS and S0~, though the prevalence
was more related to smoke.  Weekly concentrations were about 300 ug/m  BS (370
ug/m3 TSP) and 400 |jg/m3 S02-
     Studies of the acute effects of air pollutants and exacerbations in
chronic respiratory disease related to pollutant exposures have been conducted
by various investigators using absenteeism records.  The use of these records
is complicated by the lack of shorter illnesses, the specific diseases (if
really present), the nature of the population under study, the absence of
weekend information, the absence of co-morbidity information, the  absence of
covariable information (including smoking), and by  such variables  as  day-of-week
                                   14-117

-------
TABLE 14-27.  AVERAGE DEVIATION OF RESPIRATORY AND
   CARDIAC MORBIDITY FROM 15-DAY MOVING AVERAGE,
         BY S02 LEVEL (LONDON, 1958-1960)
S09 Level
(pg/m3)
400-499
500-599
600-799
800-899
900+
TABLE
Smoke Level
(pgAi3, BS)
500-599
600-699
700-799
800-1099
1100+
Number
of days
9
6
9
6
5
Mean
Deviation
2.2
5.1
6.9
12.8
12.8
14-28. AVERAGE DEVIATION OF RESPIRATORY AND CARDIAC
MORBIDITY FROM 15-DAY MOVING AVERAGE,
BY SMOKE LEVEL (BS) (LONDON, 1958-1960)
Number
of days
9
6
9
8
7
Mean
Deviation
3.2
-0.7
2.4
4.9
12.9
                    14-118

-------
effects,  season, holidays, etc.   Nevertheless,  these studies  have been meaningful,



when appropriately done and when some of the shortcomings have been overcome.



     Dohan and Taylor   and Dohan   studied relationships between 24-hour air



pollution concentrations (measured biweekly) and respiratory  Illnesses lasting



more than 7 days in female workers in five United States cities.   The workers,



all with one company, received insurance payments after the seventh day of



illness when a physician attested to the illness.  Over a period of 3 years



(1957-1960), illness absence rates were related to measured concentration of



suspended particulate sulfate but not to TSP (range 100 to 190 ug/m ), benzene-



soluble organics or specific trace metals.  Among the five cities the lowest

                                                                          o

case rate was associated with mean 24-hour sulfate concentration of 7 ug/m



and the highest rate was associated with mean 24-hour sulfate concentrations



of 20 ug/m3.


                 68
     Ipsen et al.    studied employees from the same company but restricted



their investigations to one city and approximately 20,000 employees.  As an



indication of illness frequency, the sum of dispensary visits during a particular



week was divided by the average working population.  Air monitoring data were



obtained from the Department of Community Health Services of the City of



Philadelphia, Air Pollution Control Section.  Data obtained included daily



measurements of TSP, suspended sulfates, and soiling index (CoHs), but not



SOp.  Results indicated that periods of high particulate sulfate levels and



low temperatures were associated with high morbidity and that low sulfate



levels and high temperature were associated with low morbidity.  No pollutant



had a notable effect over those of weather variables, but the sum of the air



pollutants, although actual concentrations were not reported, were  said to be



positively correlated with prevalence measured on the same day, or  with a lag
                                   14-119

-------
of 7 days.  This study did not consider the significant age differences,
smoking habits, or differences in weather and climate among these cities.
     Gregory60 found that in the 1950's, sickness absences at a Sheffield
steelworks increased as monthly mean concentrations of smoke (BS) and SCL
increased.  The monthly data provide little information relative to the actual
effective air pollution values.  These original data were reviewed by Holland
et al.  who concluded that rough judgment estimates of the concentrations
associated with increases in sickness absences were 24-hour means above 1,000
    3                                  3
ug/m   for smoke (BS) and above 850 ug/m  (0.3 ppm) for SO^.
     Gervois et al.   made a comparison of sickness absence records of French
employees, with daily variations in smoke, S02, and temperature, for 89 days
during a winter season.  Although pollution concentrations were similar in
each of two towns  involved in the study, positive associations between pollution
and illness were obtained in only one.  In this town, some association was
found  after adjusting for temperature.  Although the daily pollution data were
not given, the highest 24-hour mean values in the town with the positive
                               3
association were about 200 ug/m  for both smoke and SO-.  The mean values for
the 3-month period were 53 ug/m  for smoke and 37 ug/m  for S02; therefore, an
estimate of higher values associated with increased illness could be between
100 and 200 ug/m   for both smoke and SOp.
     Verma et al.    reported that in a multiracial population of males and
females 16 to 64 years of age who worked for an insurance company in New York,
minimum respiratory disease absences occurred on hot days  (maximum temperature
>76°F) when the 24-hour mean S02 levels were low (29 to 143 M9/m3; 0.01 to
0.05 ppm).  Higher S02 levels increased absence rates.  On cooler days (maximum
temperature <50°F), when S02 and suspended sulfates both were high, respiratory
                                   14-120

-------
Illness  absence rates were highest.   Air pollution data for this  study  were



provided by the Department of Air Pollution Control  of the City of New  York



but information for particulates  was  not reported.


                       20
     Burn and Pemberton   found that  incapacity for work due to bronchitis



among Sal ford,  England, workers exceeded the expected number by a factor of



two when 24-hour mean smoke concentrations exceeded 1000 ug/m  for 2 consecu-



tive days, thus relating bronchitis morbidity to smoke.   It is  possible,



however, that the episode conditions  indicated by smoke concentrations  above



1000 ug/m  may have included sufficient S02 or derivatives (HpS04 or sulfates)



to produce the increased morbidity.



     Additional information on the relationships between air pollution  concen-



trations and absences from work has been reported from the British Ministry  of


                               62
Pensions and National Insurance  .  This information indicates  that sickness



absences (October 1961 to March 1962) for bronchitis, influenza,  arthritis,



and rheumatism all occurred more  frequently in high-pollution areas.  Daily



pollution measurements were not provided, but data from five areas in Scotland



and around London showed correlations between bronchitis and pollution that



were stronger for S0? than for smoke.  In these areas, the lowest bronchitis



inception rate appeared to be related to smoke levels between 100 and 200


    3                                 3
ug/m  and SOp between 150 and 250 ug/m  (0.053 and 0.081 ppm).   In South



Wales, however, more bronchitis appeared to be associated with lower pollutant



concentration, and lowest inception levels appeared to be less than the values



stated for the other study areas.  The cause of the higher bronchitis rates  in



South Wales is not clear.



14.4.6  Pulmonary Function Studies


                   7ft-ftl
     Lawther et al.      have reported on relationships between ventilatory



function measurements in four subjects and daily concentrations of  smoke and
                                   14-121

-------
S0? from 1960 to 1971.  The tests performed daily included forced vital  capacity:
forced expiratory volume, maximum midexpiratory flow, and peak expiratory flow
rates.  During the period of study, 24-hour smoke concentrations ranged from
10 to 650 ug/m3, and 24-hour S02 ranged from 50 to 1500 ug/m3.  Increases in
S02 were most consistently associated with poorer test results.   However,
small decreases in function were associated with large increases in S02-  Peak
flow  rates in all subjects were related significantly with either smoke or S02
(p <  0.05), but were reduced by only 4 percent.
      Emerson   conducted weekly spirometric measurements on 18 patients with
chronic airway obstructions during 1969-1971 in London.  They found them (FEV,
and MEFR) to correlate with changes in atmospheric conditions and with air
pollution.  FEV, was more correlated with temperature.  Average smoke (BS)
                           3
concentrations were 45 ug/m  together with average SOp concentrations of 190
ug/m  (0.07 ppm) pollution figures were averaged for 5-day periods while
operometric measures were made on specific days.  Only one subject had significant
responses.  This is a weak study   '     although some authors    consider it
to demonstrate levels of no effect.
           83
      Ramsey   studied bronchoconstricting tendencies and pulmonary function on
a daily basis over a 3-month period in seven male, non-smoking asthmatics 19
to 21 years old.  Three spirograms were produced each  day at  hourly intervals.
A Warren & Collins 13.5 liter respirometer was used.   The three values were
averaged for FEV^^ Q, MEFR, MMFR, and flow rate.  No  information was provided
on the method and techniques for calibrating the instrument.  Results were
analyzed by multiple regression, and values were considered significant  only
when p < 0.001 (r > 0.42).  Results showed that in three of the seven subjects,
one or more of the pulmonary function tests (MEFR, MMFR, flow rate, 10  to 25
                                   14-122

-------
or 50 percent volume) was correlated with mean air temperature  on  the  day  of
the tests  or on the previous day.   Two subjects also showed correlation, each
in a single test parameter,  with barometric pressure on the previous day,  and
two showed positive, not negative,  correlations between specific test  results
and daily  mean ozone concentrations.   None of the test results  showed  significant
correlation with 24-hour TSP measurements that averaged 82.5 ±  35.5 ug/m
(maximum,  175 ug/m ), or 24-hour sulfate concentrations that averaged  3.2  ±
1.8 ug/m  (maximum, 7.5 ug/m ).   Protein (daily mean, 1.28 ± 0.7 ug/m  ) and
total organics (average, 22.1 ± 9.8 ug/m ) also showed no significant  correla-
tions with test results.  The investigator concluded that temperature  and
barometric pressure appear to be more instrumental in promoting tendencies to
asthmatics' dyspnea than do exposures to ambient air pollutants even when
levels of  the pollutants exceed Federal air quality standards.
                    327 328
     Shepherd et al.   '    studied 10 respiratory patients for 3  months.
Several function measurements were  negatively correlated with relative humidity
and CoH of 8 or more per day (1140  ug/m ).  Lebowitz et al.    tested  pre- and
post exercise lung function in children 6 to 12 years of age in a  smelter  town
on 4 days  with high temperature and varying S02/TSP (measured near the test
site), and in children 10 to 12 in  an urban area on 4 days with high temperature
and varying TSP (measured nearby).   A portable pneumotachygraph was used in
the latter study to measure FVC and FEV, Q and MMEF in the former study.   The
two instruments were compared in a  group of subjects and differences were   less
than one percent.   Results controlled for time of day, smoking, and respiratory
medical history, showed that exposures to high temperatures produced post
exercise decreases in FVC and FEV,  Q that were related to  the relative level
of pollution and temperature.  In comparison, a nonexercise (cross-over)
                                   14-123

-------
control group showed nonsignificant declines on high air pollution days.
During testing, outdoor temperatures were always above 86°F and relative
humidity was less than 30 percent.   S02 ranged from <1 ppm to 5 ppm and absolute
TSP was unknown during testing in the smelter town.   In the urban area, TSP on
                             3                                   3
high days averaged 106.7 ug/m  and on low days averaged 98.3 ug/m ; suspended
sulfate was low and photo-oxidant levels were not known in absolute terms but
were considered equivalent.  A control group who remained indoors in an air
conditioned building where pollution was low showed no significant differences
in pulmonary function (measured with the Collins 13.5 liter spirometer) that
could  be related to the type or degree of exercise,  day of week, or time of
day.
     Summarized in Table 14-29 are the results of quantitative studies
reviewed above as providing information on associations between morbidity
effects and elevated levels of sulfur oxides and particulate matter.
Examination of the table reveals that several studies have shown worsening
of health status among bronchi tic patients and increased hospital admissions
to be  associated with acute exposures to TSP and SOL levels as low as
200-350 and 300-500 ug/m3, respectively.  Also, other study results
suggest that decreased pulmonary function and increased respiratory
symptoms in normal populations, as well as increased symptomatology in
asthmatic patients, may all be associated with somewhat lower levels of
TSP and S02 (between 150 to 250 ug/m3 and 250 to 300 ug/m3, respectively.)
                                   14-124

-------
TABLE 14-29.•  SUMMARY OF EVIDENCE FOR MORBIDITY EFFECTS OF ACUTE EXPOSURE TO SO, AND PARTICULATES
Type of Study
Morbidity
Acute- hospital
Acute-clinical
Acute- long.
(Daily - 3 yrs)
^ Acute- long.
ro 3
Ol
ER visits
Acute - children
Acute-clinical CB/AS
Acute-clinical CB
Acute-clinical CB
Acute-AS
Reference
Martin16
Lawther et al . 53
McCarroll
et al.2d5 206
Cassell et al.208 209
Greenberg et al. 19G
Stebbings et al.216
Waller and
Lawther59
Lawther et al. 52
Stebbings and
Hayes1 5o
Cohen et al.55
24-hour average pollutant levels
at which effects appear
Effects observed
Increases in hospital admissions
for cardiac or respiratory
illness
Worsening of health status among
195 bronchitics
Increased ARI daily inc/prev
Increased ARI average daily
inc/prev
Increased cardio-respiratory
visits
Decreased FEV\75
Increased symptoms in patients
in 2 hours
Decreased condition
Increased symptoms
Increased asthma attacks
TSP (|jg/m3)
500
250 BS
(344 TSP)
100 BS
(200 TSP)
145 BS
(245 TSP)
260 BS
(340 TSP)
700
6500 BS
(1° resp.)
400 BS
250-350 BS
200 (60 RSP)
12SS (8SN)
150 (20SS)
S02 (ug/m3)
400
300-500
372
452
715
300
2860
450
300
100
200

-------
                        TABLE 14-29 (continued).
Type of Study
Acute-clinical
visits
Absenteeism
Absenteeism
Reference
Heimann54
Gervois et al.61
British Ministry
24-hour average pollutant levels
at which effects appear
Effects observed
Increased visits by CRD
patients
Increased, male workers
Increased, male workers
TSP (ug/mj) I
226
100-200 BS
100-200 BS
™2 (M9'm /
350
100-200
150-250
Pension62

-------
14.5  MORBIDITY ASSOCIATED WITH LONG-TERM POLLUTION EXPOSURES


14.5.1  Introduction


     Morbidity means the presence of any state of illness or disease.   It may


represent acute disease or chronic disease.   It may represent symptoms in one


organ system or in many.  It may even represent temporal  variations in symptoms


of a specific or a general nature.  The incidence of morbidity represents the


new onset of morbidity, while the prevalence represents the presence of mor-


bidity.   The incidence rate is usually the number of new cases over the number


of persons at risk in a given place during a given time.   Prevalence rate is


the number of present cases over the number at risk in a given place for a


given period of time.  Incidence and prevalence are usually obtained by


questionnarie.  In general, morbidity is harder to ascertain than mortality,


but is usually a more sensitive indicator of health effects of ambient air

                        J.t/7                             24O
pollutants.   (Goldsmith, 1977:  Lebowitz, 1973a, Speizer, 1969).


     Studies of morbidity associated with long-term pollution exposures


represent the largest portion of epidemiologic air pollution studies.   This is


true in part because it is easier to characterize long-term exposure (one or


more years) than short-term exposure (24 hours or less).   For convenience the


studies are divided into six subcategories, based on the health end point:


(1) chronic bronchitis prevalence studies, (2) other respiratory disease/symptom


prevalence studies, (3) panel studies of acute respiratory disease, (4) pulmonary


function studies, (5) studies combining respiratory disease symptoms with


pulmonary function, and (6) hospitalization-clinic admission-absence studies.


     Emergency room visits, hospital admissions, and physician visits represent


one measure of morbidity.   They have been used frequently in examining the
                                  14-127

-------
health effects of different levels of ambient air pollutants.   Unfortunately,
appropriate denominators (the number of those at risk) are not generally
available in studies that use these measurements, and the populations so
described may be very specific sub-populations, presenting difficulties of
definition and preventing generalizations from the results.
     Absenteeism from work or school due to specific morbidity is sometimes
used to determine the effects of pollutants.   This method presents difficulties
in ascertaining of cases and of causes.  Even more than hospital and physician
visits, absenteeism is directly related to the day of the week, the season,
and other social and behavioral factors.  Absenteeism is also dependent on
interpretation by health or administrative personnel.  Very often, absenteeism
is not examined unless it exceeds a certain number of days, and this seriously
limits it as a sensitive indicator of pollutant effects.
     In the various types of epidemiologic studies, changes in some biological
function over time may be a good indicator of the effects of pollutants.  Such
changes may include altered pulmonary function, alterated immunologic responses,
or altered biochemical activities or functions.  These are usually quite
sensitive measures of biological activity, although they do not necessarily
represent meaningful stages of morbidity.  Such measurements usually require
an    expenditure of greater resources and greater cooperation on the part of
subjects or patients.  Changes in function are measured in terms of percent
change over time or change in absolute function  in individuals over time.
     Morbidity studies typically employ one of three experimental design
strategies:  spatial, temporal, or spatiotemporal.   Spatial studies examine
health end point differences between communities  (geographic areas) with
                                  14-128

-------
differences in pollution exposure.   Since it is impossible to find communities
with characteristics that are identical except for pollution exposure, it is
necessary to account for these differences.   This can be done either by sub-
dividing the communities into similar subgroups or by adjusting for the
differences in the analysis.   These differences typically include age, race or
ethnic group, sex, socioeconomic status, smoking habits, and general health
care.  A critical examination of any spatial study must consider all factors
exerting an effect on the health end point.   A study's credibility depends on
the adequacy with which it considers these factors.
     Temporal studies associated with long-term pollution exposure axe less
common than spatial studies.   A temporal study compares the changes of the
health end point through time with the changes in pollution.  Each community
acts as its own control, making the factors critical to the spatial studies
much less important.  Temporal factors such as temperature, season, other
meteorologic factors, and influenza cycles become critical.  The appropriate
statistical analyses for such studies often have not been available at the
time of analysis.  Studies should be judged on their ability to cope with
these factors and problems.  Many long-term temporal studies are also spatial
studies, and thus offer a comparison of the two designs.
     Common to both spatial and temporal designs is the problem of estimating
pollution exposure.  The specificity of exposure assessment ranges from crude
indices such as coal combustion to sophisticated continuous monitors at several
locations.  Unfortunately, even the most sophisticated devices have a history
of problems such as gross inaccuracies and non-specificity.  More difficult is
the extrapolation from the measurements at a monitoring site to individual
                                  14-129

-------
exposure levels.  A major improvement in this characterization would be the



use of personal monitors.  Although studies have been undertaken using these,



none have yet been published.   Qualitative studies of morbidity associated



with long-term exposures to particulate matter or sulfur oxides are summarized



in Table 14-30.  Studies yielding more quantitative information on the same



subject are discussed in more detail in the next several sections.



14.5.2  Chronic Respiratory Disease Prevalence Studies



     Studies of the relationships between air pollution concentration and the



prevalence of chronic bronchitis have been reported from several countries.



Among the studies of morbidity, the chronic bronchitis indicator has most



consistently given positive associations.  Nevertheless, there are a number of



problems encountered in attempts to interpret the data reported.  These arise



from the fact that criteria for diagnosing chronic bronchitis are not con-



sistent around the world.



     Historically, chronic bronchitis has been the most commonly utilized



representation of obstructive lung diseases and has most often been defined or



quantified in terms of answers to the British Medical Research Council's



Respiratory Questionnaire (BMRC), in one of its several versions.  This



definition generally implies that the subject has a persistent cough and/or



phlegm, meaning cough and/or phlegm that occurs on most days for as many as 3



months of the year; in addition, the definition may require that the subject



has had these symptoms for at least 2 years.   Although labelled "chronic



bronchitis," this illness differs from clinically diagnosed chronic bronchitis



in several  respects.   The clinical diagnosis may be made on the basis  of the



presence of one or more criteria, including not only responses to that



question in a clinical setting, but also responses to questions about  wheeze,
                                  14-130

-------
     TABLE  14-30.  QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE  OF  CHRONIC
               RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
   Study
         Characteristics
      Findings
Fairbairn and
 Reid265
Mork
    266
Deane  et al.267
Cederlof,39
 Hrubec et al.40
Comparison of respiratory illness
 among British postmen living
 in areas of heavy and light
 pollution
Questionnaire and ventilatory
 function tests of male trans-
 port workers 40-59 years of age
 in Bergen, Norway and London,
 England
Questionnaire and ventilatory
 function survey of outdoor
 telephone workers 40-59 years
 of age on the west coast of U.S.
Chronic respiratory symptom
 prevalence in  large panels  of
 twins in Sweden and in the
 U.S. Index of  air pollution
 based on estimated residential
 and occupational exposures  to
 S02, particulates, and CO
Sick leave, premature
 retirement, and death
 due to bronchitis or
 pneumonia were closely
 related to pollution
 index based on visibility

Greater frequency of
 symptoms and lower
 average peak flow rates
 in London.  Differences
 were not explained by
 smoking habits or socio-
 economic factors

Increased prevalence of
 respiratory symptoms,
 adjusted for smoking and
 age, a larger volume of
 morning sputum and a lower
 average ventilatory function
 in London workers, and  in
 the English compared with
 American workers.  No
 differences in symptom
 prevalence between
 San Francisco and
 Los Angeles workers,
 although particulate
 concentrations were
 approximately twice  as
 high  in  Los Angeles

Increased prevalence  of
 respiratory symptoms  in
 twins  related to smoking,
 alcohol  consumption,
 socioeconomic character-
 istics,  and urban  residence,
 but not  to indices  of  air
 pollution
                                      14-131

-------
     TABLE 14-30   QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF CHRONIC
                RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
    Study
         Characteristics
      Findings
Bates et al.268-270
Bates271
Yashizo272
Winkelstein and
 Kantor273
Jshikawa et al.275
Fujita et al.276
Comparison of symptom prevalence,
 work absences, and ventilatory
 function in Canadian veterans
 residing in 4 Canadian cities
10-year follow-up study of
 Canadian veterans initially
 evaluated in 1960, and
 followed at yearly intervals
 with pulmonary function tests
 and clinical evaluations
Bronchitis survey of 7 areas of
 Osaka, Japan, 1966, among
 adults 40 years of age and ove
Survey of respiratory symptoms
 in a random sample of white
 women in Buffalo, New York
Comparison of lungs obtained at
 autopsy from residents of
 St. Louis and Winnipeg
Prevalence survey (Medical
 Research Council questionnaire)
 of post office employees  In
 Tokyo and adjacent areas, 1962
 and re-surveyed in 1967
Lower prevalence of symptoms
 and work absences and better
 ventilatory function in
 veterans living in the lest
 polluted city

Least decline in pulmonary
 function with age in veterans
 from least polluted city
Bronchitis rates, standardized
 for sex, age, and smoking
 were greater among men and
 women in the more polluted
 areas.  Bronchitis rates
 followed the air pollution
 gradient.

In nonsmokers 45 years of age
 and over, and among smokers
 who did not change residence,
 respiratory symptoms were
 correlated with particulate
 concentrations obtained in
 the neighborhood of residence.
 No association of symptom pre-
 valence with S02 concentrations

Autopsy sets, matched for age,
 sex and race, showed more
 emphysema in the more polluted
 city.  Autopsied groups may
 not reflect prevalence of
 disease in general population

Two-fold  increase over time  in
 prevalence of cough and  sputum
 production in same persons,
 irrespective of  smoking  habits.
 Change was attributed to
 increasing degrees of air
 pollution
                                          14-132

-------
   TABLE 14-30*   QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF  CHRONIC
               RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
   Study
         Characteristics
      Findings
Reichel,277
 Ulmer et al.278
Nobuhiro et al.279
Comstock et al.280
Speizer and
 Ferris281-282
Linn et al.283
Prindle et al.284
Respiratory morbidity prevalence
 surveys of random samples of
 population in 3 areas of West
 Germany with different degrees
 of air pollution
Chronic respiratory symptom
 survey of high and low exposure
 areas of Osaka and Ako City,
 Japan

Repeat survey in 1968/1969 of east
 coast telephone workers and of
 telephone workers in Tokyo
Comparison of respiratory
 symptoms and ventilatory
 function in central city and
 suburban Boston traffic poll ice-
 men
Respiratory symptoms and function
 in office working population
 in Los Angeles and San Francisco,
 1973
Comparison of respiratory
 disease and lung function
 in residents of Seward and
 New Florence, PA
No differences in respiratory
 morbidity, standardized for
 age, sex, smoking habits,
 and social conditions,
 between populations living
 in the different areas

Higher prevalence of chronic
 respiratory symptoms in more
 polluted areas
After adjustment for age and
 smoking, no significant
 association of respiratory
 symptom prevalence with
 place of residence

Slight but insignificant
 increase in symptoms pre-
 valence among non-smokers
 and smokers, but not
 exsmokers, from the central
 city group.  No group
 differences in ventilatory
 function

No significant difference  in
 chronic respiratory symptom
 prevalence between cities;
 women in the more polluted
 community more often reported
 nonpersistent (<2 years)
 production of cough and  sputum

Increased airway resistance  in
 inhabitants of more polluted
 community.  Differences  in
 occupation, smoking, and
 socioeconomic  level could
 account for these differences
                                         14-133

-------
    TABLE 14-30 .   QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF CHRONIC
                RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
    Study
         Characteristics
      Findings
Watanabe285
Anderson and
 Larsen286
Collins et al.287
Peak flow rates in Japanese
 school  children residing in
 Osaka
Peak flow rates and school
 absence rates in children  6-7
 years of age from 3 towns  in
 British Columbia
Death rates in children 0-14
 years of age, 1958-1964,
 in relation to social and air
 pollution indices in 83 county
 boroughs of England and Wales
Lower peak flow rates in
 children from more polluted
 communities.   Improved peak
 flow rates when air pollution
 levels decreased

Significant decrease in peak
 flow rates in 2 towns
 affected by Kraft pulp
 mill emissions.  No effect
 on school absences.
 Ethnic differences were
 not studied

Partial correlation analysis
 suggested that indices of
 domestic and industrial
 pollution account for a
 greater part of the area
 differences in mortality
 from bronchopneumonia and
 all respiratory diseases
 among children 0-1 year
 of age
                                           14-134

-------
shortness of breath,  and attacks of wheeze with shortness  of breath.   The
clinician is also likely to use chest radiography results  and/or pulmonary
function test abnormalities,  as well as the results of physical  examination,
in making a diagnosis.   Although there is some correlation of persistent cough
and/or phlegm with these other symptoms, it is far from perfect, and  nay even
be quite disparate.    '    '   '     Nlso, although chronic bronchitis may  be  a
disease marked by mucus  gland hyperplasia and other morphological  changes, the
relationship of the morphological change with the symptoms and/or the
physiological changes are quite imperfect.
     Criteria for inclusion and exclusion are pertinent in chronic bronchitis.
They are specifically relevant in studies of the incidence of disease, since
respiratory diseases  have slow onsets in most cases (except possibly  for
childhood asthma and  bronchiectasis associated with childhood lower respiratory
tract illness).   Chronic bronchitis often occurs in conjunction with  emphysema
and/or asthma and must be differentiated from these other  illnesses.
     Methodological problems encountered in studies of chronic bronchitis
relate not only to difficulties of definition, but to perceptual differences
between observer and  observed, sensitivity and specificity of measurements,
the lack of long-term exposure information, and the frequent lack of infor-
mation on other important variables.  The occurrence of chronic bronchitis
has been related to occupation, smoking, socioeconomic status, and other
demographic characteristics as well as to ambient air pollution levels.  Many
studies have failed to consider one or more of these factors, making inter-
pretation of results  more difficult.
     Several extensive studies on associations between air pollution and
chronic respiratory disease have been conducted on European populations.
                                  14-135

-------
                 28
Lambert and Reid,   for example, surveyed nearly 10,000 British postal  workers



(age 35 to 59) for respiratory symptoms indicated by response to a self-



administered MRC questionnaire.   Current air pollution data were used to



determine associations with symptoms where possible.   However, the areas  from



which such data were available included only about 30 percent of the study group



Consequently, an index of pollution developed by Douglas and Waller in 1952,



from domestic coal consumption,  was used as well.  The areas covered by the



index included 88 percent of the study group.



     The results, adjusted for age and smoking habits but not socioeconomic



status (Table 14-31) show relationships for both males and females by both



pollution indices.  One reasonable conclusion from the study may be that a



greater prevalence of cough and phlegm occurred in areas in which annual  mean

                                  3
smoke concentrations were 150 ug/m  or more than in areas in which smoke



concentrations were 100 ug/m  or less.  These investigators also developed



data showing that smoking was an important factor in acquiring chronic



bronchitis and that the combined effect of smoking and pollution exceeded the



sum of the individual effects.  Failure to consider socioeconomic status might



have affected the results,    but this is not very likely since the entire
                                                    248
population consisted of a single occupational group.   '

                     pco

     Holland and Reid    surveyed respiratory symptoms, sputum production, and



lung function levels in post office employees in both central London and



peripheral towns.  Over the age of 50, London men had more frequent and more



severe respiratory symptoms, produced more sputum, and had significantly  lower



lung function tests.  Socioeconomic factors were presumed the same, the



occupational exposures were homogeneous, and corrections were applied  for



smoking.  There were some physique differences in the rural  areas  and
                                  14-136

-------
             TABLE 14-31.  PREVALENCE RATIOS FOR PERSISTENT COUGH AND PHLEGM
              STANDARDIZED FOR AGE AND SMOKING, BY AIR POLLUTION INDICES
Smoke (BS)
annual mean,
pg/m3
<100
100-150
150-200
200+
SMOKE
Males
97
112
116
134
Females
93
120
116
129
SO,
Males
87
96
120
118
Females
103
110
115
120
Douglas and
Waller
Index
Very low
Low
Moderate
High
Males
88
91
117
118
Females
95
94
97
115
Source:  Lambert and Reid, 1970
                              28
                                        14-137

-------
allowances were made for these in the statistical  evaluation.   Unfortunately,



no quantitative air quality determinations accompanied these results.


                       302
However, Brasser et al.     have furnished some applicable 24-hour average S02


                                             3                       3
values for London (St.  Pancres), ie.  100 ug/m  in  summer and 500 pg/m  in



winter, and  Gloucester, Petersborough and Norwich,  England, ie.  75 ug/m  S02



and 200 ug/m3 S02, respectively, for  summer and winter.      Holland and Reid



concluded that the most likely cause  of their observed difference in respiratory



morbidity between the men working in  Central  London  and those in the three



rural areas was related to the differences in the  local  air pollution.   These


                 ftfi 1fi? ?63
and other studies  '*    by Holland and coworkers demonstrate this gradient



between respiratory disease and air pollution as well  as a gradient between

                                                                 QC 1 CO
such disease and smoking.  Lung function gradients were also seen  '    indicat-



ing effects above 75 ug/m3 S02 and 200 ug/m3 TSP.247


                   89
     Holland et al.   studied the occurrence of chronic bronchitis in 2365



families in two areas of a London suburb that had  different air pollution



concentrations.  Area 1 was reported  to have had far worse pollution than area



2 during the previous 10 years.  Between 1962 and  1965, the particulate matter



(BS) dropped in area 1 from 108 to 72 ug/m ,  and the S02 first increased from



210 to 260 pg/m2 (0.08 to 0.10 ppm) and then decreased to 238 pg/m3 (0.08



ppm).  In area 2, smoke decreased from 175 to 73 ug/m3 and S02 decreased from



279 to 193 |jg/m  (0.10 to 0.07 ppm).   Trained health visitors conducted



personal interviews, obtaining information on present and past respiratory



symptoms in parents and children, on  social and environmental conditions of



the family, and on the parents' occupation and smoking habits.



     Morning cough or phlegm was strongly associated with smoking in both fathers



and mothers.   There was a weak social class gradient for symptoms within smoking



categories.     There were no differences between  area 1 and area 2  in
                                  14-138

-------
the occurrence  of  symptoms  in  fathers.   However,  mothers  and male and female

siblings  all  reported  significantly more symptoms in area 1, the area with

presumed  higher past BS  and S02  (no specific  data confirmed past levels) and

known higher  present S02-

                      334
     Colley and Holland     studied the  symptoms in all  the members of the 2365

families  in the London suburb.   They attempted to assess  the influence of

various factors:   smoking,  area  of residence, place of  work, overcrowding,

family size,  social class and  genetic factors.   They showed that area of

residence was not  as important for the  prevalence of cough when compared to

home and  occupational  hazards, smoking  and social class.   In mothers, smoking

and area  of residence  were  important; but social  class  was not.   In children,

an effect of  area  of residence was demonstrated.

     In addition to the  above  British studies, there exist several reports

concerning a  long-term study on  the effects of air pollutants on British

schoolchildren.  Because the findings of this study appear to be important but

controversial,  it  is discussed in some  detail here, since not all of the

results have  yet appeared in the peer reviewed open scientific literature.

Considering that two authors of  the report by Holland et al. (1979)    are

also coauthors  of  these  studies, Holland et al.'s own descriptions are used

where available.   Holland et al. (1979) described these studies in a lengthy

paragraph on  page  613  of their report:

     One  study  in  the  United Kingdom concerned with exposure/response has
     been presented in a preliminary communication (10).*  It consisted
     of data  for primary schoolchildren aged 6-11 years in 10 areas  in
     England.   The parents  were  asked about respiratory illnesses in the
                                  14-139

-------
     past year.   The air pollution  data,  obtained  from  smoke  (BS) and
     sulfur dioxide samplers,  were  collected  either  at  or within 0.8 km
     (0.5 mi)  of the schools.   The  results  indicated a  statistically
     significant relationship  between  the frequency  of  colds  going to the
     chest during 1972-1973 and pollution measurements  taken  In November,
     1973, after allowing for  differences in  the distributions of age,
     sex, and  social class between  the areas.   Although it was stated
     that the  relationship could be found for smoke  (BS)  levels from 10
     to 130 ug/m ,  four factors cast doubt  on so precise  an interpre-
     tation.   First, smoking in the home  was  not considered;  second,the
     pollution measurements were taken after  the period to which the
     questionnaire related and in some areas  smoke abatement  orders
     were being put into effect; third, the 10 areas in the analysis
     were a non-randon sample  of the set  of 28 areas in the whole study;
     and fourth, the findings  were  not replicated  in the  same study
     using data collected two  years later.  A second report from this
     longitudinal study using  data  collected  in 1975 indicated no relation-
     ship between symptoms and either  smoke (BS) or  sulfur dioxide
     levels in the 19 areas with substantial  pollution  data for the period
     to which  the questionnaire related (28).*

     After the (November 15, 1979)  preliminary draft of this  chapter 14 was
                         301
reviewed by Holland et al., their letter  to the Administrator of the U.S.

Environmental  Protection Agency dated  January 11,  1980  stated:

          The  discussion of the study  by  Irwig and his  colleagues (ref. 98)
     (14-92) is incomplete as  it fails to identify the  fact that what  is
     quoted is a preliminary communication  and the later definitive
     .communication failed to substantiate the earlier results.-
          The  preliminary report presented  data for  primary schoolchildren
     aged 6 to 11 years in ten areas in England.   The parents were  asked
     about respiratory illnesses in the past  year.  The air pollution  data,
     obtained  from British standard smoke and sulphur dioxide samplers,
     were collected either at  or within half  a mile  of  the  schools.  The
     results indicated a statistically significant relationship  between
     the frequency of colds going to the  chest during 1972-73 and pollution
     measurements taken in November 1973, after allowing for  differences
     in the distributions of age, sex, and  social  class between  the areas.
"The above references (10) and (28) in the Holland et al.  (1979) text refer to:
 (10) Irwig L, Altman DG,  Gibson ROW,  Florey CduV.  Air pollution:   Methods to
 study its relationship to respiratory disease in British schoolchildren.  Pro-
 ceedings of the International Symposium on Recent Advances in the Assessment of
 the Health Effects of Environmental  Pollution.   Volume I.   Luxembourg, Com-
 m\ssion of the European Communities,  1975, pp.  289-300; and reference
 (2*8) Melia RJW, Florey CduV, Swan AV:  The effect of atmospheric smoke and sul-
 fur dioxide on respiratory illness among British schoolchildren:  A prelimi-
 nary report.   Paper given at the Vllth International Scientific Meeting of the
 International Epidemiological Association, Puerto Rico, 1977.
                                  14-140

-------
    Although it was stated that the relationship could be found for
    smoke (BS) levels from 10 to 130 ug/m , four factors cast doubt on
    such an interpretation.  First, smoking in the home was not con-
    sidered; secondly, the pollution measurements were taker after the
    period to which the questionnaire related, and in some areas smoke
    abatement orders were being put into effect; thirdly, the ten areas
    in the analysis were a non-random sample of the set of 28 areas in
    the whole study; and fourth, the findings were not replicated in the
    later study discussed below.


    A second report from this longitudinal study of data collected in 1975

indicated no relationship between symptoms and either smoke or sulphur dioxide

levels in the 19 areas with substantial pollution data for the period to which

the questionnaire related.  (Note:  Reference 1 in the above quotation refers

to the Melia, Florey and Swan, 1977, paper read at the 1977 Puerto Rico meeting

footnoted on the prior page).

    Some of the implications of these above-quoted descriptive passages are

that:


    1.  The Irwig paper was a "preliminary communication", and the Melia
    paper was the "definitive communication" on the subject.

    2.  In the Irwig report, "smoking in the home was not considered",
    but it was in the Melia report.

    3.  The Melia report "indicated no relationship between symptoms and
    either smoke (BS) or sulfur dioxide  levels".

However, the facts of these studies may be  interpreted quite differently.

    First, the Melia paper was perhaps just as "preliminary" as  the  Irwig

paper.  In their own title of their paper cited in Holland et al.  (1979),
                                  14-141

-------
Melia et al.  described it as "A preliminary report".   Further,  the pre-meeting

abstract of the paper states:   "The results of Irwig  in 1973  will be  compared

with those from 1974 and 1975"...   However, when the  paper was  presented in

September 1977, it stated at the end of the introduction:   "Due to a  problem

arising in the data processing, information collected in 1974 was not available

at the time of writing".

     Consequently, it is hard to understand how the 1977 paper  is definitive,

since the 1974 data have not been reported yet even in draft  form, and neither

the 1975 paper nor the 1977 paper have passed the intense scrutiny of a peer

reviewed scientific journal.

     Secondly, smoking was not considered in either the Melia paper  or the

Irwig paper as confirmed by the authors'  description  of their "Method of Data

Collection".  Melia, Florey, and Swan (1977) state:

          No information on the smoking habits of members of  the house-
     hold or of the children themselves was obtained  in the study.

Consequently, the possibility that the children themselves were already smok-

ing was not considered.  The possible importance of smoking as  a confounding

factor in these studies, however, is clouded by Holland et al.  (1979) in

pointing out (page 604):

     Since 1969, there have been many more surveys in children.  In-
     creasing numbers of investigators have realized  that the young have
     special advantages as subjects for the study of  air pollution.
     Under the age of nine years, they are unlikely to smoke cigarettes.

That is, since the Irwig and Melia studies were of schoolchildren "aged 6-11

years", perhaps a small proportion of the children over nine years old may

have begun smoking cigarettes, but probably the vast  majority of those studied

did not; and this would lessen tremendously the likelihood that smoking may

have been an important confounder affecting the outcomes of the two studies.

If it were an important factor, however, then it would not be any more appropriate
                                  14-142

-------
to assert  that  the  later  Melia  findings  somehow contradict the  earlier Irwig
findings than to  accept the  initial  Irwig  findings  for 1973 without hesitation.
The matter would  simply remain  an  open question and,  since it 1s  possible that
more "smokers"  were included among the low pollution  area "control" populations,
smoking may  have  actually obscured even  more  significant results  than those
reported in  the two papers.   Apropos to  the latter  point, it is interesting
that the Melia  report  actually  did indicate a possible statistically significant
relationship between symptoms and  air pollution, but  the authors  apparently
"corrected away"  such  significant  differences.
     Tables  14-32 and  14-33  from Melia,  Florey, and Swan report the summary of
seven questions on  respiratory  disease and its symptoms for boys  and girls in
areas of low and  high  smoke  and SOp pollution.   If  there is no  association of
air pollution with  health, we would expect that out of the 28 comparisons
listed that  14  will show  a positive association and 14 will show a negative
association  .   Instances  of  positive associations are indicated in the table
by (+) and cases  of negative or inverse  associations  by (-).  Because there were
equal numbers of  boys  reporting day or night cough  independent of smoke (BS)
level a zero is placed in Tables 14-32 and 14-33 to indicate that it is neither
plus or minus within the  significant figures reported by Melia, Florey. and
Swan (5.9  vs 5.9).   The positive and negative associations seen are summarized
in Table 14-34.
     Since Melia, Florey  and Swan  (1977) do not report the detailed results of
their regression  analysis to allow for  independent  evaluation of the "effect
of the interfering  factors"  that they corrected for,  it is difficult to under-
stand and  reconcile their statement:
                                  14-143

-------
                                    TABLE 14-32
THE PREVALENCE (%) OF RESPIRATORY
HIGH SMOKE POLLUTION IN BOYS AND
Respiratory symptom
or disease
Morning cough
Day or night cough
Wheeze
Colds to Chest
Asthma
Bronchitis
Respiratory illness
No. of children
Boys
Low smoke
pollution
3.0
5.9
9.6
24.5
2.5
4.6
28.4
1064
SYMPTOMS AND
GIRLS. FROM

High smoke
pollution
4.0 (+)
5.9 (o)
10.0 (+)
21.9 (-)
1.6 (-)
4.2 (-)
25.7 (-)
867
DISEASES BY
MELIA ET AL.

Low smoke
pollution
1.4
3.2
6.5
18.7
1.1
3.3
22.5
1050
LOW AND
, (1977)
Girls
High smoke
pollution
5.7 (+)
8.7 (+)
7.8 (+)
19.7 (+)
0.5 (-)
3.8 (+)
24.1 (+)
873
                                       "3
*Low smoke pollution:   12.0 - 34.9 ug/m

 High smoke pollution:   35.0 - 73.0 |jg/m


(+) Positive association of symptom with  air pollution increase

(-) Negative association of symptom with  air pollution increase

(o) No association of  symptom with air pollution increase
                                  14-144

-------
                                   TABLE 14-33

THE PREVALENCE (%) OF RESPIRATORY
HIGH S02 POLLUTION* IN BOYS AND
Respiratory symptom
or disease
Morning cough
Day or night cough
Wheeze
Colds to Chest
Asthma
Bronchitis
Respiratory illness
No. of children
Boys
Low S0.2.
pollution
3.3
6.2
8.6
21.7
2.6
4.0
25.6
1199
SYMPTOMS AND
GIRLS. FROM

High SO^
pollution
3.8 (+)
5.5 (-)
11.8 (+)
26.1 (+)
1.4 (-)
5.1 (+)
29.8 (+)
732
DISEASES BY
MELIA ET AL.

Low SO-aL
pollution
2.1
4.2
6.5
17.8
0.8
2.8
21.8
1181
LOW AND
(1977)
Girls
High SOa
pollution
5.4 (+)
8.1 (+)
8.0 (+)
21.3 (+)
0.9 (+)
4.7 (+)
25.5 (+)
742
*Low £6^ pollution:  19.0- 49.9 ug/iri



 High  SO^ pollution:  50.0 - 145.0 ug/m3



(+)  Positive association of symptom with  air  pollution increase



(-)  Negative association of symptom with  air  pollution increase



(o)  No association of symptom with air  pollution increase
                                  14-145

-------
          TABLE 14-34.   SUMMARY OF ASSOCIATIONS (±)  OF  POLLUTION  WITH  HEALTH
                       DATA FROM MELIA,  FLOREY AND SWAN (1977)
  Respiratory symptom            Smoke (BS)                Sulphur dioxide  (SOp)
      or disease            Boys            Girls          Boys           Girls

Morning cough                +                +            +               +

Day or night cough           0                +            "               +

Wheeze                       +                +            +               +

Colds to Chest               -                +            +               +

Asthma                       -                -            -               +

Bronchitis                   -                +            +               +

Respiratory illness          -                +            +               +

TOTAL (+)                    2657

(+) Positive association of symptom with  air pollution  increase

(-) Negative association of symptom with  air pollution  increase

(o) No association of symptom with air pollution increase
                                  14-146

-------
         The prevalence  in boys tended to decrease and that for girls to
     increase with "increasing  levels of smoke pollution, but conversely,
     the prevalence in boys tended to increase and that for girls to
     decrease with increasing  levels of S0?.

     Since all health question categories for girls showed an  "uncorrected"

association with S02 (including asthma) and  these associations were  larger

than  the associations with BS  in 5 out of 7  cases it  is hard to understand,

without carefully reviewing the regression analysis in  it's entirety,  how the

correction to the questionnaire responses could  have  been so overwhelming to

wipe  out any associations for  the girls.

     The results for the  boys  in both cases, however, do not appear  to be

significant, since we expect 3.5 plus and 3.5 minus in  each case and the
                                                2
chi-square with one-degree of  freedom is 2 (1.5) 73.5 = 1.28;  P > 0.25.

     The chi-square with  one-degree of freedom for the  girls in regard to
                              2
smoke is computed as:  2  (2.5) /3.5 =3.57;  P =  0.06.   An alternate  test of

the probability of obtaining 6 or more "heads" out of a total  of 7 flips of  an

honest coin (P of "heads" = P  of "tails") is 1/16 or  0.0625.   These  values,

"on the edge of statistical significance," indicate that the association with

BS may not be unreasonable.  However, for sulphur dioxide, the probability  of

obtaining 7 out of 7 positive  responses when no  underlying association is

present is (1/2)  or 1/128 (P  = .008) which  is clearly  statistically significant.

     If we combine the data for boys and girls,  we expect a total  of fourteen

positive and fourteen negative signs for the associations,  if  ino  association

exists between health and air  pollution.  If we  assume  that the  null association

for Boys and day or night cough with smoke  is  negative, then we  have a total

of 20 positive responses  and 8 negative  responses.
                                  14-147

-------
                                                           2
     The chi-square sum with one-degree of freedom is  2 (6) 714  =  5.14  (P  =


0.025) 50 the overall  test for the children shows  a statistically  significant


association of air pollution and health.


     Perhaps, if boys  start smoking at an earlier  age  than girls,  this  might


explain the absence of observed associations of health effects for the  boys


with atmospheric levels of BS.   The lack of positive associations  for the


boys, however, would in no way  negate the finding of  positive results  for the


girls.  Nor would any failure to find positive associations for one or  another


of the groups studied by Melia in any way negate positive findings obtained by


Irvug  at an earlier time and with different subjects.


     Approaching the evaluation of the Ir>ig  and  Melia studies  in the  above


manner would be consistent with recommendations made by Holland et al.  (1979)


which essentially hold that, when any study is performed  with a group  of


individuals at a certain period in their life while they are  exposed to an atmosphere


of variable pollution levels, the results of the study must stand or fall  on


its own merits.   It is obviously impossible to repeat  the study precisely.


Even if we go back to the same location at a later time and recapture the  same


individuals, they will all be older and the pollution  levels  will  be different.


Such changes of course were occurring between the  time of the Iriviq and Melia


studies and Holland et al. even noted that "smoke  abatement orders were being


put into effect."


     Holland et al.  (1980) also point out, in a discussion of the Van der


Lende study, that


          Hypotheses are not strengthened or weakened, they are accepted
     or rejected on the basis of available evidence.
                                  14-148

-------
     It is difficult for this statement to be reconciled with the statement


quoted previously from Holland et al.  (1979) that doubt is cast on the 1973


findings of Irwig because


     the findings were not replicated in the same study using data
     collected two years later.


In fact, contrary to that assertion, we find that a careful  examination of


results from Melia et al.  (1977) suggests that there were likely observed


positive associations of respiratory symptoms-disease with air pollution,


which would make their findings consistent with Irwig et al.  (1975).

                                               29-31
     A series of studies from Poland by Sawicki      reported higher preva-


lence rates of chronic bronchitis in males (all smoking categories) and females


(smokers and nonsmokers but not ex-smokers) in a high-pollution community.


Rates were adjusted for age, sex, and smoking habits.  The annual mean concen-


tration of particulate matter in the high-pollution area was 170 ug/m  (BS)

                     3
compared with 90 ug/m  (BS) in the low-pollution area.  S02 concentrations


were 125 and 45 ug/m , respectively.  During the heating season when more


smoke was emitted, the average concentrations of smoke for the high- and


low-pollution areas were 240 and 120 ug/m  (BS) and, for SOp, 200 and 65

    3
ug/m , respectively.  No consistent relationship was found between the chronic


bronchitis prevalence rate and length of residence in the high-pollution


community.  Some reviewers    have taken this as being evidence  indicating


that Sawicki's findings do not show a relationship between air pollution and


bronchitis, but other reviewers304'308'312'313'3143  have indicated that  a


positive association appears to exist, and the present authors concur with


thts latter conclusion.
                                  14-149

-------
                                       181
     A repetition of this study in 1973    also tended to confirm further the



relationship between the prevalence of chronic bronchitis and air pollution



levels.  By 1973, annual smoke concentrations in the high pollution area

                 •J                           O

averaged 190 ug/m  (BS) compared with 86 ug/m  (BS) for the low-pollution



area.  S09 average annual concentrations were 114 and 46 ug/m ,  respectively,



for the high and low pollution areas.  Both chronic bronchitis and asthma were



more prevalent in the high pollution area in males and females aged 31 to 50



and in smokers.  Chronic bronchitis was also more prevalent in female non-



smokers in the high pollution area in both 1968 and 1973.   The investigator



demonstrated an interaction between air pollution and smoking.   Between the



earlier study and 1973, the persistence of asthma and chronic bronchitis was



greater in males ages 31 to 50 in each smoking group in the high pollution



area.  The incidence of asthma/chronic bronchitis was also greater in females



in several age groups in the high-pollution area.


                    32
     Petrilli et al.   studied chronic respiratory illness, rhinitis, influenza,



and bronchopneumonia in several areas of Genoa, Italy, in relation to air



pollution concentrations, between 1954 and 1964.  Respiratory illness rates in



non-smoking women over age 64 with a long residential history and no



industrial exposure history was strongly correlated with S02 concentrations.



These investigators found that all illness rates were higher in industrial



districts where annual mean pollution concentrations were >210 ug/m3 (0.008



ppm) for S02 and >190 ug/m  for high volume mean TSP concentrations.  Illness



rates rose in Genoa from 1954-1961 to 1962-1964 by 207 percent.   Illness rates



were high also in a nonindustrial area where mean S0? was 100 ug/m   (0.035



ppm) and TSP was 180 ug/m .
                                  14-150

-------
     In  addition to the above European studies,  several  analogous  investigations



have  been  reported for Japanese population study groups.   For instance,


                 38
Tsunetoshi  et  al.    performed a prevalence survey (MRC questionnaire)  in nine



areas of Osaka and Hyogo prefectures,  Japan.   They studied about 30,000



Japanese over  40 years of age.   Pulmonary function was measured by a spiro-



meter; maximum values  were used.   Multiple regression analysis indicated



increasing prevalence  of chronic bronchitis (adjusted for sex and  smoking)



related  to the gradient of air pollution (sulfation rates and dustfall)  in  the



different  areas.   The  prevalence ranged from 4 percent where the sulfation


                             2                   3
rate  was close to 1 mg/100 cm /day (about 80 ug/m  S02) to 10 percent in areas


                                              ?              3
where the  sulfation rate was  about 3 mg/100 cm /day (240 ug/m  S02).  TSP



levels were not given.


                  183
     Suzuki et al.     reported on data collected in each of six study areas  in



Japan.  Information was obtained from about 400 housewives over 30 years of



age.   The  BMRC respiratory symptom questionnaire was administered once each



year  between 1970 and  1974.   The air pollutants monitored in each area included



S02,  sulfur oxides, NO and N02, CO, TSP (high volume), and dustfall.  The



prevalence of  respiratory symptoms was associated with the annual  arithmetic



means measured.   The incidence of cough, phlegm, or persistent cough and



phlegm was higher among smokers and in the over-60 age group.  These



respiratory symptoms were related to the concentrations of TSP (p <0.05) and



S02 (p <0.01)  through  1972.   S02 levels in 1971 were 94-97 ug/m3 (.036 to



.037  ppm)  in the high  areas.   They decreased to 58-69 ug/m3 (.022 to .024 ppm) in



1974. TSP levels in 1971 in  the high areas were between 206 and 434 ug/m



decreasing between 122 and 374 ug/m  in 1974.
                                  14-151

-------
     Toyama et al.    '     studied the prevalence of respiratory  symptoms  in



relation to S0?.   Prevalence rates from 2.8 to 3.7 percent  in  males  ages  40  to



59, after adjusting for age and smoking,  were found in areas of  a /ion-industrialized



rural town with SO^ concentrations of less than 30 ug/m  (0.01 ppm)  and TSP


                              o                    312 318
concentrations of 106-341 ug/m  (mean of  197).  Tani   '    performed a  study



around a pulp mill  and  in controlled areas in Japan.   A consistent  relationship



was demonstrated between the prevalence of bronchitis  and sulfation  rates



(candle method).   A prevalence of about 3 percent in both sexes, ages 40  to

                                                                         2
59, were found in areas where the sulfation rate was around 0.6  mg/100  cm per

                          3

day (approximately 48 ug/m  S02) compared to about 8 percent  in  areas where


                                    2                               3
the sulfation rate was  1.2 mg/100 cm  per day (approximately 96  ug/m SOp).



No data were provided on TSP.


           312 319
     Yoshii   '    noted an association between chronic pharyngitis  accompanied



by histopathological changes at biopsy in Yokkaichi, Japan, in sixth grade



children.  In heavily polluted districts, sulfation rates were much  more  than


           2                  3
1 mg/100 cm  per day (>80 ug/m  S02); in moderately polluted  districts, they


                                 2                       3
ranged from 0.25 to 1.0 mg/100 cm  per day (20 to 80 ug/m  SOp); in the control


                                    2                  3
area it was less than 0.25 mg/100 cm  per day (<20 ug/m  SCO.



     An EPA CHESS study on chronic respiratory disease (CRD)  was reported on


                212
by Chapman et al     for populations studied in 1970 in four communities in



Utah (Salt Lake City, Ogden, Kearns, Magna) to assess the effects of smelter



emissions of sulfur oxides (SOp and suspended sulfates).  Other pollutants



(TSP and nitrates) were estimated to be low to moderate; but concurrent trace



metal data were not collected.  Questionnaire distribution to parents was



through elementary school children and by mail for high school  students.



     Response rates of  85 percent and 35 percent were found for child-carried



and mailed questionnaires, respectively.   Although the 65 percent nonresponse
                                  14-152

-------
rate to mailed questionnaires may have increased the possibility of serious



reporting bias,  the authors indicated that similar inter-community CRD differences



were observed  for both sets of parents.   Respondents were excluded if they had



incomplete questionnaires,  a residential  change within the previous two years,



or occupational  exposure to irritants such as coal dust,  cutting oils, asbestos,



mine dust, smelter fumes,  cotton dust and foundry dust.   Subsequent analysis



showed that exclusion for occupational reasons results in a conservative



estimate of effects attributable to pollution.   All races were included, but



the proportion of black respondents was trivial.  No covariate measurements



were made to assess possible effects of religion or ethnic composition on



response patterns, although Salt Lake City has proportionately fewer Mormons



and Magna more Spanish Americans.  Educational attainment was comparable,



however, in the four communities.  CRD prevalence rates reflected pollution



levels faithfully in the different communities; and differences (2 to 7%) in



CRD rates between high and low areas were statistically significant within sex



and smoking status groups (Table 14-35).   Relative risks were also different



statistically  and air pollution had one-third the risk of smoking in mothers



and fathers (Table 14-35).   Effects were additive.



     Because of potential  biasing factors, such as "CHESS" network air quality



measurement problems discussed in Chapter 3 and the IR (1976)    and problems



in the use of  dispersion modeling to make certain pollution estimates,  several



reviews107'301'312'338 have questioned the validity of the reported  findings



of the Utah CRD study, although one critique1   ultimately judged the  reported



health effects differences between the study communities to be  sound  (see



Appendix A for this chapter).  With regard to the CHESS air quality  measurements,



however, the same report    found that detected deficiencies  in analyses  were
                                  14-153

-------
TABLE 14-35 Chronic Prevalence Rates and Pollution Levels in
                       Four Utah Cornmunities, 1870
Area I Smoking
Lou 3 areas
Kon-Smokers
Smokers
Magna
Kon-Smokers
Smokers
Source of Risk2*2
Prevalence Rate *
Mothers Fathers
4.16 3.00
15. BO 19.60

6.20 6. 81
22.25 26. BO
**
2 Relative
Mothers
1.00(4.16)
1. BO

1.25
6.Z5
0.33
Risk Ratios21
Fathers
1.00(2.00)
6.63

2.27
6. 93
0.35
2* 1S70 Local
TSP(vg/ms) Si
69-84 2.

70



Levels
Wvgtf.
,6-25.7

107.4



 * Relative Prevalence^ Prevalence in specific group/Prevalence in non-smokers in

   lou pollution area (baseline rates in parenthesis).

 ** Ratio of Relative Prevalence due to air pollution/Relative Prevalence due

    to Bmoking.
                                       14-154

-------
sufficient, especially for suspended sulfate estimates, such that the published



"CHESS" estimates were unacceptable as a basis for quantifying pollutant



health effects relationships.   Fortunately, local air monitoring by the Utah



State Department of Health was available for some pertinent years and was



judged    to be more accurate than "CHESS" estimates.  Based on such local



data Magna was highest in S02, Ogden had the lowest S02 levels.  Kearns and



Salt Lake City had exposures midway between Ogden and Magna.   The 1970-71



local monitoring data for Magna can be contrasted to the other three "low"



pollution areas as shown in Table 14-35.  Since the TSP levels were nearly



constant over time and similar across the four communities, they were unlikely



(alone) to be producing the differential health effects reported.   Therefore,



observed differences in prevalence between the study communities appear to  be



more likely associated with higher Magna SCL levels, acting either alone or in



combination with concurrently observed TSP levels.  Precise quantisation of



the past or then current CHESS TSP or SCk levels associated with the health



effects observed in the Utah study, however, may not be possible, as concluded



elsewhere.107'312  On the other hand, to the extent that the 1970-71 local  air



monitoring data may be representative of fairly stable SOp and TSP levels in



the study communities over many years, then the local monitoring values, or



more accurately, the corrected estimate values shown in Table 14-35 for Magna



might serve as rough pollution indices associated with CRD effects in smelter



areas similar to Magna.


                   212
     Chapman et al.    also reported on another CHESS study, involving military



recruits at the Chicago Induction Center from June 24, 1969, to February 20,



1970.  Adult chronic respiratory disease (CRD) prevalence was determined by



means of a measured modified BMRC self-administered  questionnaire  that  inquired
                                  14-155

-------
whether the subject usually coughed and produced phlegm for at least 3 months



of the year.



     A similar questionnaire had been validated for self-administration in a



1971 Japanese study,   but validating data were not available for this survey;



still, it probably gave a reasonable good indication of the difference in



ranking of communities based on CRD prevalence.  The questionnaire located the



subjects by their current residence, which was used to categorize recruits



into three groups:  (1) Chicago proper, Gary. Hammond, Whiting, and East Chicago,



(2) other Chicago suburbs, and (3) other Illinois and Indiana areas.  All



recruits living outside Illinois and Indiana were excluded, as were those not



living at their current address for at least 3 years.  Symptom prevalence



rates for Chicago and its immediate suburbs were almost identical and were



consistently higher than the rates for other Illinois and Indiana areas for



both blacks and whites (Table 14-36). These differences persisted even after



adjustments were made for educational level of the recruits.



     Questions have been raised   '    regarding the ability to associate the



above reported "urban" health differences with specific air pollutants, especially



in view of problems associated with estimation of the air quality data upon


               212
which published    quantitative conclusions concerning study results were



based. Concerning the latter point, other applicable (NASN) aerometric data



for the greater Chicago area during the time of the study exists and is



summarized along with CRD prevalence results in Table 14-36.  The annual



average arithmetic means for the 1969 NASN aerometric data suggest  that Chicago



proper, East Chicago, and Hammond were highest in particulates, but the suburbs



may have been somewhat higher in SOp.  For both pollutants it appears that the



other Illinois and Indiana areas were generally distinctly lower, although the
                                  14-156

-------
                   TABLE  14-36.   CRD  PREVALENCE RATES FOR CHICAGO RECRUITS*
1 	 Annual Average
Chronic bronchitis prevalence, percent
Community
Other Illinois,
Indiana
Suburbs
Chicago
Bl
Nonsmokers
9.0
9.4
9.4
acks
Smokers
9.3
12.6
12.9
Whi
Nonsmokers
4.3
5.5
5.2
tes
Smokers
16.7
19.8
18.3
1969 NASN Levels
TSP
(pg/
42-95
72-150
129-172
3 S02
14-32
94-292
85-138
*Based on 1969-70 Chicago  Inductee  "CHESS"  study reported by Chapman et al.'
                                        14-157

-------
available data were quite sparse.   Based on these limited aerometric data,



increased symptom rates would appear to be associated with both increased



particulates and increased SO^, but the data provide no basis



to distinguish the relative effects of the two pollutants.   Use of these data



as estimates of SO  or TSP chronic exposures associated with Increased morbidity

                                  Pi p

effects reported by Chapman et al.    for the Chicago CRD study must be qualified



somewhat, however, in view of the lack of more precise information on how



representative such data are for actual long-term exposures of the study



populations.


                                          212
     Placing the studies by Chapman et al.    on United States "urban" and



"smelter-exposed" populations into a broader perspective also encompassing



other studies evaluated above, one finds that numerous studies have demonstrated



that higher chronic respiratory disease prevalence rates are associated with



elevated pollution levels in a number of locations around the world.  These



not only include sites in the United States, but also in Great Britain, continental



European countries, and Japan.  In addition, efforts have been made to utilize



reported air quality data available for the various study areas in order to



derive at least approximate estimates of ranges of ambient SO^ and particulate



matter air concentrations likely associated with the occurence of the chronic



respiratory disease effects documented by the various studies.



14.5.3  Other Respiratory Disease/Symptom Prevalence Studies



     Yoshida et al.    investigated the prevalence of bronchial asthma in



relation to the SO^ air pollution exposure among Japanese school children.



Precise data were not included in the published report, but inspection of the



figures indicates that in general  the prevalence rate was between two and



three percent when S02 monitored by the lead candle sulfation rate  method was
                                  14-158

-------
                             2                3
between  0.5  and 1.0 mg 100 cm /day (40-80 ug/m ).   For the most polluted area,


                           2                     3
more than  1.5  mg S02/100 cm /day (110 to 120 ug/m ),  the prevalence rate



exceeded five  percent.   In other respects (frequency  of exacerbations of



illness, school  absence record,  and reaction to allergies), patients in the



high pollution area did not differ significantly from those in the low



pollution  area.


            182
     Rudnick,     as part of a well-designed and methodologically-sound study,



collected  information by a self-administered questionnaire on respiratory



symptoms and disease in 3805 children, 8 to 10 years  old, living in three



communities  in Poland with differing air pollution concentrations.  The question-



naire sought information on respiratory symptoms and  symptoms of asthma during



the previous 12 months.   Mean SO^ concentrations in the higher pollution area



for the  years  1974 and 1975 were 108 to 148 ug/m3 for S02 and 150 to 227 ug/tn3



for smoke.   The low pollution areas had S0? concentrations of 42 to 67 ug/m

                                         3
and smoke  concentrations of 53 to 82 ug/m .   Most symptoms of respiratory



illness  in both boys and girls occurred more frequently in the high pollution



area but the differences were, in general, nonsignificant.  There was a higher



prevalence of  breathlessness, sinusitis and asthma attacks in boys living in



the high pollution area but only "runny nose in the last 12 months" occurred



more frequently in girls in the same area.  There were no significant differ-



ences between  the frequencies of nonchronic cough, attacks of breathlessness,



shortness  of breath, or multiple cases of pneumonia associated with the differ-



ent pollution  levels.   While the above results are highly suggestive of at



least some SOp and TSP related health effects, difficulties  in being able to



fully evaluate the statistical analyses upon which the reported findings are



based argue  for caution in utilization of the reported findings.
                                  14-159

-------
                       90
     Douglas and Waller   studied a cohort of a national  sample  of  children



born in the United Kingdom during the first week in March 1946.   They pro-



spectively examined the occurrence of respiratory illness in the children in



relation to the estimated intensity of air pollution 1n the area of their



residence.  The areas in which the children lived were assigned  to  one of four



pollution groups on the basis of estimates derived from domestic coal consumption



in 1951-52.  An effort to validate the index later, on the basis of measured



smoke (BS) and S02 measurements in 1962 and 1963, indicated that the estimates



were reasonably good.  At the time of the measurements, SOp varied  from about


       3                                                        3
90 ug/m  (0.03 ppm) in the low-pollution areas to about 250 ug/m  (0.09 ppm)



in the high-pollution areas as shown in Table 14-37.   Information on respiratory



illness and symptoms was obtained from the children when they were  6, 7, and



11 and, if they had lived the first 11 years of their lives in the  same area,



similar information was gathered when they were 15, 20, and 25 years of age.



No significant relationship was observed between upper respiratory tract



infections and increasing air pollution levels, in contrast to a high significant



and close correlation between lower respiratory tract infection  prevalence



rates and increasing air pollution level as seen in Table 14-37.  In fact,



these relationships are very consistent for all of the measures  listed.



     The lowest concentration of smoke and sulfur dioxide were 67 ug/m  and 90



ug/m , respectively.  "Higher illness rates were noted in all higher pollution



classes;"    and "Socio-economic status was important in the study but a



relationship.. .still existed within spearate social classes."     Douglas and


      90
Waller   suggested that these children probably were exposed to higher pollution



concentrations in their early lives than suggested by the measurements made in



1962-63 because of the improvement that followed the 1956 United Kingdom Clean
                                  14-160

-------
  TABLE  14-37   Frequency of Lower Respiratory Tract  Infections  of
                   Children in Britain by Pollution  Levels, %Q
Lower respiratory
tract infections
First attack in first 9 months

At least one attack in first
two years

More than one attack in first
two years:
  Boys
  Girls
  Middle class
  Manual working class

Admission to hospital in first
five years:
  Lower respiratory infection
  Bronchitis
  Pneumonia
        Mean annual Pollution levels,
        Very LowLowModerateHigh
Smoke:  67         132    190         205
S02:    90	   133    190         251
         7.2

        19. M
         5.7
         2.9
         3.0
         5.1
         1.1
         0.0
         1.1
11. «4   16.5

24.2   30.0


 7.9   11.2
 8.1
 7.7
 14.0
10.8
 2.3
 0.9
 l.M
10.9
12.1
 7.7
13.9
 2.6
 1.0
 1.6
17.1

34.1


12.9

16.2
 9.7
 9.3
 3.1
 l.M
 1.8
 From Douglas and Waller, 1966.
                              90
                                   14-161

-------
Air Act.     However, the children in areas with lower concentrations actually


probably experienced little change in exposure while those in higher polluted


areas probably experienced much higher levels previously.


     Further study of this population at 20 years of age indicated that in


these now young adults, cigarette smoking had the greatest effect on respi-


ratory symptom prevalence, followed by a history of lower respiratory tract


illness under 2 years of age.   At this time of their lives, social class and


air pollution had little effect.   The standardized prevalence rate (percent),


however, was higher among the group who had lived in high-pollution areas


(11.51) than in those who had lived in the low-pollution area (10.20) but the


difference was not significant.


     This study would appear to indicate that the effects of exposure to air


pollutants in high concentrations during the first 11 years of life had dis-


appeared by age 20, unless there was a history of lower respiratory illness


before age 2.  However, no information is provided in the report to indicate


the concentration of pollution to which the children were exposed after 1957


when they were 11 years old.   Nevertheless, various reviewers have con-


sistently accepted this as a valid study although they have disagreed somewhat


regarding the specific S02 and particulate levels associated with the observed


effects.


     A final survey, when the study population was 25 years old, confirmed the

                                                               go
observation made 5 years earlier.  At this time, Kiernan et al.    reported


that smoking continued to have the greatest effect on respiratory symptoms and


lower respiratory illness.  The association with air pollution was again a


positive one and stronger than had been observed 5 years earlier, but was  not


statistically significant.
                                  14-162

-------
     The lasting impact of respiratory illness during the early years  of life

                               93 94
was confirmed by Burrows et al.   '     These investigators observed more than


2600 adults over 20 years of age and found that histories of pediatric


respiratory illness were associated with the current prevalence of respiratory


symptoms,  obstructive airway disease, and ventilatory impairment.   The authors


concluded  that childhood respiratory illnesses cause the adult lung to be


unusually  susceptible to the adverse effects of a variety of bronchial irri-

tants and  infectious agents.

            95
     Taussig   also produced evidence that effects of respiratory illnesses  in


childhood  persist into later years.  This investigator concluded from  studies


of children that a past history of croup or bronchiolitis, whether or  not


asthma was present, was associated with an increased prevalence of abnor-


malities in lung function.  The predominant alterations were found in  those


tests believed to evaluate small airway function (V    25; V.   V).  In
                                                   uiaX      1 SO

addition,  these high risk children showed exercise-induced bronchospasm that


also was independent of an allergic history.


     The association between air pollution and lower respiratory tract illness

                                96
was observed also by Lunn et al.    These investigators studied respiratory


illness in 5- and 6-year-old schoolchildren living in four areas of Sheffield,


England.  Air pollution concentrations showed a gradient in 1964 across four

                                                                   3
study areas for mean 24-hour smoke (BS) concentrations from 97 ug/m  to 301


ug/m  and  the same gradient for mean 24-hour SCK concentrations from 123 ug/m


to 275 ug/m .  The following year, the concentrations of smoke were about 20


percent lower and SCL about 10 percent higher, but the gradient was preserved


for each pollutant.  In high-pollution areas, the 24-hour mean smoke  concen-


tration exceeded 500 ug/m3 30 to 45 times in 1964 and 8 to 15 times in  1965.
                                  14-163

-------
SOp exceeded 500 ug/m3 11 to 32 times in 1964 and 5 to 23 times in 1965.



Information on respiratory symptoms and illness was obtained by questionnaires



completed by the parents, by physical examination, and by tests of pulmonary



function (FEVQ ?5 and FVC).   Socioeconomic factors (SES) were considered in



the analyses, but home heating systems were not.   Although certain differences



in SES between areas were noted, the gradients between areas would exist even



when the groups were divided into social class, number of children in house,



and so on.     Positive associations were found between air pollution concen-



trations and both upper and lower respiratory illness.   Lower respiratory



illness was 33 to 56 percent more frequent in the higher pollution areas than



in the low-pollution area (p <0.005).


                                    97
     In a second report, Lunn et al.   gave results for 11-year-old children



studied in 1963-64 that were similar to those provided earlier for the younger



group.   Upper and lower respiratory illness occurred more frequently in



children exposed to 24-hour mean smoke (BS) concentrations of 230 to 300 ug/m



and 24-hour mean SOp concentrations of 181-275 ug/m  than in children exposed


                        3                    3
to smoke (BS) at 97 ug/m  and SOp at 123 ug/m .  This report also provided



additional information obtained in 1968 on 68 percent of the children who were



5 and 6 years in 1963-64.  By 1968, the concentrations of smoke (BS) were only



about one-half of those measured in 1964, and SOp concentrations were about 10



to 15 percent below those measured in 1964.  By 1968 the pollution gradient no



longer existed, so the combined three higher pollution areas were compared



with the single original low-pollution area.  Lower respiratory illness pre-



valence measured as "colds going to chest" was 27.9 percent in the low-



pollution area and 33.3 percent in the combined high-pollution areas, but the



difference was not statistically significant (p >0.05).  (Ventilatory function
                                  14-164

-------
results were  similar.)   Also,  the  9-year-old children had less respiratory



illness than  the  11-year-old group seen  previously.   Since 11-year-old children



generally  have  less  respiratory  illness  than do 9-year-olds,  this represented



an-anomaly that the  authors suggested may have been  the result of Improved air


                                                  96 97
quality.   It  should  be  noted that  these  Lunn et al.   '    findings have been



widely accepted245'248>301>307'308'312 as being valid,  and,  on the basis of



changes observed  between the two surveys, the NAS report on  particulate matter



concluded  that  levels of effect  were 100 ug/m3 BS and 120 ug/m3 SO  307



     Hammer et  al.    and French et al.     reported  on two studies,  conducted



as part of the  EPA CHESS Program which investigated  the occurrence of lower



respiratory disease  (LRD) in United States children  less than 12 years of age



New York City.    '      In the  two  studies, data were obtained from questionnaires



asking mothers  to recall how many  times  each of their children under age 12



had had pneumonia, croup, or bronchitis  during the previous  3 years.   Data



were gathered also on related  hospitalizations and physician visits.   Validation



studies of the  questionnarie yielded highly significant correlations between



the illnesses reported  on the  questionnaire and confirmatory hospital and


                 257
physician  records.


                 214
     Hammer et  al.    reported on  a study of historical acute lower respiratory



disease in children  aged 1 to  12 years surveyed retrospectively by questionnaire



among parents in  four New York metropolitan communities representing different



exposures  to  sulfur  dioxide, particulate matter and  suspended sulfates.



Morbidity  patterns were similar  with regard to age for blacks and whites, but



pneumonia  was more frequent and  bronchitis and other chest infections were



less frequent among  blacks than  whites in each community.  Rates of "any  lower



respiratory disease" (a combined category), croup, bronchitis, and "other"
                                  14-165

-------
chest infections were significantly higher among black and white children



residing in the communities with exposure to higher pollution.   Pneumonia and



hospitalization were significantly higher only among white children 1n the low



exposure community but the absolute rates were low for both conditions in all



communities.  Differences in family size and composition, crowding, parental



cigarette smoking or indoor air pollution due to gas stoves or gas space



heaters could not explain the morbidity excesses in the high exposure communities



Significant differences in LRD in the previous 3 years were found for all ages



(1-12) after adjusting for sex and education of head of household.  Estimates



of the average annual pollutant concentrations associated with excess childhood



respiratory morbidity in this study were 160 to 260 ug/m  of sulfur dioxide,


             3                                                   3
82 to 96 ug/m  of total suspended particulates, and 13 to 14 ug/m  of suspended



sulfates as measured by the New York City Department of Air Resources (NYC

                                    7QC

DAR).  As reported by French et al.,     there was an increased relative risk



of acute lower respiratory disease in all family members in the high pollution



areas, especially for those with 3 or more years residence in the areas, and



after adjusting for parents'  smoking habits.



     French et al.    conducted a similar study in the children (ages 1-12) in


                                      212
the families studied by Chapman et al.     in the four Utah communities.  The



prevalence rates of reported past lower respiratory diseases (LRD) were  similar



for those residing in the communities less than 3 years.  For those with three



or more years of residence, the rates were similar for the three  low pollution



communities Magna's prevalence rates, in those with the 3+ years  residence,



were significantly higher:   age-, sex-, and SES-adjusted attack rates  for one



or more LRDs were 38.2 in Magna vs. 26.5 to 29.0 in the other three areas;



age-, sex-, and SES-adjusted attack rates for two or more LRDs were 23.4 in
                                  14-166

-------
Magna vs 14.6 to 17.2 in the other three areas.  Again, local monitoring
indicated similar TSP averages for the four areas (about 70 ug/m3), but higher
SCL readings in Magna (107 mg/m  or more).
     Some of the comments discussed for other EPA CHESS Program studies (see
also Appendix A) may also apply to the above studies by Hammer et al214 and
French,    to the extent that similar methodological tools or procedures were
used as in the other studies.  Especially applicable, then, are questions
raised    concerning:  (1) air quality measurements obtained by "CHESS" monitor-
ing in the study locations at the time immediately proceeding and during the
collection of health effects data and (2) the estimation of historical exposures
for the study populations from limited past local air monitoring data.  Caution
must, therefore, similarly be applied in regard to full acceptance of the
published "CHESS" air pollution values for these studies.  As judged by IR,
the local values (shown above) are more accurate, and they have been used to
estimate exposures.  Since these studies   '    are in children, prior exposures
are likely similar to those presented.
     Another retrospective survey conducted by Hammer    '    regarding the
frequency of lower respiratory illness in children was undertaken in 1971 in
the south east, using similar questionnaire sampling as employed in the above
New York studies.    '     Data were obtained by questionnaire from parents of
about 10,000 children aged 1 to 12 years.  The two communities represent
intermediate and high particulate exposures with low S02 exposures.  The
analysis of data indicated that in the high exposure community (Birmingham)
there was significantly increased respiratory  disease  over that  for the lower
exposure community (Charlotte), based on  statistically significant results
obtained on 10 of 17 measures of respiratory morbidity.  This  included more
                                   14-167

-------
pneumonia and croup among blacks and more lower respiratory disease,



bronchitis and croup among whites in Birmingham than in Charlotte,  as shown in



Table 14-38.   There was also a consistent trend for the association of more



illness and hospitalization with higher pollution to become stronger in older



children.  This suggests that the effect increased with extended exposure.



The investigators assumed that cigarette-smoking for children under age 13  in



the South was minimal, equally distributed,  and did not affect their results.



The investigators concluded that differences in parental  recall, questionnaire



reliability,  family size, crowding,  or parental smoking habits were not likely



explanations for the excess morbidity in the high-pollution areas,  since these



factors did not differ significantly between communities.   Therefore, the



results were taken to be indicative  of associations between increased lower



respiratory disease rates in children and exposure to moderately elevated



particulate matter levels in the presence of low S02 levels.   Asthma rates



clustered in families, were higher in male children and female parents, and



were comparable to other studies.  Significant increases  of lower respiratory



disease were also reported for asthmatic children in the  high exposure community.


                     214 257
     The above Hammer    '    study,  peer-reviewed and published as  a Harvard



University doctoral dissertation, would appear to provide important and mean-



ingful findings demonstrating significant respiratory effects in children



associated with elevated particulate matter air concentrations in the presence



of low levels of SO,,, suspended sulfates, and suspended nitrates.  The response



rates were excellent in both communities, though significantly lower in Charlotte



(88 percent)  than in Birmingham (95  percent) and significantly lower for



Blacks (84 percent) than for Whites  (89 percent) within Charlotte.   The small



differences in response rates in absolute terms, however, appear unlikely to
                                  14-168

-------
                                   TABLE  14-38.  FOUR-YEAR REPORTED RATES OF ONE OR MORE EPISODES
                                  OF  LR& AMONG"WHITE AND BLACK CHILDREN, BY COMMUNITY EXPOSURE
                                                     SOUTHEASTERN U.S.  1971
Adjusted age-specific rates, (%) ,C7


Type of LRO
*ny LRO


Croup

Bronchitis

Pneumonia

Hospltallratlon


Pollution
Exposure
Charlotte
Birmingham

Charlotte
Bi rmingham
Charlotte
Birmingham
Charlotte
Birmingham
Charlotte
Birmingham


1-4
35.0
38.9

17.5
16.3
23.1
28.7
9.0
10.3
5.5
5.8
White
age
5-B
29.9
36.3

14.2
16.3
20.4
26.2
6.3
8.5
2.7
6.1


9-12
22.0
26.4

9.3
12.2
14.9
18.6
5.2
6.3
0.9
2.4


1-4
27.8
24.0

10.8
8.6
13.7
10.6
14.0
15.1
4.0
5.7
Black
age
5-8
16.4
20.6

7.0
7.9
7.8
7.9
8.3
13.7
1.8
2.9
A1r Pollution Levels - 1971^
(annual averages In pg/m )
9-12
12.7
15.9

4.7
5.9
6.3
6.9
8.9
10.2
1.3
2.5
City Year
Charlotte 1971
Birmingham 1971
1960-1971 avg.
Charlotte 93
Birmingham 155






TSPa RSP
74 40. 7b
133 57. 2C
TSP
(74-112)f 8
(133-169) 10






,,d ,Md
J 3 j™
9.6 1.7
11.8 2.5
SS
(4-10) 17
(9-16) 15






S02
16.3"
12.1
so,
(13-20)
(6 <25)






?Values obtained from trend lines.
°TSP x .55.

-------
have affected the overall  study results in view of excellent  internal  consistency
in lower respiratory disease morbidity patterns among blacks  and whites  within
both study communities, with morbidity patterns being similar 1n relation to
age, sex, parental education, and history of asthma in each of the communities.
The fact that many of the  most likely potential confounding or covarying
factors were adequately controlled for in terms of the particular multivariate
age-, sex-, race-, and socioeconomic level - specific statistical analyses
employed is another strength of the study.  In addition,  smoking does  not
appear to be a credible factor accounting for the observed results, especially
those for the children in  the 1 to 4 and 5 to 8 year old  age  groups.   Lastly,
the 1960-71, 1964-71, and  1968-71 air quality estimated shown in Table 14-39
respectively index lifetime exposures for the 9-12, 5-8,  and  1-4 year  old
children constituting the  present study populations.   Thus, if those air
quality data are accurate  and adequately representative of the respective
study population exposures, it would seem to be possible  to define a relatively
narrow range of annual average TSP concentrations likely associated with the
childhood respiratory disease effects observed in the study.
     In regard to further critical assessment of the Hammer   '    study, it
should be noted that it was not specifically discussed in the Congressional
Investigative Report,    which evaluated other EPA CHESS Program studies com-
pleted earlier.   On the other hand, the present Hammer study appears to have
avoided well most all of the methodological shortcomings of the  types noted
for various other specific CHESS Program  studies in the IR    review.   Only in
a recently published review by Holland et al    has there appeared any specific
critical comments regarding the study, and those were directed  to  an earlier
unpublished draft report on the study.  Referring  to the draft  report, Holland
et al301 noted:
                                  14-170

-------
I
»—•
••J
Total
Suspended
Particulates
                           TABLE 14-39.   ESTIMATED3 POLLUTANT EXPOSURE LEVELS IN CHARLOTTE, NORTH CAROLINA..,
                          (INTERMEDIATE EXPOSURE) AND BIRMINGHAM,  ALABAMA (HIGH EXPOSURE):   1960-1971liJ>
                                           Estimated Pollutant Concentrations, ug/m
Pollutant
Community
1960-63
Average
1964-67
Average
1968-71
Average
1960-71
Average
                        Charlotte
                        Birmingham
107
168
 93
159
 79       93(74-112)°
139      155(133-169)
Sulfur
Dioxide
Suspended
Sul fates
Suspended
Nitrates
Charlotte
Birmingham
Charlotte
Birmingham
Charlotte
Birmingham
17
<25
6
10
2
2
16
11
9
11
2
3
17
13
10
14
1
3
17(13-20)
15(6-<25)
8(4-10)
10(9-16)
2(1-3)
2(2-3)
       aAll values obtained from reference 257 and based on both measured and estimated values.   Twenty- four hour integrated
        estimates of concentrations were measured expressed in micrograms per cubic  meter.   For  each year,  the average of
        all daily estimates was computed.  For periods of several years,  the average of the individual  years is tabulated.
        For the period 1960 to 1971, the average for the 12-year period is shown together with the range of the 12 indi-
        vidual years.
        Range in parentheses

-------
     Rates of illnesses in the two cities were compared in three  age  groups
and by race after adjusting for sex and education of head of household.   The
rates were higher in Birmingham except for blacks (sic) 1-4 years of  age.
However, in another analysis, consistent differences were only found  for
whites (sic).  Although parental smoking was considered, 1t was not Included
in the analyses.  No discussion was given of the validity of the  data or
consistency of results in different sectors of the cities, as had been pro-
vided by Love et al.  In light of the results of the prospective  study (ie.  by
Love et al),* this retrospective study, with its Inherently less  reliable
data,requires more detailed analysis than is provided in the draft paper
before the observed effects can reasonably be ascribed to differences in
levels of total suspended particulates (HV).

Reference to the Love et al prospective study concerns a different CHESS

Program study of acute respiratory disease during fall, winter and spring of

1970-71 and 1971-72 in preschool and schoolchildren in Birmingham and Charlotte

a study which failed to demonstrate higher acute respiratory disease  rates in

Birmingham and, for which, internal inconsistencies existed with regard to

social class, race, and smoking.

     All told, the above Holland et al    comments do not seem to provide any

compelling reasons for rejecting the findings or conclusions contained in the

later, more thorough and complete, published analyses   '    of the Hammer

study, judged by prominent American epidemiologists and statisticians (on

Hammer's doctoral committee) to be methodologically sound and appropriately

interpreted.  Thus, for example, the failure to find higher rates of respiratory

disease for Blacks age 1-4 in Birmingham, does not negate the finding of other

statistically significant, internally consistent, and biologically plausible

Increases in respiratory disease rates in Birmingham for other Black age

groups and all White age groups.  Nor are the Hammer findings negated by the

failure of the Love et al prospective study to find analogous effects at a
*Editors' insertion.
                                  14-172

-------
later time  when  available  air  quality  data  indicates  that  lower  TSP  and  SOp



levels existed  in both  study  communities  along  with  smaller intercommunity



differences than  at  the time  of the  Hammer  study.  Also,  perhaps  acre Importantly,



the -Love et al  study used markedly different data  collection procedures  (telephone



survey versus questionnaires  in the  Hammer  study,  etc.)  and health  endpoint


neasurements.


                             257
    Also in his  later  report,    Hammer  does demonstrates  the  validity  of the
data and  the  consistency  of  results  (see  above).   In addition,  Hammer



demonstrated  that parental smoking was  not important in his  findings,  which



confirms  the  findings  of  other epidemiological  studies.338'339'340



     Two  key  issues  that  remain and  must  be considered before accepting  the



specific  quantitative  dose-effect relationships implied by Hammers'  published



analyses    '     are:   (1) the  representativeness of the reported air quality



data as reflections  of the respective exposures of the different study popu-



lations;  and  (2) the validity  and accuracy of Hammers' published quantitative



estimates for air levels  of  TSP, SO-, and other pollutants in Birmingham and



Charlotte during the 1960-71 period  (as shown in Table 14-38 and 14-39).



     With regard to  the first  issue, it should be noted that annual  average



TSP and S0? estimates  for years before 1964 are based on data obtained from  a



single monitoring site in Charlotte  and Birmingham each, and the published



estimates for those  years (1960-64)  shown in Table 14-39 are thusly likely to



be the most tenuous  in reflecting actual  exposures in comparison to data



obtained  with multiple monitoring sites in later years.  The estimates listed



in Table  14-39 for 1964-1968 are derived from results obtained via multiple



county, NASN,  or other Federal monitoring sites situated as depicted in Figures



14-5 and  14-6-   The  estimates  listed in Table 14-38 and 14-39 for 1968-71 are
                                  14-173

-------
                   IIHUINCHAM.AIAIAUA
                 8    I     1    )
                 U-l    I    I    I
                              c^T                  s.«
                              n          A   •• '•«
                                                                           • A
                                                                           J. II
                                                                           N.I]
                                                                                              SITE lOIHTiriCATION

                                                                                              >•  •  HOI MAI STUDY

                                                                                              «L  A  BASH

                                                                                              C     CME»
                                                                                              J. _•  JIFFtRSON
                                                                                                    COUNTY
Figure 14-5   Locations of air monitoring stations in Birmingham  Alabama from u»h  K
in Hammer study were obtained.                    mingnam. Alabama, from which air quality data employed

-------
                                       CHARIOTTI. NOR1H CAHOtlN*
Nl
 o
CHtSS
      MtCKKNIURC COUNTY
       Figure 14-6  Locations of air monitoring stations in Charlotte, N. C. from
    which air quality data employed in Hammer  study were obtaineo.
                                              14-175

-------
also derived from the same multiple county,  NASN,  and other Federal  monitoring



sites dispersed at points shown in Figures 14-3 and 14-4 so as,  in general,  to



cluster around major air pollution emission  point  sources within Cjiarlotte and



Birmingham metropolitan areas.



     Additional "CHESS" monitoring sites were set  up in late 1969 at locations



indicated in Figures 14-3 and 14-4, with one site  (o) being situated in each



of three residential neighborhoods (sectors) in each city and generally further



distant from any of the high emission point  sources than the other monitoring



sites; the CHESS sites were also within 1% to 2 miles of the residences of



each of the study population families living in the respective sectors and



were situated, except for one,  at approximately six feet off the ground on



flat, relatively open terrain.   Thus such sites would appear to  be likely to



yield data well representative  of exposures  of the various study populations,



exposures likely to be less than the air levels of pollutants monitored at the



other sites closer to known pollution sources:  and, consistent with this,



"CHESS" estimates of TSP and S02 levels for  1969-71 are distinctly



lower than the estimates based  on the other  monitoring data for the same



period.  Thus, the available "non-CHESS" monitoring data shown in Table 14-39



for TSP and SO,, levels would seem to clearly represent the maximum estimates



of the highest possible annual  average (arithmetic mean) exposure levels



likely to be associated with the respiratory disease effects demonstrated by



the Hammer study.113'257



     Turning to the second issue noted above, that concerning the validity and



accuracy of the Hammer study air quality measurements, it should be noted that



the Investigative Report    concluded that the TSP measurements obtained for



other CHESS Program studies by  means of procedures yielding the CHESS estimates
                                  14-176

-------
alluded to above were among the most consistent and reliable of the CHESS air
quality estimates obtained and likely errored toward underestimation of actual
TSP levels by,  at most, 10 to 30 percent.   Increasing the reported113'257
Hammer study CHESS estimates by 30 percent, to allow for the naxiwum likely
error associated with them, results in their approaching analogous estimates
from the other monitoring networks more closely, but still remaining distinctly
lower (being about 80-90 ug/m  for Charlotte sectors and 110-120 ug/m3 for
Birmingham sectors).   As for the S02 air quality data, the IR107 concluded
that errors in SOp measurements in other CHESS studies may have resulted in
underestimations of S02 levels by 50 to 100 percent or more, which means that
published Hammer study S02 levels (being similar to the other monitoring
estimates) might, theoretically, range up to still very low levels of 25 to 35
ug/m .  On the  hand, as discussed in the IR    the sensitivity of the SOp
analytical methods employed in "CHESS" monitoring is such that 50^ values
under 25 to 50 ug/m  cannot be considered to be significantly different from
zero.  In other words, regardless of the precise S02 values actually present,
there appears to be no question that they were equally low (nearly zero)  in
both Charlotte and Birmingham.
14.5.4  Pulmonary Function Studies
     Impairment of pulmonary function  is likely to be one of the  effects  of
exposure to air pollution since the pulmonary  system  includes the  tissues that
receive the initial impact when toxic materials are  inhaled.  Acute  and  chronic
changes in function may be significant biological responses to  air pollution
exposure.  A number of studies have been conducted  in an  effort to relate
pulmonary function changes to the presence  of  air pollutants in various  European,
Japanese, and American communities.
                                   14-177

-------
                                                                        74-77
     Studies in the Netherlands reported by van der Lende and colleagues



compared lung function in a large population group in 1969 and again in 1972.



In a more polluted area, age-, health-, and smoking-adjusted FEV^ Q values in



men. increased from the first to the second survey rather than decreasing with



age as expected.  This was associated with a concurrent decrease in air pol-



lution concentrations.  The highest 24-hour values for SOp during the time of



the surveys in the high-pollution area were 160 and 300 ug/m , respectively.



in 1969 and 1972; the highest 24-hour smoke values were 40 and 100 ug/m .



Again, neither pollutant can be implicated individually.   The investigators



considered other possible causes of the improved pulmonary function but con-



cluded that the most plausible was the effect of reduced air pollution.



Expected decreases were seen in a rural area.   The authors explored possible



sources of bias in the study but were unable to explain their results on that



basis.  A third survey of this population, conducted in 1977, found that,



under the improved air quality condition, expected decreases in pulmonary



function values in the aging population was observed.  This strengthens the



possibility that the former pollution concentrations were related causally to

                     4
the pulmonary status.


                    33
     Becklake et al.   used pulmonary spirometric and closing volume function



tests (and symptom reporting) in three areas of Montreal Canada and did not



find significant differences in children or adults that were associated with



TSP levels.   In the three areas studied, ambient S02 was reported to be 15,



123, and 59, and annual mean high-volume TSP values were 84, 95, and 131


    3
ug/m , respectively, for the low-, intermediate-, and high-pollution areas,



but there was a large overlap between areas.  In a later report (Aubry et



al.    ) discriminant analysis was utilized to control for smoking, after which



differences in health variables were not significant.
                                  14-178

-------
     Hanfreda et al.    studied pulmonary function in one rural  and one urban
population  (25 to 54  years old) residing in the Winnepeg area of Canada in
order to  determine the effect of any urban factor.   Pulmonary function was
assessed  by single breath N2 tests and by force vital capacity using a dry
rolling Seal  Spirometer.   Tests were repeated until  three gave results within
10 percent  of each other  or a maximum of five determinations was reached.
Annual mean concentrations of SCL were about 15 ug/m3 (0.005 ppm) in both
areas, although the authors stated that subjects in the urban area may have
been exposed part of  the  time to the 30 ug/m  (0.01 ppm) that is measured  in
the more  polluted part of Winnipeg.   Annual mean TSP concentrations were
reported  to be no more than 56 pg/m  in either study area, although those  in
Winnipeg  were 73 to 78 ug/m .   The study results indicated that total lung
capacity, vital capacity  on expiration, residual volume, and closing volume in
men and women were very significantly related to height, age, and smoking
status (p < 0.05).  However, there were no differences associated with the
place of  residence.   Thus an urban factor was not apparent in a low-pollution
urban area.
                  218 264
     Kagawa et al.    '    investigated the effects of photochemical air pol-
lution (oxidants, ozone,  hydrocarbons, NO, N02, SOp, suspended particulate
matter),  temperature, and humidity on respiratory functions of Tokyo school-
children.   Ventilatory function was measured weekly for 29 weeks, June-December
1972, in  21 schoolchildren and again from November 1972-March 1973.  Of seven
measures  of respiratory function, maximum expiratory flow rate showed the
highest correlation (p <0.05) with the greatest number of environmental vari-
ables.  Among environmental variables, temperature significantly affected a
number of respiratory functions, being positively correlated with  Rflw in
                                  14-179

-------
particular.  Partial correlations showed,  however,  that regardless  of
temperature, ozone, sulfur dioxide, and N02 alone also played significant
roles in affecting individual respiratory  functions.
                    ft7
     Zapletal et aT.   studied pulmonary function in 111 healthy 10- to
11-year-old children who had lived for at  least 5 years in highly polluted
areas of Czechoslovakia.  Only 19 (17 percent) of the children demonstrated
baseline abnormalities in FEV,.   They were studied further;  6 of the 19 showed
significant reductions in maximal flow rates at low volumes.   The investigators
concluded the FEV, and flow abnormalities  might be related to air pollution.
Air concentrations of S0« and TSP were in  excess of 240 ug/m  (daily averages)
on more than 7 days a month during winter.
     Holland et a!.101'102 and Bennett et  al.103 reported the results of
studies of pulmonary function in schoolchildren, aged 5, 11, and 14 years,
living in two urban and two rural areas of Kent, England.   Peak expiratory
flow rate (PEFR) was measured with a Wright Peak Flow Meter.  Approximately
10,000 children were included in the study populations.  Mean smoke concen-
trations in the two urban areas for the period from November 1966 to March
1967 were 69 and 50 ug/m  (BS).   Smoke measurements were available from only
one of the rural areas, and these averaged 34 ug/m .   The other rural area was
said to be at least as clean.  Mean peak expiratory flow rates, adjusted for
differences in age, height, and weight as  well as for a history of bronchitis
or pneumonia, social class, and the number of siblings in the family showed
significant area differences.  In the highest area (Rochester), the lowest
levels of PEFR were found to be independent of parents' social class, family
size, and past history of respiratory illness.  The four factors operate
independently and additively.  Differences between other areas did not corre-
spond to differences in air pollution concentrations.  Thus, mean values of BS
                                  14-180

-------
          3                    3
of 70  ug/m  in winter (123 ug/m  TSP) were associated with reduced PEFR,  but
30 to  50 ug/m  BS were not.   Smoking in the home and other pollution were not
considered in this study.   Also details on instrument calibration and number
of trials for each child were not given.
                    112
     Col ley and Reid    reported results of respiratory symptoms and lung
function (PEFR) in approximately 10,000 children ages 6-10 in different parts
of England.   They examined relationships with S02 specifically.   Mean values
were found in the different areas from 33 ug/m  to 150 ug/m3 of S02 (converted
lead peroxide sulfation rates).  Smoke levels were not provided.  The biggest
gradient they found was between respiratory symptoms and social  class by area;
the biggest differences occurred in social classes IV and V.  They found an
association of lower respiratory tract infections with the air pollution
gradients, but no association for upper respiratory tract infections.
Differences were not explained by domestic circumstances (persons per dwelling,
rooms per dwelling, crowding).  (The trends followed similar trends in the
                                                                             248
frequency of killing and disabling bronchitis among adults  in the same areas.   )
     Turning to American studies on morbidity effects associated with long-term
                 195
exposures, Ferris    conducted a carefully executed study of absence rates and
pulmonary function in first and second grade schoolchildren in  seven schools
in areas of Berlin, N. H. with different concentrations of  air  pollution.
                                                                    2
Pollution measurements included sulfation rates  in ug of S03/100 cm /day and
                             o
average dustfall in tons/mile /30 days.  Indications were that  SO^  was about
four times more concentrated in the area of highest than  lowest pollution  (619
i 246 vs. 130 ± 101 ug of S03/100 cm2/day) and  that particulates were nearly
five times more concentrated in the area of highest pollution (62 ± 16 vs. 13
± 7 tons/miIe2/30 days).  Maximum particulate and S02  levels did  not occur in
                                  14-181

-------
the same area.  In spite of the differences in pollution,  school  absences for
respiratory illnesses were not significantly different between schools;  nor
was their any relationship between social  class and absence rates.     Pulmonary
function tests (peak flow with Wright Peak Flow Meter and  forced  vital capacity
and 1-second forced expiratory volume from a Stead-Wells spirometer) during
the winter (January) showed no significant relationship to school.   However,
such measurements taken in summer significantly related to particulate air
pollution, as shown by individual comparison T-tests following an overall
analysis of variance (ANOVA) comparing results obtained with children from
different schools in high, medium, and low pollution areas.
     Holland et al. (1979)301 evaluated the Ferris195 Berlin study results as
follows:
     The children in the school in the most polluted area  tended  to have
     lower peak expiratory flow rates (both sexes), forced vital  capacity
     and forced expiratory volume (girls only) than in one or two schools
     from areas with intermediate levels of dustfall.  However, no differences
     were found between children in the most and least polluted areas.
     The method of carrying out individual t tests between so many schools
     is an unwise statistical practice:  the analysis of variance is more
     appropriate as it indicates to what extent the variation between all
     the schools could have occurred by chance, given the  hypothesis that
     there were no real differences.  Since the result of  the analysis of
     variance was not reported it is probable that no significant differences
     between the schools could be found.
     Of course exactly the opposite inference should be drawn from the one
stated by Holland et al.    on the basis of the above information; that  is,
one must assure that the individual t-test comparisons between shcools would
not have beers carried out unless significant overall differences were first
obtained by means of the ANOVA in keeping with standard statistical  procedures
associated with ANOVA usage.  It is difficult to understand  how Holland  et
   301                                                             195
al.    missed information clearly stated  in the Ferris publication   confirming
that, in fact, this was done (as quoted below):
                                  14-182

-------
          The results of the tests of pulmonary function were  tested  for
     significant differences among the schools by a one-way  analysis  of
     variance.   If significant difference was noted,  a two-tailed  t test
     was  done (table 12).   Pulmonary function in pupils of School  A was
     significantly lower than that in pupils of several other  schools,
     particularly in the June 1967 study.

Furthermore,  use of one-tailed t-test may have been more appropriate  In this

case, to  test the hypothesis that air pollution was causing  the  observed

health effects differences and may have identified even more statistically

significant differences due to particulate pollution.

     Mostardi and Leonard    compared measurements of pulmonary  function  (VC,

FEV1, MMF, and V02max) in 42 volunteer male high school students from a pol-

luted area with similar measurements for 50 male students from a rural area.

The subjects  in this 1973 study had all participated in a 1970 study  in which

measurements  were limited to VC and FEVyc-  Air pollution concentrations  in

both study areas declined somewhat between 1970 and 1973 but results  of the

two studies were similar.   In 1970 the group in the polluted area  had a mean

VC (3.27  ± SE 0.07) lower than the group in the cleaner area (3.54 ±  SE 0.10)

p <0.05.   In  1970, means were higher (4.65 ± SE 0.11 for the polluted area and

5.04 ± SE 0.10 for the rural pollution area) but the difference  remained  (p

<0.01).   The  mean FEV 75 in 1970 also was lower in the polluted  area  (2.57 ±

SE 0.10)  than in the low-pollution area (2.90 ±SE 0.08, p <0.01) but  the  mean

FEV, values in 1973 (4.09 ± 0.09 and 4.20 ± 0.08) were not significantly
                                                                    2
different.  Annual mean S02 concentrations measured as mg S02/100  cm  /day by

the lead  peroxide candle method ranged in the high pollution area  from 1.014

in 1970 to 1.020 in 1972 (81.1 to 81.6 ug/m3) and in the low pollution area

from 0.763 to 0.36 (61 to 28.8 ug/m ).  Comparable data were not collected in

1973.  Annual mean suspended particulate matter concentrations ranged in  the
                                  14-183

-------
high pollution area from 77 to 110 ug/m ,  and in the low-pollution area from


71 to 83 ug/m .   The investigators suggested that the differences in test


pesults may have related to the differences in pollution.   The Inclusion of


blacks did not affect the results, although smoking may have.   SES (apart from


race) may have also had some effect.   The  area in which the study was done is


heavily industrialized and the differences in the measured pollution levels


may have been adequate indices of difference in risk experienced in the high



pollution area.

                         pep
     Mostardi and Martell    reported on 173 and 161 students, respectively,


from the same urban and rural areas.   They tested FVC and FEV jr on subjects


residing in the areas for 4 or more years.  The groups were analyzed separately


by sex and males were analyzed separately by whether or not they smoked ciga-


rettes.  The two groups were comparable in anthropometric characteristics.


Higher values for pulmonary function were reported in the rural area for all


males, females, and smoking males.  While a higher proportion of smokers were


found in the urban area (12 percent versus 6 percent in the rural area), the


authors stated that this did not influence their results.   They did not analyze


by race in this study, because they found that the lung function differences


persisted in their previous study after exclusion of the three black students


in the urban area.



     Pulmonary function was also studied in Cincinnati schoolchildren  in

                       215
1967-1968 by Shy et al.   .   Children from schools in an industrial valley  of


Cincinnati were compared with children from schools in a non-industrial  river


valley on the east side of the metropolitan area.  Two each upper-middle


white, lower-middle white, and lower-middle black schools were selected  from


each valley.  Air monitoring stations within three blocks of  the  schools
                                  14-184

-------
showed that 7-month average TSP values were from 18 to 32 ug/m  higher in the



industrial  valley than in the non-industrial  valley,  but corresponding differences



for suspended sulfates,  suspended nitrates, and SOp ranged from 0.1 to 1.1,



0.1 to 0.8, and 0.6 to 10.4, respectively.   Thus, the Industrial valley had



Bore TSP than the non-industrial valley, but its levels of SS, SN,  and S02



exceeded those in the non-industrial  valley by very small margins.   Arithmetic



averages over the 7 months of the study ranged for TSP from 96 to 114 ug/m  in



the more polluted industrial area and from 77 to 82 ug/m  in the cleaner



areas.  SOp for the 7-month average ranged from 39 to 51 ug/m  in the polluted



areas and from 40 to 45 ug/m  in the  clean areas.  Ventilatory function was



measured as the forced expiratory volume at .75 second (FEV 75) on  a Stead-Wells



water-filled spirometer once weekly on each child during each of the study



months.   The better of two satisfactory forced expiratory maneuvers obtained



on each test day was used for all computations.  Height, sex, and race were



used to make adjusted FEV ,r comparisons.  The study was confined to 394



second graders who participated in weekly measurements during November 1967,



February 1968, and May 1968.  These students represented 93 percent of second



graders in the classrooms selected.  Mothers were interviewed to obtain socio-



economic data.   The educational attainment of fathers was similar for corresponding



schools in the industrial and non-industrial valleys.


                   215
     The Shy et al.     data showed that average height adjusted FEV 75 in



"clean" schools exceeded that in "polluted" schools in all 3 months for lower-



middle class whites and in 2 of 3 months for upper-middle whites.  Blacks con-



sistently had lower FEV 75 values, and a pollution effect was  seen among



blacks during only one of three study periods.  The absolute  differences  in



average FEV 75 were roughly 40-120 ml (< 10 percent)  in most  cases.   A
                                  14-185

-------
multivariate analysis of variance was applied which allowed for testing of



community effects adjusted for a possible month effect and for the covariates



height, sex, race, and social class.   The dependent variable for each child



was his vector of three monthly average FEV 75 values.   They concluded from



this analysis that suspended sulfates had the strongest association with



FEV 75.  These studies support the notion that FEV 75 was 3 to 10 percent less



among white second graders in the industrial valley than among those in the



non-industrial valley.


                                                                              215
     In 1970 to 1971, a ventilatory function study was conducted by Shy et al.



in New York as part of the EPA CHESS Program.  It included children ages 5 to



13 who attended schools situated within 1.5 miles of air monitors.  Riverhead,



Bronx, and Queens were represented by three schools each.  Only white children



were included in the analysis.   Unfortunately, the electronic spirometer used



to assess pulmonary function exhibited drift (<350 ml).  This could bias the



study results only if one community was systematically studied with a spirometer



with extreme drift or if the drift varied in phase with the rotation of spirometers



through communities.   The variability of the observations is increased by



random distribution of drift, since the community effects (60 ml or less) are



much smaller than the drift.      However, during testing periods, the instruments



were calibrated against a Stead-Wells volume spirometer.  They also were



tested for reproducibility by obtaining six or seven successive FEV 75 measurements



with trained subjects and comparing them with the results obtained with the



Stead-Wells spirometer connected in series.  Percent differences  in pulmonary



function ranged from -7.0 to +6.6, about the same as the accuracy of any



spirometer.
                                  14-186

-------
    Families of children  studied  in  Riverhead,  Queens,  and  Bronx, were  similar
in  regard to age distribution  and  parental  smoking  habits.   Income and educa-
tional attainment decreased  in the order  Queens,  Riverhead,  and Bronx.   No
comparison of children's smoking habits is  reported,  although  this aay have
been crucial in interpreting the results  in view of statistically significant
differences in pulmonary function  being found  only  for  older children.1
    Male FEV 75 values, adjusted  for height and age, from Riverhead  (the  low
pollution community) were  intermediate between Queens and Bronx (the  two
higher pollution communities)  for  three of  four test periods.  For females,
the Riverhead values exceeded  Bronx and Queens values in each  test period, but
the differences usually were less  than 50 ml.   Riverhead height-adjusted
FEV 75 values were  largest during  one of  four  test  periods for young  males and
females, and during three  of four  for older males and females.  The average
differences were inconsistent.  However,  the analyses for  individual  test
periods  do show statistically  significant differences for  older males and
                   215
females.  Shy et al.    speculate  that lack of differences  in  5-  to 8-year
olds may be due to  improved air quality  in  years since  the early  childhood
period of the older subjects studied. As noted above,  local monitoring  levels
were judged accurate,    and were  used to assess area differences in  this
study.
    Chapman et al.213 performed an EPA  CHESS  Program survey of the  ventilatory
function of 7997 black and white elementary schoolchildren in  Charlotte, North
Carolina and Birmingham, Alabama,  during the 1971-1972  school  year.   These
cities had been selected for study because  they exhibited a gradient of exposure
to  suspended particulates, and had low levels  of other pollutants.   Birmingham
had an average RSP  of  45 g/m3  compared with 33.4 in Charlotte.  The ventilatory
                                  14-187

-------
function test employed was the three-quarter second forced expiratory volume
(FEVQ 75).  Two instruments were utilized in each area sequentially (a hot
wire anerometer in the first two surveys and a dry-seal spirometer thereafter).
     In all eight age-, sex-, and race-specific subgroups, nean age- and
height-adjusted FEV 7& readings were consistently lower in the more polluted
city, Birmingham.   This finding strongly indicated that exposure to particulate
pollution had exerted a deleterious effect on the FEV« -,,- of children in
Birmingham.  The results may be consistent with either of two alternate hypotheses:
first, that exposure to TSP (high RSP and suspended sulfates) from the beginning
of life onward promotes impairments in FEV 75 in later childhood; or second,
that such particulate exposure for the past several years promotes such impairments
The authors assumed, possibly wrongly,    that children ages 12 and under do
not smoke appreciably nor differently in the two areas.  See Appendix A for
more discussion of this point.
     Intercity differences in mean FEVQ 75 were smallest in fall, greater in
winter, and greatest in spring.  Intercity differences in TSP, RSP, suspended
sulfates, and suspended nitrates parallelled this pattern.  Because ventilatory
function testing was performed on only three occasions, and the first two used
a different instrument than used in the third, it was not possible to test the
seasonal differences in FEV ,,. as a function of changes in particulate concen-
trations.   Sulfur dioxide and suspended nitrates were present in low
concentrations in both cities, both during the year of study and throughout
the lives of the children under study.  Thus, it was unlikely that either of
these pollutants had exerted important deleterious effects on FEV0 75 in
either city.   Beyond this point, it was not possible to determine which specific
particulate fraction or fractions had exerted the strongest effects of FEVQ 7r.
                                  14-188

-------
14.5.5  Studies Combining Respiratory Disease Symptoms with Pulmonary Function


                34
     Neri  et al.    compared the prevalence of chronic bronchitis and results



from respiratory function tests in Ottawa and in Sudbury,  a Canadian smelter



town.   The authors reported that the smelting operation in Sudbury emitted



large quantities of S02 at the time of the study, but that they were far lower



than quantities emitted in former years.   The operation shut down when 24-hour



•ean concentrations of SOp reached 850 ug/m  (0.3 ppm) or  the TSP reached 500



ug/m .  Twenty-two shutdowns occurred during the 2-year study period.   Three-



year mean  values for high-volume TSP and SOp were 93.0 ug/m  and 52.1 ug/m ,

                                                         •}              O
respectively in Sudbury.   In Ottawa, there were 45.8 ug/m   and 90.5 ug/m ,



respectively.



     In Ottawa, the prevalence of chronic respiratory disease and reduced



pulmonary  function values were associated with smoking and age but showed no



relationship to duration of residence.  However, in Sudbury, length of residence



was associated with increased rates of chronic respiratory illness, and living



in Sudbury for any period of time was associated with reduced pulmonary function



In Sudbury, smoking, occupation, and age were associated with the prevalence



of chronic respiratory illness and impaired pulmonary function.  After adjusting



for smoking, age, and occupation, residence in Sudbury was associated with



excess respiratory disease and diminished ventilatory function.  Neri et al.



found that the mean ratio of FVC to FEV for 3280 Ottawa residents in 1969 to



1971 was higher than the mean for 2208 Sudbury residents in 1972-73.  The



difference was significant for both males and females and held true even after



considering age and smoking habits (p <0.001).  The prevalence of chronic



bronchitis also was higher in Sudbury males (p M3.03), but no difference was



found for  females.  Holland et al.301 discussed the effects of the  short-term



high exposures 1n Sudbury, but did not negate the study.
                                  14-189

-------
     Cohen et al.    made a comparison of respiratory symptoms  and  pulmonary
function tests in two similar groups of nearly 2000 nonsmoking adults  each.
They found no indication that either increased symptoms  of chronic lung disease
or impairment of lung function as reflected by spirometry or flow  volume loops
was caused by a twofold difference in peak values of oxidant air pollution,  or
differences between 78 and 124 ug/m  annual average TSP  (annual  mean S02
                                 3
concentrations were about 43 ug/m ).
                      179
     Ramaciotti et al.    determined rates for the occurrence of bronchitis
symptoms in 1182 men in Geneva in relation to the ambient SO^ concentration  at
the site of residence, the number of cigarettes smoked per day,  and age.
Because the prevalence of chronic bronchitis among non-smokers was very low,
these were excluded from the study.   Information on illness symptoms and
demographic factors was collected by means of the BMRC questionnaire and the
aerometric data were collected by the Institut d1Hygiene, Geneva.   The study
covered the period 1972 to 1976 and found 98 cases classified as chronic
bronchitis, 477 classified as having intermediate symptoms, and 637 subjects
were asymptomatic.  Regression analysis (Linder-Berchtold method)  was used to
determine associations.  The adjusted incidence of chronic bronchitis within
the group increased from 2 percent to approximately 20 percent as  the consump-
tion of cigarettes increased from 1 to 50 per day; from  2 percent  to about 16
percent as age increased from 18 to 65 years; and from 4 percent to about 12
percent as annual  mean SCL pollution levels increased from 10 to 60 ug/m .
Similar adjusted rates showed no significant slopes for  the group  with less
severe symptoms (intermediate group).  Peak respiratory  flow (PFR) decreased
from 500 to 470 liters/min on the average as cigarette consumption increased
from 1 to 50 cigarettes per day; from 530 to 40  liters/min as age  increased
                                  14-190

-------
from  18  to  65  years;  and from 500 to 475 liters/min as  annual  S0?  pollution



levels increased  from 20 to 65 pg/m .   Similar relationships were  observed in



the  intermediate  group.   The levels of S02 smoke and NOp observed  1n  the  study



were  positively associated with the prevalence of chronic bronchitis.



     A series  of  studies,  reported on from the early 60s to the »id-70s,



have  been conducted by Ferris, Anderson, and others.   The Initial  study Involved



comparison  of  three areas within a pulp-mill town in northern  New  Hampshire.


                                 41 47
In the original prevalence study,  '   no association was found between question-



naire-determined  symptoms and lung function tests in the three areas  with



differing pollution levels after standardizing for cigarette smoking.   The


                                                                  47
authors  discuss why residence is a limited indicator for exposure.     The



study was extended to compare Berlin, New Hampshire, with the  cleaner city of



Chilliwack, British Columbia in Canada.     Sulfation rates (lead candle method)



and dustfall  rates were higher in Berlin than in Chilliwack.   The  prevalence



of chronic  respiratory disease was greater in Berlin, but the  authors conclude



that this difference  is due to the interaction between age and smoking habits



within the  respective populations.  Higher levels of respiratory function in



some cigarette-smoking groups in the cleaner area were observed, but this



difference  could  be due to socioeconomic and ethnic differences as well as  air


                                                                    248
pollution.   Ethnic differences could have been a confounding factor.      The



S02 level in Berlin,  NH, in 1961, may also be in doubt since it is based on  a


                                312
2 month  period at a single site.



     The Berlin,  New  Hampshire, population was followed up in 1967 and again



in 1973.42'45   During the period between 1961 and 1976, all measured indicators



of air pollution  fell.  In the 1973 follow-up, sulfation rates nearly doubled



from the 1967  level (0.469 to 0.901 mg S03/100 cm2/day) while TSP values fell

                   
-------
             TABLE   14-40.   POLLUTION  LEVELS, BERLIN, NEW HAMPSHIRE,

                          DURING THREE STUDY PERIODS


1961
1966-1967
% decline
1961-1966/67
1973

Total dustfall
gm/m2/30-day
18.4
14.3
22%
--
—

TSP (HV)
ug/m3
180
-131
28%
--
80
Sulfation
(lead peroxide)
mg S03/100 cmVday
0.731
0.469
36%
—
0.901
Sulfation*
converted to
S02 pg/m3
55
37
28%
--
66
*Assuming all  sulfur in  the  form  of  S0?.




       During  the 1961 to  1967  period,  standardized  respiratory  symptoms  rates


  decreased and there was  an indication that  lung  function also  improved.


  Between the  period 1967  to 1973, age-sex standardized  respiratory  symptom


  rates and age-sex-height standardized pulmonary  function levels were  unchanged.


  The authors  conclude that  either the  air pollution change was  not  associated


  with a change in respiratory  health or  that  the  study  was not  sensitive enough


  to detect an effect.   However,  the type of  cigarette smoking may have changed.


  Internal  migration may have been an additional factor.  For these  various


  reasons,  these  studies are difficult  to interpret.247t312,314b

                     16ft
       Bouheys et al.    used the NHLI  questionnaire to  obtain information on


  the prevalence  of  respiratory symptoms  in study  subjects 7 years old  or more


  in an industrial urban and a  rural community in  Connecticut  in 1973.   Annual


  mean TSP  concentrations  had been 88 to  152  pg/m   in the urban  area during  the
314b
                                    14-192

-------
previous 7 years, but similar data were not available for the rural area.   In


1973,  the year of the study, S02 annual concentration was 13.5 ±1.7 and 10.9


±1.6  ug/m ,  respectively, for the urban and the rural area, both low.   Annual


mean-TSP concentrations were 63.1 ±3.7 and 39.5 ±4.2 for the urban and rural


areas, also relatively low.   Means were based on approximately 1 measurement


per week.   Results, adjusted for sex, race, age, smoking, occupation, and


previous residence of the bronchitic symptom of "usual cough and phlegm"


showed significant decreasing gradient from lifetime urban to lifetime rural


among  non-smokers but not among smokers.   Shortness of breath also showed an


association with residence that was most pronounced among non-smoking women


(12.8  percent lifetime rural and 19.2 percent lifetime urban).  However,


asthma occurred more frequently among the rural residents.  Inconsistencies


with indoor exposures were present in the data as well.

                 go
     Irwig et al.   studied relationships between air pollution and respiratory


disease in British schoolchildren.  Information on 1816 children was collected


by self-administered questionnaires.   Positive responses to questions concerning


the occurrence and frequency of respiratory symptoms were associated with results


of pulmonary function testing (PEFR) and the data analyzed by a regression


method specially designed to handle quanta! data.  The air pollution levels


used were the mean smoke and SCL for November, 1973.  Both pollutants were


found  to be significantly associated with a history of colds going to chest


(p <0.05).  Over the range of smoke levels in the analysis (10 to  130 ug/m  ),


it was predicted by the equation that for each increment of 10 ug/m  of smoke


(ignoring S02) 0.77 percent more of the population would have colds  to the


chest.  The authors report that similar results were obtained with S02, ignoring


smoke, but the measured concentrations of S02 (H202 method) were not reported.
                                  14-193

-------
They did conclude that the analysis suggests that dimunition of smoke or SC^



from 130 to 10 ug/m  would result in a decline in prevalence of colds going to



chest of as much as 49 percent in the highest risk group,  and at least 12



percent in the lowest risk group.


                     99
     Kerrebijn et al.   collected data from fourth and fifth grade students on



the relationships between respiratory symptoms or pulmonary function tests and



the concentrations of pollution in areas in which they lived.   Data on respiratory



illness and social and domestic circumstances of the family were obtained by



means of a self-administered questionnaire.  Pulmonary function measurements



for the approximate 2400 children were made over the period of April 2 to June



8, 1973 to correspond with the period of low viral infections and few high air



pollution peak concentrations.  At the time of examination, height and weight



were recorded; peak expiratory flow rate was measured in standing position



with a Wright Peak flow Meter (highest of five readings recorded), forced



vital capacity and forced expiratory volume in 0.75 second were measured in



the sitting position with Lode D-53 watersealed spirometers (the highest of



three values recorded) and the maximum expiratory flow at 50 percent vital



capacity and at 25 percent vital capacity were measured in the standing



position with a Monaghan M402 pulmonary analyzer connected to a rapid recorder.



The Peak Flow Meters were calibrated once a day over their full range with a



Godart calibration set and with standard flows.  All measurements were



corrected to standard flows.   The Monaghan instruments also were calibrated at



their peak flow reading with the Godart set.



     Children living in the high pollution area showed a higher prevalence of



cough during the day or at night.  Ventilatory function tests showed no



differences between the high and low pollution areas.  Depending on the
                                  14-194

-------
criteria  used  to  define chronic  respiratory disease,  prevalence  in  the  high



pollution area was  1.3  to  1.6 times  that in the low pollution  area.   Annual



nean  concentration  of SOp  1n  the low pollution area was  50 ug/m   as a result



of a  change  in fuel  from oil  to  gas  that began only 3 years earlier.  Prior to



the change the annual mean S02 concentration had been equal to that 1n  the



high  pollution area or  150 ug/m   or  higher.   Particulate measured as standard



smoke (BS) was low  in all  areas, usually below 30 ug/m3  for annual  means.



     Biersteker and van Leeuwen    '     reported on pulmonary function measure-



ments and bronchitis histories in 935 elementary schoolchildren  living  in  two



areas of  Rotterdam  with differing air pollution levels.   In a  new suburb,  the


                                        3                           3
winter median  for smoke (BS)  was 40  ug/m ;  that for SOp  was 120  ug/m  (0.04



ppm).  Concentrations of smoke and SO^ in older downtown districts  were about



50 percent higher.   After  adjustments for height, no differences in peak



expiratory flow rates were found for boys or girls.  A history of bronchitis



was more  common in  the  more polluted area;  however, the  differences in  socio-



economic  levels were not controlled  and may have been be a factor in the



difference seen.



     The  results  of the studies  discussed above are summarized in Table l4-40a.



It can be seen there that  various studies have demonstrated pulmonary function



deficits  (as assessed by lung function tests) or chronic respiratory disease



rates to  be  associated  with TSP  and  S02 air levels of approximately 100-200



ug/m  .  Still  others (mainly EPA CHESS studies) have been reported  as indicating



that  such effects may occur at somewhat lower levels; however, questions have



been  raised  regarding the  interpretation of these study results as  discussed



1n the 19^6  Investigative  Report (see also Appendix A).   These include concerns



regarding some of the air  quality measurements reported for TSP, S02, and



suspended sulfate (SS)  levels, the specific nature of which may lead to
                                  14-195

-------
                             TABLE 14-40a
             SUMMARY OF LONG-TERM EXPOSURE STUDIES OF PULMONARY FUNCTION
               DEFICITS AND CHRONIC RESPIRATORY DISEASE
       Type of Study
Reference
Effects observed
Annual average pollutant levels
    at which effect occurred
TSP (|jg/ma)         S02
UD
       Cross-sectional and
        long  (2 areas)
      Cross-sectional
        (2 areas)
        (children)
van der Lende74 77
Improvement in lung function
 accompanying an improvement in
 air quality
   100 BS
 (24-hr avg.)
  (200 TSP)
    300
(24-hr avg.)
Cross-sectional
(3 areas)
Cross-sectional
(4 areas)
Cross-sectional
(2 areas)
(children)
Goldberg et al.109
House et al.108
Kerrebi jn et al . "
Increased chronic respiratory
disease
Increased chronic respiratory
disease
Increased cough, no decreased
pulmonary function*
78-82
70
(15 SS)
low (<30 BS)
(<80 TSP)
69-160
107
150
*(low area > 3 years
ago same, now lower)
Yoshida et al.176
Increased asthma
                       110-120
      Cross-sectional and
       long (2 areas)
Sawicki and
 Lawrence (1977)181
Increased previous CB and
 asthma.   Increased persistence,
 males 31-50.   Increased incidence,
 females, some ages.
     169
    114
      Cross-sectional
       (3 areas) children
Rudnick182
Increased respiratory symptoms      150-227 BS
 in boys.  Increased Rh.  in girls  (240-340 TSP)
                       180-148
Cross-sectional and
retro- long (4 areas)
(children)
Cross-sectional
(2 areas) (children)
Cross-sectional
(3 areas) (children)
Nelson et al.114
Hammer113'257
Shy et al.215
Increased LRD (« residence)
Increased LRD
Decreased adjusted FEV0>75 in
children > 8 years
70
133
(SS=14)
72-82
107
<25
69-160

-------
                                                         TABLE 14-40a  (continued).
Annual average pollutant levels
at which effect occurred
Type of Study
Cross-sectional
(2 areas) (children)
Cross-sectional
(2 areas) (children)
Cross-sectional and
Reference
Shy et al.215
Chapman et al . 213
Neri et al.34 35
Effects observed
Decreased adjusted FEV0>75
Decreased adjusted FEV0<75
Decreased FEV../FVC and increased
CB L
TSP (ug/nr3)
96-114
45 RSP
93 with peaks
S02 (ug/m3)
(= and low)
( = S02 & low)
with higher average
in lower AP areas

I
!-•
to

-------
reinterpretation of those findings suggesting that reported health effects may
be associated with somewhat higher TSP or SO^ levels (i.e., >100 to 150
   »3>.
                                  14-198

-------
14.6 CHAPTER SUMMARY  AND  CONCLUSIONS
14.6.1  Overview  Summary  of  Chapter Contents  -
    In the preceding sections  of  this  chapter,  an  extensive  array  of  information
was discussed concerning:  (1)   methodological considerations that  must  be
taken into account  in evaluating community  health epidemiology studies (Section
14.1); (2)  critical  assessment of practical  applications  of  air quality
measurement techniques employed in the  collection of sulfur oxides  and particulate
matter data utilized  in related community health studies  (Section 14.2); (3)
critical  review of  such studies on mortality  effects associated with acute  and
chronic exposures to  sulfur  oxides and  particulates (Section  14.3); (4)
critical  review of  studies of morbidity associated  with acute exposures  to  the
same pollutants (Section  14.4); and  (5)  critical assessment  of morbidity
effects associated  with chronic exposures to  sulfur oxides and particulate
matter.
    Through the  discussion  in  Section  4.1, it was  seen that  numerous  methodo-
logical factors,  including covarying  or confounding variables, can  potentially
affect the results  and interpretation of community  health studies.   It was
also seen, through  material  summarized  in Section 14.2, that  a number  of
sources of errors have been  identified  as having affected sulfur oxides  and
particulate matter  air quality  measurements obtained in both  the United  Kingdom
and the United States and used  in  British and American epidemiology studies
which provide the bulk of the information reviewed  in this chapter.  It  was
further noted that  while  such errors  in air measurements can  at times  be
fairly large, they  also often act  to  introduce both positive  and negative
biases into air quality data sets  that  tend to cancel each other out,  especially
when considering  data grouped or averaged over long time periods (monthly;
                                   14-199

-------
annually) from the same sites or across several  geographic areas classed as
"low" or "high" pollution areas.  At other times, however, it also became
clear that certain measurement errors were such  as to introduce either
consistently negative or positive bias into particular British or American
sulfur oxides or particulate matter data sets used in various community
epidemiology studies providing information on quantitative air pollution/health
effects relationships.  It was further noted that such biases due to air
quality measurement errors must be taken into account in evaluating such
epidemiology studies -- not for the purpose of discrediting such studies but
rather to understand better the error limits likely associated with the reported
quantitative findings derived from them and to thereby allow for more accurate
interpretation of overall patterns of pertinent  results.
     Turning to the critical assessments of pertinent community health mortality
and morbidity studies contained in Sections 4.3, 4.4 and 4.5, results of many
of the better known and often cited quantitative studies discussed in this
chapter are summarized in Tables 14-41 and 14-42.  More specifically, Table 14-42
summarized chronic exposure study results.  If the results of all the various
studies summarized were accepted as being valid, then certain conclusions
might be drawn regarding air levels of sulfur oxides and particulate levels
associated with mortality or morbidity effects,  as discussed in the next
several chapter overview subsections.
                                   14-200

-------
                                        TABLE 14-41  SUMMARY TABLE - ACUTE EXPOSURE  EFFECTS
fSJ
O
Type of Study
Mortality (episodic)
British
Dutch
Japanese
USA
(Non-episodic)
Reference
Table 14-1
Table 14-2
Table 14-2
Table 14-2
Martin and Bradley11
Martin6
Glasser and
Greenburg222
24- hour average pollutant levels
at which effects appear
Effects observed
Excess deaths
Excess deaths
Excess deaths
Excess deaths
Increases in daily mortality
Increases in daily mortality
above the 15 moving average
Increases in daily mortality
TSP (pg/mj)
546*
300-500
285
570 (5 CoH)
500*
500*
350-450**
S02 (pg/m3)
994
500
1800
400-532
(1 hr max: 2288)
300
400
524

Morbidity

Martin16
Lawther et al. 53
Greenberg et al.196
Lawther et al . 52
Stebbings and
Hayes190
Increases in hospital admissions 500*
for cardiac or respiratory illness
Worsening of health status among
195 bronchitics
Increased cardio- respiratory
ER visits
Increased clinical condition
in CB patients
Increased symptoms in chronic
bronchitis (CB) patients
344* (250 BS)
357** (260 BS)
529* (400 BS)
344* (250-350 BS)
200 (60 RSP)
(12SS) 8 SN)
400
300-500
715
450
300
100

-------
                                                  TABLE 14-41 (continued).

Type of Study Reference
Cohen et al.55
McCarroll et al.163
Cassell et al.208 209
Stebbings and
Fogleman et al.216
24- hour average pollutant levels
at which effects appear
Effects observed
Increased AS attacks
Increased ARI daily
inc/prev
Increased ARI average
daily inc/prev
Decreased FEV0>75 (children)
TSP (Mg/m3)
150 (20SS)
160* (1.2 COM)
205* (2 COM)
700
S02 (Mg/mJ)
200
372
452
300

Converted from BS (British Smoke).

-------
                                          TABLE 14-42  SUMMARY TABLE -  CHRONIC EXPOSURE  EFFECTS
      Type of Study
Reference
                                                                                        Annual  average  pollutant levels
                                                                                            at  which effect occurred
                       Effects observed
                                  TSP
S0
      Mortality (geog.)
Winkelstein188
                       Increased mortality
                                     125-140
not significant
                               Zeidberg and
                                colleagues16-18
                       Increased mortality
                                                             55-60
                                                            30
      Morbidity
      Longitudinal  and
       cross-sectional
Ferris
 et al.41 42
                47
Higher rate of respiratory
 symptoms; and decreased lung
 function
                                                              180
      55
fo
o
      Cross-sectional
       (2 areas)
Sawicki (1972)31
                       More chronic bronchitis,
                        asthmatic disease in smokers;
                        reduced FEV%
                                       250*
     125
      Cross-sectional
       study of school-
       children in 4 areas
Lunn et al.96 97
                       Increased frequency of res-
                        piratory symptoms; decreased
                        lung function in 5-year olds
                                       260*
     190
      Follow-up of school-
       children in 4 areas
Douglas and Waller90
                       Increased lower respiratory
                        tract infection
                                   197*  (130  BS)
     130
      Cross-sectional study
       of children in 4 areas
Hammer et al.214
                       Increased incidence of lower
                        respiratory diseases
                                     85-110
   175-250
      Cross-sectional  study
       of high school
       children in 2 areas
Mostardi and
 colleagues177 258
                       Lower FVC,  FEV0i75  and maximal
                        oxygen consumption
                                     77-109
    96-100
      Cross-sectional
       (multiple areas)
Lambert and Reid28
                       Increased respiratory symptoms
                                   160*  (100  BS)
   100-150
      Cross-sectional
       (3 areas)
Goldberg et al.109     Increased CRD
                                                             78-82
                                                         69-160

-------
                                                      TABLE 14-42 (continued)
Type of
Study Reference Effects observed
Annual average pollutant levels
at which effect occurred
TSP (|jg/m3) S02 ((jg/m3)
Cross-sectional
 (4 areas)
                         House et al.108
                       Increased CRD
                                    70 (15SS)
                      100-150
Cross-sectional
 and Long (2 areas)
Sawicki and
 Lawrence (1977)181
Increased Prev CB and AS
Increased persistance, Males
 31-50; Increased incidence,
 Females, some ages
    169+
                                                                                                         114-130
Cross-sectional
 (3 areas)
Rudnick182
Increased respiratory symptoms
 in boys.  Increased Rh in girls
 221-316*
(150-227 BS)
Cross-sectional
 2 areas (children)
Shy et al.215
 Chapman et al.213
Decreased adjusted FEV>75
96-114 (45 RSP)
                                                                                                         108-148

l-f
1
o
Cross-sectional and
retro- long in 4 areas
(children)
Cross-sectional
2 areas
Cross-sectional
3 areas (children)
Nelson et al.114

Hammer113 257

Shy et al.215
Increased LRD

Increased LRD

Decreased adjusted FEV<75 in
children > 8 years
70

133
(SS=14)
78-82
107

<25

69-160
                                                                                                        (= and low)
 Converted from BS (British Smoke).
**Converted from CoH.

-------
14.6.1.1  Health Effects of Acute Exposure to SCL and Particulate  Matter
     Studies  providing evidence of acute health effects  of sulfur  oxide and
particulate matter are summarized in Table 14-41.   Overall,  various British,
Dutch,  Japanese and American episodic mortality studies  appear to  suggest  that
•ortality effects can occur at or above 300-500 ug/m3 S02-   The three  non-episodic
mortality studies listed in the table suggest that mortality effects can be
seen when TSP levels reach 500 to 600 ug/m  and S02 concentrations reach 300
to 500  ug/m .   These three studies summarize a relatively small body of data
from two winters in London and five winters in New York  City.   The stated
effect  levels may be conservative, however, since examination of the detailed
evidence from these studies presented in Section 14.3 suggests the possibility
of an exposure-response relationship at lower levels of  these pollutants.
More complex  time series studies of daily mortality have also found associations
between mortality and these pollutants at lower levels.   The size  of the
estimated effects has proved to be sensitive to model specification and  choice
of other adjustment variables.  Although the possibility of mortality  effects
of TSP  and SOp levels below those cited in Table 14-41 cannot be excluded, it
is unlikely that this question can be resolved in the near future by observational
studies.  Thus, the minimum air levels at which acute mortality increases
might be projected to be seen would be 300-500 ug/m  for both TSP and SO^,
based on the  studies summarized in Table 14-41.
     Numerous studies reporting morbidity effects associated with acute exposures
are also listed in Table 14-41.  Worsening of symptoms  in bronchitis patients
an£ increased hospital admissions in Britain were reported to  occur at TSP and
SO. levels of 300 or 350 to 500 ug/m3 or more.  A United  States study, however,
found exacerbation of symptoms among bronchitics at  200 ug/m   TSP and 100
jjg/m  SO, and asthmatics were reported to  show  increased  attacks  at 150 ug/m
                                   14- 205

-------
TSP and 200 (jg/m  SOp.   Also, spirometry tests were reported to  show decreases
in lung function at 700 ug/m  TSP and 300 ug/m  SOp.   However, van der Lende
saw improvement in lung function among adults when pollution levels were
                     3                   3
reduced from 245 ug/m  (TSP) and 300 ug/m  (S02).   Acute upper and/or lower
respiratory illness also has been reported to occur at levels as low as at 160
ug/m  TSP (24-hour averages).  Overall, then, the  summarized studies suggest
that (1) very severe morbidity effects, e.g., worsening of symptoms in bronchitic
patients, clearly occur at TSP and SOp levels of approximately 300 or 350 to
500 ug/m , and (2) less severe but significant morbidity effects may occur
                                                           o
with acute exposure at levels of approximately 150-300 ug/m .  These studies  r
do not, however, provide a basis for separately estimating the health effects
of SOp and particulates.  Since these two forms of pollution have important
common sources, their levels tend to usually vary  together over  time.
14.6.1.2  Health Effects of Chronic Exposure to SO- and Particulate Matter
     Mortality and morbidity studies that have been reported as  demonstrating
associations between mortality, illnesses, or decrements in pulmonary function
with annual average levels of particulate matter of SOp are summarized in
Table 14-42.  As seen in that table, the two mortality studies  suggest that
                                                               o
mortality effects can occur at annual levels of 125 to 140 ug/m  or less of
TSP and SOp.  In the morbidity studies, lower respiratory disease, chronic
bronchitis, and reduced pulmonary function results were reported that are
indicative of morbidity effects likely clearly occurring at annual average TSP
                                o
or SOp levels of 150 to 250 ug/m  or more.  Other study results summarized in
the table suggest an association of various morbidity effects with concentrations
                                3
in excess of about 70 to 80 ug/m  TSP and SOp concentration in excess  of  96  to
107 ug/m .  As with studies of acute effects, many of these studies could be
                                   14-206

-------
further interpreted not only as demonstrating that health effects  are
exposure-related but also that they increase as these pollutants  increase  over
the entire range of exposures studied and no clear "no effect"  level can be
determined on the basis of presently available information.   Also, in  general,
these studies cannot be used to distinguish between the effects of sulfur
oxides and particulates.   In several studies, however, TSP effects were reported
to occur in the presence of low or non-significant levels of $Q  188«212»213»215»257
14.6.1.3  Health Effects of Atmospheric Sulfates
     Conversion to sulfate compounds, including sulfuric acid,  has been proposed
as a major pathway by which sulfur dioxide and possible other sulfur compounds
may exert toxic effects.   However, only a few community health studies have
attempted to measure and assess health effects associated with suspended
                                   190
sulfates (SS).  Stebbings and Hays,    for example, reported increased symptoms
in patients with 24-hour averages of 12 ug/m3 SS (200 TSP, 60 RSP, 8  SN, 100
                           212
S02).  Also, Chapman et al.    reported increased chronic respiratory  disease
prevalence rates in a high pollution community with an annual average  of 15
    3                                 257
ug/m  SS (70 TSP and 107 SO^)-  Hammer    further reported increased lower
respiratory disease prevalence rates in a high pollution community with an
annual average of 14 ug/m  SS (133 TSP and SOp >17).  Thus, suspended sulfate
levels of 12 ug/m  (daily) or more and 15 ug/m  (annually) might be interpreted
as being important based on those results.
14.6.1.4  Respirable Particulates Effects
     As discussed in Chapter 11, particles below 15 ug/m  MMAD are important.
Respirable suspended particulates (RSP) £3um,  have been measured  in only a  few
American epidemiology studies, e.g., those by  Hammer,    '    Stebbings  and
Hayes,190 and Shy and Chapman et al.213'215  The latter study was  reported as
                                   14-207

-------
demonstrating decreased adjusted FEV ,,. in children in an area with  higher


pollution with RSP of 45 ug/m3 (96 to 114 ug/m  TSP and S02 very low).   Thus
               o
RSP of 45+ |jg/m  may be important.


14.6.2    METHODOLOGICAL FACTORS IMPACTING INTERPRETATION OF RESULTS


     If it were assumed that all of the results summarized in Tables 14-41 and


14-42 were derived from methodologically sound studies and were universally


accepted as valid, then the above summary of their results could be  accepted


as a reasonable representation of the likely atmospheric particulate and


sulfur oxides levels found to be associated with mortality and morbidity


effects.  However, the matter of the methodological soundness and validity of

various studies has been a matter of considerable controversy and discussion


during the past decade.  Such controversy has derived, in large part, from the


fact that certain additional risk factors can often be as important as the air

pollution variables studied in affecting human health. For example,  in earlier


discussions (Sections 14.1, 14.3, 14.4), it has been strongly emphasized that


smoking is one such factor, as are occupational exposures.  Furthermore, age


and sex co-variables can also be critical in the evaluation of health effects.


Race or ethnic group characteristics likely fall into this category as well.


In addition, numerous social variables may be highly critical in terms of


their existing direct effects on human health, as well as how they may modify


the health effects of environmental pollutants.  Such social factors include


social economic status (income, education, and occupational  levels and associated


social class status), migration, and household characteristics.  Finally,


meterological variables such as sudden temperature changes or shifts in humidity


levels may also be critical co-variables which, along with air  pollutants,


might affect health in a deleterious manner.  Parental  smoking  and  other
                                   14- 208

-------
sources of indoor pollutants may also be critical.   Other less-well  defined
social/ environmental variables, such as a greater  degree of crowding
in housing conditions, too, may represent a set of  "urban factors"  differen-
tially acting to affect health in comparison to "rural" conditions.
     Studies of the episodic effect of pollutants reviewed above usually
considered meterological variables and age as important possible co-variables;
but many essentially ignored other variables as being relatively unimportant.
Studies of urban vs. rural differences in health effects, similarly, have
often not attempted to assess the nature of possible contributing factors
other than the relative differences in concentrations of air pollutants; and
some have demonstrated urban-rural differences in health measurements that are
independent of or unrelated to air pollutant concentrations.  Only relatively
few have been successful in providing reasonably good analyses of results tha*
take such possible confounding urban-rural differences into account.
     For studies of geographical comparison, investigators generally have
attempted to achieve as much homogeneity among populations in different study
areas as possible.  In situations where this is difficult, many have tried to
record measurements of the confounding and co-variables such that they can be
adjusted for in statistical analyses.  In these studies, for instance, it is
usually considered satisfactory to either have equal sex ratios and 10-15 year
age groupings, or otherwise, to analyze results by sex and age.  Essentially
no one would claim that it is necessary to examine age groups defined by one
or two year age intervals.
     In studies of adults, results have either been analyzed by taking
smoking and pollutant levels into account separately,  so that one can determine
any additive effects of smoking and air pollution; or  study groups  that  have
                                   14-209

-------
very similar smoking habits but different pollutant exposures have been compared
On the other hand, in longitudinal studies, it has been necessary to also
measure changes in smoking habits in regard to number of cigarettes, and
whether they are low in tar/nicotine.   Many longitudinal changes «ay be associ-
ated with changes in smoking habits (Ferris et al.; Fletcher et al.).
     Social class, as mentioned before, may affect reports of health outcomes
or the actual health outcomes themselves, and this has often been controlled
for in one form or another, e.g., either through selection of similar social
groups or via statistical analyses techniques.  Some geographical studies have
ignored social class as well as other factors (e.g., Burn and Pemberton),
which makes them difficult to evaluate.  Controlling for social class in
British terms, however, may in effect also adequately control for occupational
differences, although not occupational exposures.   Studies elsewhere more
often used education or income to control for socioeconomic factors, because
such variables are highly correlated with overall  socioeconomic status and
related factors.  For example, smoking and migration are highly correlated
with social class in many countries.  Social class is also correlated with
household characteristics, such as the number in a family, the number of rooms
per house, and crowding (number of people per room).  Exposure to parental
smoking and/or sources of indoor pollution may or may not be critical, as the
relevance of those exposures remain to be more clearly established.  Ethnic
group differences, in some ways similar to social  class differences, may also
be related to physiologic differences, as in  regard to pulmonary functions.
It has usually been easier either to exclude  all but one ethnic group/race
from a given study or to analyze results for  them separately (Mostardi et al.;
Chapman et al.; Hammer et al.; French et al.; Bouhuys et al.).   Failure  to  do
so may have confounded and confused the results derived from certain other
studies.
                                   14- 210

-------
     Also,  some investigations studied only one sex within a specific  occu-
pation group in order to minimize occupational  and social  class  differences
(for example,  British Ministry of Pensions, Burn and Pemberton,  Gervois,
Ipse"n, Bouhuys et a!., Lambert and Reid,  Holland et al.,  Deane et al.,  Fletcher
et al.)-  This  may not always have been sufficient, however, 1n that urban/rural
differences, economic differences, or activity  differences may have still
existed and affected health.  Even so, this approach is generally considered
to be an acceptable way to control for occupational and social class differ-
ences.  Differential specific occupational  exposure conditions,  however,  are
almost never considered in such epidemiological studies.
     Some studies have focussed on children only, generally including children
too young to have started smoking as a means of eliminating this as a possible
important confounding factor.  Many such pediatric studies also  consider
parental factors (including social class),  as well as race, age, sex,  and
urban/rural differences.  Occasionally, past history of illness  was also
considered.  Studies of children also gain the  advantage of being able to
better quantitate life-time air pollution exposure histories.
     In addition to the above considerations, many studies have  recognized
that certain factors, such as education (or social class), may affect health
endpoint reporting levels, and therefore attempted to control for them.
Generally,  controlling for or adjusting for any similar (highly correlated)
factor across study groups has been considered sufficient to help alleviate or
minimize possible differences attributable to reporting artifacts.
     Different migration (self-selective residence) patterns, also, may have
been Important in some studies, especially those of geographical comparisons
or of a longitudinal nature (e.g., the Winklestein, Ferris,  Petrilli, Hammer
et al., French et al., and Neri studies).  Migration patterns and  self-selection
                                   14-211

-------
     In regard to evaluating other (less well-designed) studies,  it should  be
noted that some studies exist which indicate that possible confounding variables
are not always as important as they were originally thought to be.   For example,
follow-up studies on an adult cohort previously studied as children by Douglas
and Waller did not confirm original social  class differences between the
groups to be of much significance in accounting for health findings for the
groups later in life.   Also, Manfreda did not find "urban" characteristics  to
be relevant in explaining his study results, and other studies have shown that
household/familial factors are not necessarily important in all cases in
accounting for observed results.   Therefore, care must also be taken not to
over-emphasize the relative importance of potential confounding or covarying
factors not ruled out as possible alternative explanations for the results  of
a given study.  In other words, being overly critical where information is
lacking to support the likelihood of a specific confounding factor or co-variable
affecting the pattern of results obtained in a study at a particular time
represents as much of a disservice in trying to achieve an objective, balanced
appraisal of study results under discussion as would any countervailing lack
of reasonable regard for the potential importance of such factors.
     It must also be recognized that no single study alone, no matter how
well-designed or conducted in and of itself completely establishes what comes
to be accepted as a "scientific fact" defining either a relationship between
two or more variables studied or a lack thereof.  Rather, excellence in the
design and conduction of a given study, internal consistency  and biological
plausibility of its results, and their consistency with other known  results or
information all help to heighten confidence in the likely existence  of  relation-
ships indicated by that study's results.  Even greater certainty  is  attributed
                                   14-213

-------
to the probable existence of such relationships if further independent studies,
regardless of particular individual flaws, yield results consistent with such
relationships.  Thus, consistency in the overall pattern of results indicative
erf particular relationships or the overall "weight of the evidence" from more
than one study are crucial in establishing given relationships as "scientific
facts" or in determining the degree of certainty ascribed to them.
14.6.3  Quantitative Dose-Response Relationships Defined by Community Health
Studies
     In order to elucidate dose-response relationships established by commun-
ity health epidemiology studies of the type reviewed above, numerous attempts
besides the present one have been made to examine both negative and positive
information concerning such studies.  This has usually been done to determine
which are sufficiently sound methodologically to allow for reasonable conclu-
sions to be drawn from them in evaluating the overall meaning of their results
individually  and collectively.  Such attempts include critical reviews and
                                    O/IC
commentaries written by Rail (1974) ,    Higgins et al. (1974) ,    Goldsmith
and  Friberg (1977), 247 Ferris (1978), 314a and Waller  (1978). 314b  They also
include the following evaluative documents appearing  in 1978:  an American
        Society (ATS) review of Health Effects of Air Pollution (Shy et al. ,
      251
1978);    a National Research Council /National Academy of Sciejice CNRC/NAS)
document on Airborne Parti cles/^ by Higgins and Ferriv(1978)    and an NRC/NAS
document on Sulfur Oxides^ by Speizer and Ferris  (1978)     More  recent  such
reviews and commentary appearing in 1979 include:  the 1979 World  Health
Organization (WHO) document, Environmental Health  (8): Sulfur Oxides
                                 \\9
and Suspended Particulate Matter;     a report by  Holland  et al.  (1979)
written for the American Iron and Steel Institute  and appearing  in the
                                   14-214

-------
American Journal of Epidemiology; and a reply to that report in the same
journal by Shy (1979).      Some of the more salient points of these reviews
and commentaries are concisely highlighted below.
     As will quickly become apparent through the course of the discussion
below, there are certain studies that many reviews consistently rate as being
methodologically sound and their results valid.  Also, when those study results
are viewed together, collectively, fairly consistent patterns of quantitative
relationships emerge regarding exposures to sulfur oxides and particulate
matter associated with the occurence of various types of health effects,
including (1) mortality and-morbidity effects associated with acute exposures
to fairly high ranges of air concentrations of those substances and (2) mor-
bidity effects associated with chronic exposures to lower atmospheric levels
of the same agents.  Given the general concensus that appears to exist regarding
the validity of these studies, then, there seems to exist very good support
for placing considerable confidence in the overall patterns of quantitative
relationships defined by their findings.
      In regard to other reasonably well-designed studies, but for which less
of a  concensus exists regarding their likely validity, several interesting
points emerge from the subsequent discussion.  First, it becomes apparent
that, beyond some small modicum of agreement among the reviews concerning
problems associated with certain studies, the  various reviews often differ
considerably in regard to their assessments of the methodological  soundness or
validity of any given individual study.  This  derives mainly  from  different
reviewers emphasizing or citing different possible confounding or  covarying
factors as potentially being important  in affecting the  results  of a given
study — at least in their respective subjective opinions.   Secondly,  it is
                                    14-215

-------
also notable that very rarely,  if ever, have any of the reviewers presented
actual data or other information, e.g., new or additional  statistical  analyses
of study results, to support their speculations as to what factors might
represent reasonable alternative explanations, besides the air pollution
variables studied, for the observed study results.  Lastly, despite whatever
real or imagined flaws might be associated with the particular individual
studies, a surprisingly great degree of consistency exists both between most
of their results and, also, in comparison with the findings of the other
studies alluded to above as being widely recognized as being valid.  In some
cases, however, the results of some of the supposedly "flawed" studies point
toward still  lower levels of sulfur oxides and particulate matter being asso-
ciated with significant mortality or morbidity effects.  Thus, whereas not as
much confidence can yet be placed in such findings as those from the more
universally accepted studies, it is still not appropriate scientifically to
completely disregard or ignore them.  This is especially true in view of the
fact that, all too often, relationships indicated to exist by "suggestive"
evidence derived from numerous "flawed" studies are later confirmed by more
carefully designed and conducted "definitive" studies.
14.6.3.1  Review Articles and Commentary (1974-1978)--Turning to discussion of
the different reviews and commentaries listed above, Rail published a review
in 1974 on the health effects of sulfur oxides and particulate matter that
examined the then existing scientific information.  Rail's 1974 summary of
studies showing pertinent dose-effects relationships is presented  in Table
14-43.  In addition, Rail drew attention to the then current WHO evaluation
shown in Table 14-44.  In summarizing his evaluation, Rail    stated that
                                   14-216

-------
           TABLE  14-43.
           SUMMARY OF DOSE-RESPONSE RELATIONSHIPS FOR EFFECTS
           OF PARTICLES AND S02 AND HEALTH*
Averaging time
for pollution
measurements Place

Particles,
pg/m3

S02
ug/m3


Effect
24 hr
24 hr
24 hr
Weekly mean

24 hr
Winter mean

Annual
  London
  London
  London
  London

  New York
  Britain

  Britain

  Britain

  Britain
  Britain
  Buffalo
Berlin, N.H.
2000        1144       Mortality
 750         700       Mortality
 300         600       Deterioration of patients
 200         400       Prevalence or incidence of
    h                    respiratory illnesses
   6        1500       Mortality
 100-200     100-200   Incapacity for work from
                         bronchitis
  70          90       Lower respiratory infections
                         in children
 100         100       Upper and lower respiratory
                         infections in children
 100         100       Bronchities prevalence
 100,        100       Prevalence of symptoms
 100a        300^      Respiratory mortality
 180         731       Increased respiratory symptoms
                       Decreased pulmonary function
a"01d" results,  leading to original  standards.

 In coefficient  of haze units (COHS).

cAs ug S02/100 cm /day.
*
 From Rail  (1974)
                                       14-217

-------
              TABLE 14-44.   EXPECTED HEALTH EFFECTS OF AIR POLLUTION
                            ON SELECTED POPULATION*
                     Effect                             Pollutant
          Excess mortality and hospital              500          500
            admissions (24 hr mean)

          Worsening of patients with                250        500-250
            pulmonary disease (24 hr
            mean)

          Respiratory  symptoms (annual              100          100
            arithmetic mean)

          Visibility and/or annoyance                80           80
            (annual geometric mean)

          World Health  Organization
          (WHO) data

*
 From Rail (1974)
                                   14-218

-------
          Disease and death seldom, if ever, result from pollution alone.  They
         are the outcome of many factors, both individual and environmental,
         acting together.  Acute episodes of high air pollution have clearly
         resulted in mortality and morbidity. In addition to these acute
         episodes, pollutants can attain daily levels which have been shown to
         have serious consequences to city dwellers.  There 1s a large and
         increasing body of evidence that significant health effects are pro-
         duced by long-term exposures to air pollutants.  It 1s not possible to
         state a concentration below which such health effects will not occur.

               245
     Rail (1974)    elaborated further on the above points in his review, as
follows:
          Health effects may  range from discomfort through physiological
     deviations from the norm, prevalence of  symptoms, appearance of
     illness,  lost working time, and premature  retirement to complete
     incapacity and death.   In practice, it is  better to consider these
     indices in the reverse  order, starting with death, serious illness,
     and  significant disability, about which  there can be little argument,
     and  to proceed thence to  physiological deviations and minor disorders,
     the  significance of which may be open to question.  Disease and
     death seldom, if ever,  result from pollution alone.  They are the
     outcome of many factors,  both individual and environmental, acting
     together.  Any epidemiological study of  the effects of air pollution
     must allow adequately for these other factors.  Indeed, the quality
     of such studies often depends on the success with which such allowance
     has  been  achieved.  At  the  other end of  the range of health effects,
     the  implication of minor  symptoms and small deviations from some
     physiological or biochemical norm between  persons living in polluted
     and  nonpolluted neighborhoods may be imperfectly known.  Until it
     can  be shown that such  effects predispose to disease, disability,
     or reduced expectation  of life, the weight that should be given to
     them in setting standards will remain a  matter for personal judgment.
         Acute episodes of  high pollution have clearly resulted in
     mortality and morbidity.  Often the effects of high pollutant concen-
     trations  in these episodes  have been combined with other environmental
     features  such as low temperatures or epidemic diseases (influenza)
     which many in themselves  have serious or fatal consequences.  This
     has  sometimes made it difficult to determine to what extent pollution
     and  temperature extremes  are responsible for the effects.  Nevertheless,
     there is  now no longer  any  doubt that high levels of pollution
     sustained for periods of  days can kill.  Those aged 45 and over with
     chronic diseases, particularly of the lungs or heart, seem to be
     predominantly affected.
                                   14-219

-------
          In addition to these acute episodes,  pollutants  can  attain
     daily levels which have been shown to have serious  consequences  to
     city dwellers.   For many years in London,  daily deaths  and illnesses
     were clearly related to daily levels of smoke and SOp.  Comparable
     observations have been made in New York City, Philadelphia,  and
     Chicago.   In the New York - New Jersey Metropolitan area, an analysis
     of daily mortality for the years 1962-66 showed that  deaths  were
     1.5% below expectation at the lowest S02 Concentrations and  2% above
     expectation at concentrations of 500 ug/m  and above.   A  similar
     though weaker relationship was found in Philadelphia  but  not in
     Chicago.
          The implication of daily levels of SOp and particulates has
     been studied in particularly vulnerable groups, such  as patients
     with chronic bronchitis and emphysema.   Deterioration in  their
     respiratory well being has resulted from a daily concentration of
     SOp of about 500 ug/m  which is not much above the  24-hr  primary
     standard.  A few studies have even suggested that deterioration  in
     particularly vulnerable groups may occur with daily concentrations
     which are below this standard.  Confirmation of this  is urgently
     needed."
                                                         245
     In reference to chronic exposure effects Rail (1974)    concluded:

           There is a large and increasing body of evidence  that  signifi-
     cant health effects are produced by long-term exposures to air
     pollutants.  Acute respiratory infections  in children,  chronic
     respiratory diseases in adults, and decreased levels  of ventilatory
     lung function in both children and adults  have been found to be
     related to concentrations of SOp and particulates,  after  apparently
     sufficient allowance has been made for such confounding variable as
     smoking and socioeconomic circumstances.
          It is not possible to state a concentration below which such
     health effects will not occur.  In many studies the proportion of
     persons affected increases from the lowest to highest categories of
     pollution.  Had even lower categories of pollution been used in  the
     analyses, even lower critical levels might have been suggested.
          Thus, as in the case of daily mortality, the concept of no-effect
     level may be a chimera.  A reasonable conclusion from these studies
     would however be that health effects have been found when annual
     levels of particulates or SOp exceed 100 ug/m .

The essential points of these conclusions stated by Rail in 1974 have been

consistently echoed in virtually all of the other major reviews appearing

throughout the remainder of the decade, with few notable exceptions (e.g., the

"Holland Report"   ) discussed later.  Also, a fairly high degree of consistency
                                   14-220

-------
or consensus  among the reviewers can be seen as to what their published opinions



indicate to be reasonable quantitative estimates of sulfur oxides and particulate



matter air concentrations associated with the occurrence of human nortality or



morbidity effects, this overall  consistency emerging despite differences in



opinion regarding the strengths  or weaknesses of any given individual studies.


                                                     248
     For example, in another 1974 review, by Higgins,    there was provided a



dose response table as presented below (Table 14-45).  In the conclusion of



that report,  Higgins states, "Although these are rather inadequate data, it



would perhaps be reasonable to conclude that average annual levels of particulates

                                     3

and S02 should both be under 100 ug/m .  It should further be noted that,



although not  necessarily crucially used in arriving at that conclusion or



listed in Table 14-45, several additional studies were considered by Higgins



to be positive as well: that is, the McCarroll et al., Cassell et al., and



Lebowitz et al. studies; several of Lawther's studies; the Speicer studies,



the Shephard  studies, and the Becker study.  Higgins also pointed out the



relevance of  the Ciocco and Thompson follow-up study, which indicated the



major influence of episodic conditions on the elderly and infirmed.  Higgins


      248
(1974)    went on in his review, however, to speculate that the Fletcher et



al. and Angel et al. studies, showing decreases in signs and symptoms potentially



associated with decreases in air pollution, might be more related to decreases



in tar in British cigarettes (if so, this would presumably also affect many



later studies in Great Britain, including the Waller et al. and Lawther et al.



studies, the  Emerson study, etc.).  The  influence of ethnic differences, he



suggested, might have affected  results from certain  other studies  such as



those by Ferris and Anderson; and usual  inter-city differences were  suggested
                                   14-221

-------
                             TABLE 14-45.  PARTICULATE AND SULFUR DIOXIDE LEVELS AND EFFECTS ON HEALTH*
Averaging time
for pollution
measurements
24 hours








Winter

Annual



Place
London






New York
Chicago

Britain

Britain

Britain
Buffalo
Parti culates
ug/m cons
2000


1000
250

200
6
Not
specified
200

70

100
100
S00 levels
3 ?
|jg/m mg/100 cm -30 days
1000


500
500

250
1500
700

200

90

100
0.30
Effect
Mortality


Mortality
Exacerbations of
bronchitis
Increased absence from
work
Mortality
Exacerbations of
bronchitis
Correlation of
pollutants with
bronchitis incidence
Lower respiratory
infections in children
Bronchitis prevalence
Respiratory mortality
Reference
Scott, (1959)332 „
Gore and Shaddick (1958)° „
Burgress and Shaddick (1959)
Martin (1964)° 7
Waller et al. (1969)'
KQ
Angel et al. (1965)b*
McCarrol and Bradley.Qgee)331
Carnow et al. (1968)1™

Ministry of Pensions
and National-Insur-
ance (1965)
on
Douglas and Waller (1966)™

Lambert and Reid (1970)28
Winkelste1n..st fL, (1967
and 1968)J J>1
*Adapted from Higgins (1974)248 review.

-------
as perhaps influencing certain studies  such as  those by Prindle.   The  lack  of



both smoking and social  status analyses were also noted as  potentially affecting



interpretation of still  other studies,  such as  the one by Burn and Pemberton.


            248
     Higgins    also cited the Winklestein and  Kantor results on  smoking for



White females in areas of Buffalo previously studied by Winkelstein in collecting



data for evaluating air pollution - mortality relationships;  the  later smoking



data appeared to ameliorate criticism regarding the lack of smoking information



in the earlier Winklestein studies.  Higgins went on to discuss studies showing



positive associations with air pollution after  occupation was controlled for;



such as:  Fairbairn and Reid, Cornwall  and Raffle, Holland et al., Deane et



al., Holland and Reid.  Other studies,  Holland  et al., Colley and Holland,



Colley and Reid, in which smoking, residence, family size,  past history of



illness, and occupation were controlled, were also discussed in terms  of the



relevance of these factors in producing chronic lung diseases and SO ASP



health effects.  Certain other studies by Toyama, Watanabe, and Lunn were



noted as showing that declines in disease symptoms or improvements in lung



function might be related to declines in air pollution.  Some difficulties



were noted, however, as complicating the determination of precise levels of



SO  or particulate matter assoicated with the various changes observed.


                                             247
     The Goldsmith and Friberg (1977) review,    although not summarizing



specific estimates of dose-response relationships, did emphasize the positive



findings of certain critical studies deemed to be adequate scientifically,  as



part of an overall review of health effects of air pollution in a book chapter.
             «


Where appropriate, pollutant levels were indicated.  For example, in evaluating



Lawther's53 studies, Goldsmith and Friberg (1977) stated:
                                   14-223

-------
           When two winters  (1959-60 and 1964-65)  were  compared  in  terms

     of the association of exacerbations with  SOp,  the  general  impression

     was of slightly reduced and less consistent effect during  the  latter

     period.   The mean BS concentrations had then  decreased from a  mean

     of 342 ug/m ...to 129...  while SCL  had decreased only from 296 to

     264 ug/m3.
They also further stated in their 1977 review that:

           ...  even during the winter period of 1967-68,  when the daily
     data were treated statistically, a significant  correlation (5%
     level) was found with both smoke and S0?, with  mean  BS concentrations
     of only 68 ug/rn  (sd=48)3and 204 ug/ni  tsd=100) of SO"  (Note that
     the BS level,of 68  ug/m  would be approximately equivalent of
     130-140 ug/nT TSP.)

     Certain studies were also considered by Goldsmith and Friberg (1977) to

be "representative" of the effects of the SO /TPS pollutant complexes on
                                            /\

emplysema, chronic bronchitis, and asthma, including the  following:   the

studies of the Royal College of General Practitioners, Buck and Brown, Toyama;

Nose; Takahashi; Yoshida; Comstock; Deane: Holland;  Deane; Carnow; Spizer;

McCarroll et a!.; Cassell et al.; Lebowitz et al.; Winklestein; and Ishikawa.

Representative studies of the effects of SO /TSP on  asthma were: the studies
                                           f\

of Tokyo, Yokohama asthma, Zeidberg et al., Sim and  Pattle, Peranio, and

several EPA studies.  Additional studies thought to  be worthwhile and pertinent

were those of Martin, Schimmel, Buechley, Lawther et al., Goldsmith, Fletcher,

Holland, Douglas and Waller, Lunn, Holland et al., Colley and Reid, Zaplatel.

                                          314a
     A more recent (1978) review by Ferris     provides both a dose-response

table (14-46) and summary statements about his evaluation of the health

effects of exposure to levels of sulfur oxides and particulate matter.  He

states:
                                   14-224

-------
       TABLE  14-46.   SUMMARY  OF  EFFECTS  OF  SULFUR DIOXIDE  AND  PARTICULATES

                     ON  HUMAN HEALTH -  LONG TERM EFFECTS*
S°23
ug/m
250
130
120
120
98
23
425-50
55
37
66
Suspended
participates
(ppm) ug/m
(0.095) 250a
(0.05) 240a
(0.046) 180a
(0.046) 230a
(0.037)b 93
(0.009) 110
(0.162. -0.019) 195-85
(0.021)b 180
(0.014)b 131
(0.025)b 80
Effects Reference
Increased phlegm 274
production
Increased respira- 181
tory disease
Increased respira- 96,97
tory illness and
decreased pulmonary
function
Increased lower 90
respiratory
illness
Decreased FVC, 177,258
FEV0.75C
Decreased 212
FEV0.75C
Increased lower 214
respiratory _
disease morbidity
Increased respiratory 43
symptoms, decreased
pulmonary function
No effect 43
No effect 46
a                                                89
 Corrected from original  data to TSP equivalents.


 SO- equivalent calculated from lead peroxide data.



 See text for discussion  of results.
 Adapted from Ferris (1978)
                                   14-22ST

-------
           There is not much information with respect to the short term
     effects.  A study by Cohen et al.  on asthmatics indicates an effect
     at a level below present 24 hour standards for SOp and particulates;
     van der Lende noted small reversible changes in pulmonary function.
     The other study where effects have been noted is either above or
     close to the present standard, one showed no effect at levels considerably
     above the standards.  More information is available on the long term
     effects,  and it appears that the present annual averages for SOp and
     particulates are reasonable.   More information is still needed with
     respect to an effect, if any, of higher SOp levels associated with
     low levels of particulates.  Information snould also be obtained to
     develop the standard for fine particles, and in due course to try to
     make a better chemical characterization of the fine and coarse
     particles. The health effects of a considerable fluctuation above a
     mean also need a evaluation.

 For the sake of clarity, it should be noted that the 24-hr standards referred

to by Ferris     for SOp and particulates are 365 and 260 ug/m , repectively;

the present annual average standards for SOp and particulates referred to,
                         3            3
respectively are: 80 ug/m  and 75 ug/m  (annual geometric mean).
            314a                             43
     Ferris      also opined that his studies   may demonstrate certain levels

at which no effects appear to occur.  In addition, the Emerson   study was

noted as possibly yielding information on "no effects" levels. Despite minor

criticisms, the Chapman et al. study and the Mostardi et al. studies were also

considered sufficiently satisfactory to include in the dose-response summary
              314a
of the review.      However, the van der Lende et al. studies, the Cohen et

al. study and the Lawther study were apparently not considered sufficiently

adequate to include in the table, whereas the studies of Goldstein and Block,

Dohan et al. (Ipsen et al.) were considered to be inadequate.

     In the same 1978 issue of JAPCA containing the above Ferris review3143

Waller     discussed the Ferris review.  There, Waller commented on the Lawther
     report, and also stated that British smoke is not more important than

total suspended particulates.   He, too, felt that the Cohen study was weak in

some respects and that the Emerson study was weak, but not a study demonstrating
                                   14-226

-------
"negative"  findings or a "no-effect" level.   He pointed out other results


published by van der Lende in 1975,  which confirmed a later decline in function


with age.   In regard to the Ferris et al. 1973 follow-up study, Waller opined


that the air pollution measurements  were often sporadic and Inappropriate and


that there  may have been a change in smoking habits vis-a-vis filters and/or


low tar/nicotine cigarettes.   In addition, Waller apparently generally felt


that many of the other studies that Ferris utilized in arriving at his


dose-response estimates were not necessarily appropriate or adequate.


14.6.3.2  Major Evaluative Documents (1978)--In regard to the series of major

                                                                      pCl
evaluative documents appearing in 1978, the ATS document by Shy et al.


pointed out several studies considered to be critical in establishing


associations between air pollution and health effects. Besides many of the

                                          295         248            314a
above-mentioned studies alluded to by Rail   , Higgins    and Ferris,     the


Toyama and Watanabe studies, which showed an increase in peak expoloratory


flow rate with declining air pollution, were noted in the ATS report as being


pertinent and important.  The relevance of the WHO conclusions regarding SO™

a^~
&&particulate health effects (see below) was also noted and endorsed in the


ATS document.


     In another 1978 document, the NRC/NAS review on Airborne Particles


prepared by a study group chaired by Ian Higgins, Higgins and Ferris formulated


a dose-response table (14-47), utilizing those studies they felt to  be adequate


and critical.  Studies by Schimmel and bv) Emerson were considered  indicative


of negative levels.  Also, changes in funciton from an early study of Lunn's


to. a later one were used by Higgins and  Ferris to estimate SOp and particulate


levels below which they thought health effects were not occurring.   Certain


positive studies, such as those of Shephard's, although not discounted, were


not utilized in the Higgins and Ferris    dose-response table.
                                   14-227

-------
                                                 TABLE 14-47.   NRC/NATIONAL ACADEMY OF SCIENCES*
                              HEALTH EFFECTS AND DOSE/RESPONSE  RELATIONSHIPS  FOR  PARTICULATES AND SULFUR DIOXIDE
oq
Averaging time
for pollution
measurements

24 hour










Weekly Mean

6 Winter Months
Annual





*
A»J~«.»~..J *«~K UD
Place

London


New York City

Chicago
New York City

Birmingham

New York City
London

Britain
Britain



Buffalo
Berlin
P/UAC A{ _**_...**» n
Particles,
rng/m3

2.00
0.75
0.50
6 COHSa (5)d
3 COHS
Not Stated
0.145 (+?)

0.18-0.22

2.5 COHS
0.20

0.20 (>.l)d
0.07
0.10
0.10

0.08
0.18
1 •*•*+ 4 *•! A*> DAnn«+
S°23
ntg/m

1.04
0.71
0.50(4)d
0.50
0.70
0.70
0.286

0.026

0.52
0.40

0.20 (>.l)d
0.09
0.10
0.12

0.45*
0.73C
307
Effect

Mortality
Mortality
Exacerbation of bronchitis
Mortality
Morbidity
Exacerbations of bronchitis
Increased prevalence of respiratory
symptoms
Increase prevalence of respiratory
symptoms
Mortality
Increased prevalence or incidence of
respiratory illnesses
Bronchitis sickness absence from work
Lower respiratory infection in children
Bronchitis prevalence
Respiratory symptoms and lung function
in children
Mortality
Decreased lung function

References
(Gore et al.8)g
Burgess1et al.
Lawther1J ,,
Lawther et al.
Greenberg et al.,-.
Greenberg et al.
Carnow et al.174
212
Chapman et a1.?14
(Hammer et al. )
Hammer et al.257

Glasser222
69
Angel et al. »74
(Fletcher et al. )
CO
Min. Pensions
90
Douglas and Wallar
Lambert andQBeid^
Lunn et al. >3'

Winklestein et,al.21'188
Ferris et al.

     ^Coefficient of Haze Units.
      mg S0,/cm /SO.days.
     >g S0,/100 cm^/day.
     aas stated in text

-------
     In  summarizing the  dose-responses  relationships  defined  by  the  findings

included in  their dose-response  table  (14-47),  Higgins  and  Ferris  stated that

the table:

          provides estimated concentrations  of particulates  and sulfur
     dioxide that may affect health.   To reiterate, these two pollutants
     nay not be  the most important.  They serve only  as indices  of other,
     perhaps more important, pollutants.   In  London,  mortality has clearly
     resulted when 24-hr smoke concentrations have  exceeded 1.0  mg/m  and
     sulfur  dioxide concentrations have reached 0.750 mg/m  (0.288 ppm).
     These peaks used to occur in London during average annual background
     concentrations of 0.3 to 0.4 mg/m  of smoke and  0.25 to  0.30  mg/m
     (0.1-0.12 ppm) sulfur dioxide.   Such concentrations are  now fortunately
     only of historical  interest.   They should certainly not  be  tolerated.
         ,In London, 24-hr concentrations of  ~0.5 mg/m   of  smoke and 0.4
     mg/m  (0.15 ppm) of sulfur dioxide exacerbated bronchitis.  With the
     present lower concentrations, such exacerbations are infrequent.
     Some correlation stilKexisted when the  average  annual concentration
     of smoke was 0.06 mg/m  and of sulfur dioxide  was  1.70 mg/m  (0.654
     ppm).   Since then,  pollution has  declined further  in London but it
     is not  clear if exacerbations still occur with increases in pollution.
          In Britain, sick leave attributed to bronchitis appeared to
     correlate linearly with winter smoke and sulfur  dioxide  concentrations
     over 0.1 mg/m  (0.038 ppm).  It would be very  interesting to  know if
     similar correlations can still  be demonstrated at  the  present lower
     pollutant concentrations.

It should be clarified that the above noted levels  of0.06 mg/m  and  0.1 mg/m

for smoke concentrations would be approximately equivalent  to 120  and 200

ug/m3 TSP.

     Turning to findings for American cities, Higgins and  Ferris noted that:

           In New York City, 24-hr coefficient of haze  units  (CoHs)  of 5
     or more and sulfur dioxide of 2.0 mg/m  (0.769 ppm) have resulted in
     deaths; 3 CoHs and 0.7 mg/m  (0.269 ppm) sulfur  dioxide  have  caused
     illness.  Studies of daily mortality in relation to pollution suggest
     that-excess deaths may occur when sulfur dioxide is as  low as 0.35
     mg/m  (0.013 ppm).   In Chicago, exacerbations  of bronchitis were3
     associated with daily sulfur dioxide concentrations of 0.75 mg/m
     (0.288 ppm), probably in the presence of high concentrations  of
     particulates.*
          In Buffalo, mortality from respiratory illness appeared to
     increase progressively from the lowest to the highest pollutant
     concentrations.  The lowest level of smoke was <0.08 mg/m  and of
     sulfation, 0.045 mg/cm /day.  A number of other British studies
     suggest that average annual concentrations of particul|te^^and
     sulfur dioxide should both be held to under 0.100 mg/m  .
                                   14-221

-------
     In final  summary,  Higgins  and Fern's     stated:

           There is good evidence  that exceptional  episodes  of  pollution
     (>1.0 mg/m  [0.385 ppm]  sulfur dioxide and particulates) caused
     illness and death.   There  is  also a good deal.of evidence  that
     sustained lower levels of  pollution >0.1 mg/m  (0.039 ppm) of sulfur   **
     dioxide and particulates for  a number of years affect health adversely.
     Pollution predominantly  affects those who are already suffering from
     disease,  particularly of the  heart or lungs;  however, evidence,
     especially from studies  of children,  suggests that pollution can
     initiate disease as well as exacerbate it.   Particulate pollution,
     especially from sulfur compounds, probably plays a considerable role
     in the development and progression of bronchitis and emphysema.
     There have also been suggestions that it plays a role in lung cancer;
     however,  this is much more debatable.
                                                      308
     In another 1978 NRC/NAS  report, on Sulfur Oxides,     Speizer and Ferris

(308) developed graphs (figures 14-5 A and B) to depict estimates of dose

reponse relationships.   In the  process, they had to accept certain studies,

despite their minor limitations.  On the other hand,  certain studies were

excluded in the judgment of the authors because of questions raised about the

adequacy of those studies. Thus,  the studies by Greenburg et al., Goldstein

and Block, and Chiaromonte on acute effects in asthmatics have  been deemed

unacceptable.   The works of Buechley and of Schimmel  were utilized to demonstrate

negative short-term effects below  300^g/m .  Martin's study  of  short term
                                                3                 1
mortality, showing mortality  effects at 277Jxg/m  SOp and 417yw.g/m  BS and

morbidity effects at 340 and  515p.g/m , respectively, of S02 and British

smoke, although discussed as  valid, were not included in the plotting of acute
*Particulate levels expressed as 3 or 5 CoHs units are approximately equivalent
to 350 or 550 ug/m  TSP, respectively.
**TSP and S02 levels of 0.100 mg/m3 = 100 ug/nT
                                   14-230

-------
           300
        n 200
         O
         v>
           100
 \
VI
V*J
                                       |   L2J
                         100          200

                             24-hr TSP, ug/m3
                     300
                                               300
          FIGURE 14-5  A.   Acute dose-response  relationships
          from selected studies.*
                                                                         ui
                                                                         5
                                                                         o
                                            X

                                            5



                                            CM


                                            3
                                            Z
                                            Z
                                                                         O
                                                                         CO
                                               200
                                                                             100
                                                    fj NUMBERS REFER TO SPECIFIC STUDY

                                                    O INDICATES NO EFFECTS     [j[]
    0          100          200           300

         TSP ANNUAL 24-hr GEOMETRIC MEAN, ug/m3


FIGURE 14-5 B.   Chronic dose-response relation-
ships from selected studies.*
                          1.
                          2.
                          3.
                          4.
Lawther et al.
                                            53
van de Lende.at  al
Cohen et?al.
Emerson
          *Speizer,  Ferris,  et al.; NRC/NAS
                                            308
                    74
6.
7.
8.
9.
10.
11.
12.
13.
14.
Fletcher et al.274 ,01
1 Hi
Sawicki andQLawrence
Lunn et al. '97
Douglas and Waller
Ferris et al..::
Ferris et al.
Mostardi and Mattel!
Hammer et al. *
f 1 ?
Chapman et al.

-------
dose-response estimates shown in Figure 14-5A.   The work of Stebbings et al.
in the Pittsburgh episode was excluded because of a lack of prior baseline
                                         308
information.  Overall, Speizer and Ferris    concluded that short term exposure
effects occur above 300 micrograms/cubic meter of both S02 and TSP, although
the data used by them to plot dose-response relationships likely demonstrate
some effects at 200 - 230 pg/m .
                                                    308
     In terms of chronic effects, Speizer and Ferris    excluded the work of
Mostardi and Leonard because of small sample size and lack of sufficient
smoking information, even though a later study of a similar group showed that
smoking was not a significant factor.  (Mostardi's study showed effects at
levels of S02 96-100 pg/m3 and levels of TSP of 77-109 ug/m3).  Overall, it
              308
was concluded,    for chronic exposures, that annual mean 24-hour exposures
                                                        o
somewhat above the current S02 primary standard (75 jjg/m ) are associated with
increased morbidity.
     In regard to possible effects of suspended sulfates, results of studies
by Winklestein did not appear to be sufficiently clearly presented to allow
conclusions to be drawn.  Also, other studies from the EPA CHESS Program were
not considered, e.g. Chapman et al., and Hammer et al..  Thus, Speizer and
      308
Ferris    did not feel that they could draw meaningful conclusions about the
effects of  suspended sulfates.
     The World Health Organization in 1979 published a report on Environmental
Health Criteria for Sulfur Dioxides and Suspended Particulate Matter.  They
formulated  dose response relations for short term exposures (Table 14-48), for
long term exposures (Table 14-49), and have published tables  on the  expected
effects of  air pollutants on health in selected segments of the population in
terms of both short term exposures and long term exposures (Tables 14-50 and
14-51).  The tables themselves provide indication of the studies that the
                                   14-232

-------
   TABLE  14-48.   EXPOSURE-EFFECT  RELATIONSHIPS  OF  SULFUR  DIOXIDE,  SMOKE; AND TOTAL
              SUSPENDED  PARTICULATES:   EFFECTS OF SHORT-TERM  EXPOSURES*
    Concentration
     24-h mean
    values
Sulfur dioxide     Smoke
              Total
            suspended
           particulates
               Effects
     >1000
>1000
       710
       500
  750
  500
       500
       500
  250
       300
       200e
  140
               150L
London,  1952.   Very large increase
 in mortality to about 3 times normal,
 during 5-day fog.   Pollution figures
 represent means for whole area:
 maximum (central site) sulfur dioxide
 3700 ug/m ,  smoke 4500 ug/m
            (Ministry of Health,  UKt 1954)

London,  1958-59.  Increases in daily
 mortality up to about 1.25 times
 expected value (Lawther, 1963; Martin
 & Bradley, 1960).

London,  1958-60.  Increases in daily
 mortality (as above) and increases in
 hospital admissions, becoming evident
 when pollution levels shown were
 exceeded (magnitude increasing steadily
 with pollution) (Martin, 1964).

New York 1962-66.  Mortality correlated
 with pollution: 2% excess at level
 shown (Buechley, 1973).

London,  1954-68.  Increases in
 illness score by diary technique
 among bronchitic patients seen above
 pollution levels shown (means for
 whole area) (Lawther et al., 1970).

Vlaardingen, Netherlands, 1969-72.
 Temporary decrease in ventilatory
 function (Van der Lende et al.,  1975).

Cumberland, WV, USA.  Increased
 asthma attack rate among small
 group of patients, when pollu-
 tion levels shown were exceeded
 (Cohen et al., 1972).
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.

            method.
                                                                          312
 High volume sampling method.
Other measurements by Organization for Economic Cooperation and Development or
 British daily smoke/sulfur dioxide methods (Ministry of Technology, UK, 1966)
 Organization  for  Economic  Cooperation and Development, 1965).
                                       14-233

-------
    TABLE 14-49.   EXPOSURE-EFFECT RELATIONSHIPS OF SULFUR DIOXIDE,  SMOKE,  AND TOTAL
              SUSPENDED PARTICULATES:   EFFECTS OF LONG-TERM EXPOSURES*
   -Concentration
      24-h mean
    values (ug/m3)
Sulfur dioxide    Smoke
            Total
          suspended
         particulates
               Effects
       200
200
       150
       125
       1401
        60-140C
                                 1801
170
1401
           100-200°
Sheffield, England.   Increased
 respiratory illnesses in children
 (Lunn et al., 1967, 1970)

Berlin, NH, USA.   Increased respiratory
 symptoms, decreased respiratory func-
 tion in adults (Ferris et al., 1973)

England & Wales.   Increased respiratory
 symptoms in children (Colley & Reid,
 1970).

Cracow, Poland.  Increased respiratory
 symptoms in adults (Sawicki, 1972).

Great Britain.  Increased lower respira-
 tory tract illnesses in children (Douglas
 & Waller, 1966).

Tokyo.  Increased respiratory symptoms
 in adults (Suzuki & Hitosugi, unpublished
 data, 1970).
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.312
 Automatic conductimetric method.

 High volume sampler (2-month mean, possible underestimation of annual mean).

cLight-scattering method, results  not directly comparable with others.

 Estimates based on observations after end of study; probable underestimation
 of exposures in early years of study.

Other measurements by Organization for Economic Cooperation and Development or
 British daily smoke/sulfur dioxide methods (Ministry of Technology, UK, 1966;
 Organization for Economic Cooperation and Development, 1965).
                                      14-234

-------
     TABLE 14-50.   EXPECTED EFFECTS OF AIR POLLUTANTS ON HEALTH IN SELECTED
         SEGMENTS OF THE POPULATION:   EFFECTS OF SHORT-TERM EXPOSURES**
                                        24-h mean concentration (ug/m )
Expected effects                         Sulfur dioxide         Smoke


Excess mortality among the elderly              500              500
 or the chronically sick

Worsening of the condition of patients          250              250
 with existing respiratory disease


Concentrations of sulfur dioxide and smoke as measured by OECD or British
 daily smoke/sulfur dioxide method (Ministry of Technology, UK, 1966;
 Organization for Economic Cooperation and Development, 1965).   These
 values may have to be adjusted in terms of measurements made by other
 procedures.                                                              212
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.
                                    14-235

-------
     TABLE 14-51.   EXPECTED EFFECTS OF AIR POLLUTANTS ON HEALTH IN SELECTED
         SEGMENTS OF THE POPULATION:   EFFECTS OF LONG-TERM EXPOSURES3*
                                       Annual  mean concentration (pg/m )
Expected effects                         Sulfur dioxide         Smoke


Increased respiratory symptoms                  100              100
 among samples of the general
 population (adults and children)
 and increased frequencies of
 respiratory illnesses among
 children


Concentrations of sulfur dioxide and smoke as measured by OECD or British
 daily smoke/sulfur dioxide method (Ministry of Technology, UK, 1966;
 Organization for Economic Cooperation and Development, 1965).   These values
 may have to be adjusted in terms of measurements made by other procedures.,?
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.
                                   14-236

-------
             TABLE 14-52.   GUIDELINES FOR EXPOSURE LIMITS CONSISTENT
                    WITH THE PROTECTION OF PUBLIC HEALTH8'*
                                              Concentration (ug/m )
Expected effects                         Sulfur dioxide         Smoke


24-h mean                                    100-150          100-150

Annual  arithmetic mean                        40-60            40-60


aVa1ues for sulfur dioxide and smoke as measured by OECD or British daily
 smoke/sulfur dioxide method (Ministry of Technology, UK, 1966; Organization
 for Economic Cooperation and Development, 1965).  Adjustments may be necessary
 where measurements are made by other methods.  For example, smoke concentrations
 of 100-150 pg/m  convert to approximately 200-300 po/m  TSP and smoke levels
 of 40-60-jug/m  convert to approximately 80-120 ug/m  TSP.
*From    -31*
                                    14-237

-------
the WHO felt were relevant in these dose response determinations.   In addition,

                                    312
the guidelines arrived at by the WHO    for protection of public health are


shown in Figure 14-52.
            •J-l O
     The WHO    report also comments on several additional studies which they


felt were positive; the study published by Watanabe in 1966, show that 20%


increase in mortality at 200 |jg/m3 S02 and 1000 ug/m3 of TSP (24 hours). The


Yoshida study showed effects with weekly S02 above 140 pg/m  (no TSP or &S). A


study by Toyama et al. published in 1966 shows prevalence of respiratory


symptoms in males (ages 40 to 59) adjusted for age and smoking in areas with


S0? concentrations of less than 30 pg/m  and TSP less than 106-341 pg/m .


Tani (1975) reported a study around a pulp mill (compared to a controlled


area) which showed a consistent increase with prevalence of bronchitis with

                              2                                  3
sulfation rates of 1.2gm/100cm  per day (approximately 48-96 pg/m  SO^)-  In


their report, WHO points out that they think that the Cohen et al. study of


asthma was positive.  They also commented that the Lambert and Reid study did


control for social status as well as smoking, such that one can assume that


there were not likely to be further confounding factors in that study.  In


regard to the Ferris  study in 1962, the report questions the air pollution


measures and  indicates they were also limited to S0? reading in the 1973


survey.  The WHO report also questions the health index used by Lawther et  al.


in their series of studies extending from 1954 to 1968.  In regard to  the


Waller report of 1971, they felt that discrimination between effects  of pollution

                                                      •3-10
and those of adverse weather was poor.  The WHO report    presented further


information on sensory and reflex function resulting from short-term  exposures


to H2$04, and S02 and exposures of H,,SO. and S02 combined.  The review indicates


that a physiological  response occurs at short-term H^SO. concentrations of
                                   14-238

-------
                    g
from 400 to 730 ug/m  and short-term SO- concentration of from 600 to 2800
ug/m .   When concentrations of fr^SO^ and SO^ are combined, however, the same
effects occur for H2$04 at concentrations ranging from 150 to 600- ug/m3 and
S6p at concentrations ranging from 250 to 1200 ug/m .
     Other recent evaluations of dose-response relationships 1n a review by
           304
Ware et al.    are summarized in Tables 14-53 and 14-54.   Many of the same
studies accepted by WHO and others in earlier reviews are taken by Ware et al.
(1980) to be valid and to demonstrate health effects of the levels listed in
the two tables.   Certain other findings were also thought to indicate a possible
lack of effect at the levels studies, including specifically Emerson's, possibly
Ipsen's, and possibly SchimmeVs results.  Ware et al.    also discussed
Bennett's interpretation of the Waller and the Lawther data concerning the
decline of symptoms in bronchitis with declining air pollution, without however
                                             They
clarifying the bases of that interpretation.   /  also considered certain
studies of acute asthma (Derrick, Goldstein et al., Glasser et al.) as being
essentially negative.  They did not think that the initial Stebbings studies
of the 1975 Pittsburgh episode could be utilized, since pre-episodic lung
function data were not obtained as a comparison baseline.  However, a  later
Stebbings article in which post-episodic function was examined and "sensitive"
individuals were examined did not seem to be considered.   They also did not
                                     Sawicki
appear to consider the later study of    /    , although earlier studies were
included in their dose response table, and the study by Hammer in the  Southeastern
United States was not mentioned.  The Cohen et al. study of asthma was considered
weak, for unclearly specified reasons.  Morbidity during episodes was  examined,
but not included in the table (Shrenk, Ministry of Pensions and  Health, Fry)
and a few other studies were examined.  Overall, though, despite some  of  the
                                   14-239

-------
             TABLE  14-53.   SUMMARY OF EVIDENCE FOR HEALTH EFFECTS  OF  ACUTE  EXPOSURE TO  S02  AND  PARTICULATES
i
ro
Type of study Reference
Mortality Martin
and Bradley
Martin16
Glasser and
222
Greenburg
Morbidity Martin16
Lawt ber-
et al.
74
Van der Lende
24- hour average
pollutant levels at
Effects observed which effects appear

Increases in daily total
mortality above the 15
moving average

Increases in hospital
admissions for cardiac
or respiratory illness
Worsening of health status
among 195 bronchi tics
Improvement in lung function
accompanying an improvement
in air quality
500 ug/m3 (TSP)
300 ug/m (S02)
500 ug/m3 (TSP)
400 ug/m3 (S02)
580 ug/m3 (TSP)
780 ug/m3 (S02)
500 ug/m3 (TSP)
400 ug/m3 (S02)
312 ug/m3 (TSP)
500 ug/ni (S02)
245 ug/m3 (TSP)
300 ug/m3 (S02)


-------
             TABLE 14-52.   GUIDELINES FOR EXPOSURE LIMITS CONSISTENT
                    WITH THE PROTECTION OF PUBLIC HEALTH8'*
                                              Concentration (pg/m )
Expected effects                         Sulfur dioxide         Smoke


24-h mean                                    100-150          100-150

Annual  arithmetic mean                        40-60            40-60


aVa1ues for sulfur dioxide and smoke as measured by OECD or British daily
 smoke/sulfur dioxide method (Ministry of Technology, UK, 1966; Organization
 for Economic Cooperation and Development, 1965).  Adjustments may be necessary
 where measurements are made by other methods.  For example, smoko concentration;
 .^-100-150 pg/m  convert te-appTOTTmiPEe^-gaQ^^nn |ig/m-TSP and-smoke levels—
 &f 40-OO.aj'q/m—convert to appruximaLely 80-120 py/m
*From WHO l
                                    14-237

-------
the WHO felt were relevant in these dose response determinations.   In addition,
                                    312
the guidelines arrived at by the WHO    for protection of public health are
shown in Figure 14-52.
            OT O
     The WHO    report also comments on several additional studies which they
felt were positive; the study published by Watanabe in 1966, show that 20%
                                 3                  3
increase in mortality at 200 ug/m  S02 and 1000 ug/m  of TSP (24 hours). The
                                                           3
Yoshida study showed effects with weekly S02 above 140 |jg/m  (no TSP or &S). A
study by Toyama et al. published in 1966 shows prevalence of respiratory
symptoms in males (ages 40 to 59) adjusted for age and smoking in areas with
                                       3                               3
SOp concentrations of less than 30 ug/m  and TSP less than 106-341 ug/m .
Tani (1975) reported a study around a pulp mill (compared to a controlled
area) which showed a consistent increase with prevalence of bronchitis with
                              2                                  3
sulfation rates of 1.2gm/100cm  per day (approximately 48-96 ug/m  SOp).  In
their report, WHO points out that they think that the Cohen et al. study of
asthma was positive.  They also commented that the Lambert and Reid study did
control for social status as well as smoking, such that one can assume that
there were not likely to be further confounding factors in that study.  In
regard to the Ferris study in 1962, the report questions the air pollution
measures and  indicates they were also  limited to S0? reading in the 1973
survey.  The WHO report also questions the health index used by Lawther et  al.
in their series of studies extending from 1954 to 1968.  In regard to the
Waller report of 1971, they felt that discrimination between effects of pollution
                                                      312
and those of adverse weather was poor.  The WHO report    presented further
information on sensory and reflex function resulting from short-term exposures
to HpSO^, and SO,, and exposures of H,,S04 and SO^ combined.  The review  indicates
that a physiological response occurs at short-term HpSO. concentrations of
                                   14-238

-------
from 400 to 730 ug/m  and short-term SO- concentration of from 600 to 2800

ug/m .   When concentrations of H2$04 and S02 are combined, however, the same

effects occur for H2$04 at concentrations ranging from 150 to 600- ug/m3 and

S02 at concentrations ranging from 250 to 1200 ug/m .

     Other recent evaluations of dose-response relationships 1n a review by
           304
Ware et al.    are summarized in Tables 14-53 and 14-54.   Many of the same

studies accepted by WHO and others in earlier reviews are taken by Ware et al.

(1980) to be valid and to demonstrate health effects of the levels listed in

the two tables.   Certain other findings were also thought to indicate a possible

lack of effect at the levels studies, including specifically Emerson's, possibly
                                                      O f\/(
Ipsen's, and possibly Schimmel's results.  Ware et al.     also discussed

Bennett's interpretation of the Waller and the Lawther data concerning the

decline of symptoms in bronchitis with declining air pollution, without however
                                             They
clarifying the bases of that interpretation.   /  also considered certain

studies of acute asthma (Derrick, Goldstein et al., Glasser et al.) as being

essentially negative.  They did not think that the initial Stebbings studies

of the 1975 Pittsburgh episode could be utilized, since pre-episodic lung

function data were not obtained as a comparison baseline.  However, a later

Stebbings article in which post-episodic function was examined and "sensitive"

individuals were examined did not seem to be considered.   They also did not
                                     Stwicki
appear to consider the later study of   /   , although earlier studies were

included in their dose response table, and the study by Hammer in the Southeastern

United States was not mentioned.  The Cohen et al. study of asthma was considered

weak, for unclearly specified reasons.  Morbidity during episodes was examined,

but not included in the table (Shrenk, Ministry of Pensions and  Health, Fry)

and a few other studies were examined.  Overall, though, despite some of the
                                   14-239

-------
             TABLE  14-53.   SUMMARY OF EVIDENCE FOR HEALTH  EFFECTS  OF  ACUTE  EXPOSURE TO  S0? AND  PARTICULATES
ro
Type of study Reference
Mortality Martin ....
and Bradley
Martin16
Glasser and
222
Greenburg
Morbidity Martin16
Lawther,
et al.
74
Van der Lende
24- hour average
pollutant levels at
Effects observed which effects appear

Increases in daily total
mortality above the 15
moving average

Increases in hospital
admissions for cardiac
or respiratory illness
Worsening of health status
among 195 bronchi tics
Improvement in lung function
accompanying an improvement
in air quality
500 ug/m3 (TSP)
300 ug/nT (S02)
500 |jg/m3 (TSP)
400 ug/m3 (S0£)
580 ug/m3 (TSP)
780 ug/m3 (S02)
500 ug/m3 (TSP)
400 ug/m3 (S02)
312 ug/m3 (TSP)
500 ug/rn (S02)
245 ug/m3 (TSP)
300 ug/m3 (S02)

-------
                                TABLE 14-54.  SUMMARY OF EVIDENCE FOR HEALTH EFFECTS OF  CHRONIC
                                          EXPOSURE TO S02 AND PARTICULATE MATTER
 I
f\3
-pi
Type of study Reference
Longitudinal Ferris. ,_ ,.- ...
j 4 42 4o 4/
and et al . ' ' '
Cross-Sectional
Cross-Sectional Sawicki
(2 areas)
nc n~j
Cross-Sectional Lunn et al. '
study of school
children in
4 areas
Fol low-Up of Douglagnand
school children Waller
in 4 areas
214
Cross-Sectional Hammer et al.
study of
children in
4 areas
Cross-Sectional Mostardi and fi7
study of high colleagues '
school
children in
2 areas
Annual
Effects observed at
Higher rate of respiratory
symptoms; and decreased
lung function
More chronic bronchitis, asthmatic
disease in smokers; reduced FEV%
Increased frequency of respiratory
symptoms; decreased lung function
in five-year-olds
Increased lower respiratory tract
infection
Increased incidence of lower
respiratory diseases
Lower FVC, FeVnyc and maximal
oxygen consumption
average pollutant levels
which effects occurred
180 ug/m3 (TSP)
55 ug/m (S02)
250 ug/m3, (TSP)
125 ug/nT (S02)
260 ug/m3 (TSP)
190 ug/m (S02)
230 ug/m3, (TSP)
130 ug/rn (S02)
85-110 ug/«3 (TSP)
175-250 ug/"T (S02)
77-109 ug/m3 (TSP)
96-100 ug/n» (S02)

-------
above nuances of their evaluation that might differ from some of the

evaluations contained in earlier reviews,  their assessment appeared to agree

fairly well with those of others regarding studies accepted as being valid and

their interpretation.

     One additional recently appearing review remains to be discussed, the

report by Holland et al.    published in November, 1979.   That published

review was based on a more extensive report commissioned by certain American

industrial interest groups (the American Iron and Steel  Institute and member

steel companies) to be written for the purpose of reappraising epidemiologic

and other scientific evidence bearing on criteria underlying United States

National Ambient Air Quality Standards (NAAQS) for particulate matter.

     More specifically, the following was  stated at the  outset of the 1979

           301
publication    by Holland and colleagues:

     The aim of this review is to consider available epidemiologic evi-
     dence on the health effects of particulate pollution, and to examine,
     in the light of this evidence, criteria for setting standards for
     levels of suspended particulate matter in the atmosphere.

Elaborating further on their intent, Holland et al.  ' opened the final dis-

cussion of their "Conclusions" with the following statements:

     Our purpose in this report, in which  for ease of comparison we have
     followed the format of the Criteria Document, has been to assess
     the epidemiologic evidence for the effects of suspended particulates
     in the presence of other air pollutants on various  aspects of health,
     and to critically analyze the basis for setting standards for levels
     of suspended particulate.

     Close examination and critical assessment of the Holland et al.  (1979)

published review reveals that one of its most outstanding features is notable

divergence of certain of their evaluations and conclusions from scientific

appraisals of the same subject matter by other equally prominent and  know-

ledgeable international experts.  This not only includes divergence from
                                   14-242

-------
evaluations and conclusions contained in reviews by Rail, Higgins, Goldsmith

and Friberg, and Ferris published in the 1974 to 1978 period, but also marked

divergence on certain key points from the more recent appraisals contained in

the ATS, NRC/NAS, atid WHO documents published within the past two years (1978-79)

     One point of partial agreement between Holland et al.301 and the pub-

lished views of other experts concerns levels of sulfur oxides and particulate

matter capable of inducing mortality.  Holland and colleagues concluded that

     increases in deaths were discernable when smoke exceeded something
     in the range of 500-800 ug/m  (as 24-hour averages by smoke (BS) or
     equivalent method) together with sulfur dioxide of more than 700-
     1000 ug/m  (24-hour average).

This can be compared with roughly comparable conclusions by some other

evaluators and the levels of 500 ug/m  for both BS and S0? concluded by

   312
WHO    to be associated with acute mortality effects.   However, the studies

of McCarroll and of Greenberg et al.  in New York were the only ones outside

of Britain considered by Holland et al.,    Dutch, Japanese, and other U.S.

studies suggesting possible mortality effects at particulate levels below

500 ug/m  were largely ignored by Holland et al .

     Similarly, in their summary table for studies of acute morbidity related

to short term pollution exposure Holland et al.    ignore all but British
studies and accept only a few of those as being valid.  Holland et al., further

did not mention acute or chronic  pulmonary function changes in discussing

the basis for their conclusions to the effect that the evidence reviewed by

them "does not substantiate any level of air pollution below 250 ug/m  , smoke

(BS) as a 24-hour average, as having a harmful effect on health."  Holland

et al.     also stated:  "There is no scientifically acceptable evidence...

which can implicate a level at which mortality is associated with long term
                                   14-243

-------
exposure to SO /TSP."  This is in contrast to several other reviews citing



certain studies as showing such effects.   In addition, it is asserted by



Holland et al. (1979)    that no scientifically valid epidemiology studies



exist by which to establish associations between health effects and long-



term (annual average) exposures to sulfur oxides or particulate matter.



This is, of course, at variance with all  of the published expert views



summarized above.  Importantly, it should be noted that Holland et al.



did not exclude all studies on the basis of scientific merit, but excluded



many as somehow simply being irrelevant (e.g., Neri eft al.) or completely



ignored others yielding results not supporting their conclusions.  Further-



more, they failed to discuss or note many countervailing opinions existing



in the literature, eg., those expressed in the reviews by Rail, Goldsmith



and Friberg,  Shy et al., Higgins, Ferris, NAS, and WHO discussed above.



Figure 14-8 illustrates some of the striking differences between evaluations



of various key studies by Holland et al.     in comparison to those by WHO


      312
(1979)    or  other reviews such as the present EPA (1980) assessment.


                                                        301
     In view  of the divergence of various Holland Report    evaluations and



conclusions from those of other published expert reviews, it is not surprising



that the Report    has not been universally well received or accepted as a



scientifically objective or accurate reappraisal of the evidence regarding



the health effects of particulate pollution.  Thus, for example, commentary



critical of the appraisal by Holland et al.     appeared in the next issue of



the publishing journal.  In that commentary on the Holland et al. review,



Shy    states that Holland Report    comments fall into three categories:
                                   14-244

-------
 1000
 •w
 900
 700
 too
o

u.
 400
 JOO
 200
 100
| OSAKA (19621? I
IPA (mOirj'vP*-
X


1 ^HOLLAND, ET AL (1976) | j
_^
^©HOLLAND. ET AL (1979)
mtf'/ tf°
~~ EPA (1980)0' C' —



-ACUTE MORTALITY
ROTTERDAM (1960 •)•
EPA (1980)/
LONDON (19S"0-66f£J" ^
ACUTE MORBIDITY *

^HOLLAND. ET AL (1979) —
X
X
,^y
/
D WHO (1979) __

ACUTE MORTALITY
LONDON C1KMCU* O MARTIN. ET AL. (1960*4, - LONDON



_ LONDON B NETHERLANDS (1969-721
NEW YORK CITYH (1964-65) /
(1960-70) LJ '
© GLASSER & GREENBURG (1971) - NYC
C APLING. ET AL, WALLER (1977-78) LONDON
• OTHER STUDIES
ACUTE MORBIDITY _
Q LAWTHER (1970) - LONDON 1950-1975
B VAN DER LENDE (1975) - NETHERLANDS
CHRONIC MORBIDITY ^~ - ~! C COHEN. ET AL (19721 WEST VIRGINIA
WEST ^ SHEFF IE -ai963^^HOLLAND. ET AL (1979) | OTHER STUDIES
— VIRGINIA n ^ _ ~~ ' —
(1969) ^ WHO • FRANCE (1973)
(1979) 1
I
I
UK (1946-66) A WHO (1979) (
CHICAGO (19721 y CRACOW (1968-73)
	 -T- — | v (
TOKYO (1970)T 1 1 I
* ! 1
BERLIN, NH (1967-73)^ WHO (1979) j
I |
|r SOUTHEAST U.S.A. (196&71) J ]
CHRONIC MORBIDITY
A LUNN, ET AL (1967. 1970) • SHEFFIELD. UK
A DOUGLAS* WALLER (1966) -UK
/\ FERRIS, ET AL (1973. 1976) - BERLIN. NH
y SAWICKI (1972) - CRACOW. POLAND —
Y OTHER STUDIES

(III
         100
                 200
                          300
                                  400
                                          500
                                                  600
                                                          700
                                                                  too
                                                                          900
                                                                                  1000
                              TOTAL SUSPENDED PAHTICULATES.
    Figure 14-8.
Comparison of interpretations-of studies evaluated by Holland
et al. (1979), U1 WHO  (l§^)3no   or other reviews such as those
in the NRC/NAS documents    '     and the present chapter.  Aside
from the British studies  noted  for London and Sheffield.and the
1960-64 New Youk City  mortality  study,  Holland et al.    either
ignored the other studies shown  or evaluated them as being in-
valid based on methodological flaws or  reinterpretation of their
findings.  "OTHER STUDIES"  not  specifically identified in the
above key include those reported by:  Gervois et al.-,.-Ta-France
(1973); Martinlb D London £1958-60);  Mostardi et al.  '*"  V
Chicago (1972); Hammer11"5'"7 V  Southeast USA (1969-71);
Suzuki and-bitosugi V  Tokyo (1970).   The dashed lines depict
 HO (1979)    conclusions regarding SOp and particulate levels
associated with acute  (24-hr) mortality, acute morbidity, and
chronic (annual) morbidity.
                                        14-245

-------
     1) a low level  of criticism of negative studies;  2)  a high level  of

     criticism of roost positive studies;  3)  a polemical,  often broad-brushed

     criticism of  EPA  Studies.


                                      31 ^
In regard to the negative studies,  Shy    further notes:   "the possibility of



systematic measurement errors or of confounding,  that  may have biased the



results toward the null hypothesis  of no  effect,  is not addressed..."  Shy



also states that it appears that Holland  et  al.     rejected positive studies



if there were any possible confounder, even  if they lacked evidence that the



potential confounder was indeed differentially distributed between exposed and



referent populations.   Shy    provides a  table (Table  14-55) listing comments



by Holland et al. regarding certain studies, as well as his own rebuttal



remarks, and questions whether the  Holland et al.  group adequately addressed



the concepts of sensitive populations groups, appropriate margins of safety,



or other considerations relevant to a determination of health effects criteria



in their discussion of dose-response relationships.



     It should also be noted that the Holland Report,     while in press, was



submitted for consideration by international experts of the WHO Task Group on



Environmental Health Criteria for Sulfur  Oxides and Particulate Matter as



they neared finalization of the WHO (1979) document "Environmental Health

                                                               •3-1 p
Criteria (and) Sulfur Oxides and Suspended Particulate Matter."     That



group of international experts individually  reviewed the Holland Report and



provided comments on it to the WHO.  Those comments, together with others



received from international organizations such as the  International Iron and



Steel Institute, were then considered by the Chairman  of the Task Group
                                   14-246

-------
    TABLE  14-55.   EP1DEMIOLOGIC STUDIES SUGGESTING AN EFFECT OF PARTICULATE AIR
  POLLUTION AT CONCENTRATIONS AT OR NEAR THE U.S.  AMBIENT AIR QUALIJX,STANDARD
             AND COfWENTS BY SHY313 ON THE REVIEWS OF THEM BY HOLLAND ET AL.301
  Author and
location of $tudy
       Findings
           Comments
        321
Lindeberg
 Oslo, Norway
Average deaths per week
 during 1958 - 1965
 winters were signifi-
 cantly correlated with
                        levels
                        smoke
        of S00 but not
Winkelstein et al.
 Buffalo, New York
                 188
Geographic association
 between mortality from
 chronic respiratory
 disease among 50 - 69-
 year-old men and partic-
 ulate  levels over the
 range  of380 to more than
 135 ug/m  annual average
 (HV).
Van der  Lende et al.    Comparison  of  lung  func-
 Netherlands
 tion  between  1969 and
 1972  revealed improved
 function 1n the residents
 of  a  polluted area that
 experienced improved air
 quality over  the 4-year
 interval.   No similar
 functional  change occur-
 red in residents of a
 cleaner rural area.
Holland et al.  state that there
 may be confounding with long-
 term trends 1n air pollution
 levels and with influenza
 epidemics.  However, no evidence
 1s presented showing a correla-
 tion of Influenza epidemics with
 air pollution levels, nor are
 data presented on the long term
 air pollution trends.

Holland et al.  state that these
 results were not adequately
 standardized for age, social
 class, ethnicity, occupation,
 nobility or smoking habits.
 These limitations are Inherent
 1n mortality-based geographic
 studies.  However, the authors
 did stratify on age and social
 class, and there Is no positive
 evidence that other risk factors
 were correlated with the distri-
 bution of particulate levels.

Air quality changed  from 160 3
 ug/m  (smoke, BS) to 40 ug/m
 during the 1969 - 72  interval.
 Holland  et al. state that  firm
 conclusions cannot  be drawn "in
 the absence of direct evidence
 on changes in  lung  function in
 random  samples of  urban  popula-
 tions."   This  scientific  purism
 would tend to  cause rejection
 of the  results of  most air
 pollution epidemiologic data.
                                           14 - 247

-------
     TABLE 14-55.   EPIDEMIOLOGIC STUDIES SUGGESTING  AN  EFFECT OF  PARTICULATE AIR
   POLLUTION AT CONCENTRATIONS AT OR NEAR THE  U.S. AMBIENT  AIR OUALUX, STANDARD

               AND COMMENTS BY  SHY313 ON THE  REVIEWS OF THEM BY  HOLLAND  ET AL.301
   Author and
location of study
       Findings
           Comments
Gervois et al.
 Two towns in France
Levy et al.70
 Hamilton, Ohio
Ferris et al.
 Berlin, N.H.
             46
An association was
 reported between employee
 sickness absence records,
 adjusted for temperature,
 and day-to-day variations
 in smoke and SOp.  Highest
 daily values for each were
 200 ug/m ,  with 3-month
 means of 53 ug/n  (smoke,
 BS) and 37
A significant correlation
 was found for weekly
 hospital admission for
 respiratory infections
 and an index of air
 quality over a 12-month
 period.  Effect was
 adjusted for temperature.
An improvement in respira-
 tory symptoms and pulmo-
 nary function was noted
 in the same persons
 examined in 1961 and 1967,
 and these changes were
 accompanied by a decline
 in particulates from 180
 Mg/m, (HV) in 1961 to 131
 pg/m5 (HV) in 1967.   A
 later follow-up study in
 1973 showed a further
 decline in particulates
 by 1973 to 80 um/mj (HV).
 even while S0? levels
 increased.   Tne latter
 decline was not accom-
 panied by a change in
 pulmonary function or
 respiratory symptoms.
Holland et al.  claim that "the
 seasonal distribution of respira-
 tory infections could have had
 some confounding effect."  Adjust-
 ment for temperature would remove
 some of the seasonal effect, but
 no evidence was provided that
 season was correlated with air
 pollution levels.
Holland et al.  feel that there
 nay be confounding of seasonal
 respiratory disease frequency
 and air pollution.  Again, no
 evidence for actual confounding
 is presented,  and temperature
 adjustment provides at least a
 partial control for seasonal
 effects.

The orginal investigators
 interpret these results to
 indicate that all the benefit
 occurred from the reduction in
 particulates,  and that the gase-
 ous sulfur compounds did not
 have an effect at these levels.
 Holland et al.  state that data
 from different years are not
 comparable.  However, the
 original investigators speci-
 fically addressed this issue
 and failed to find evidence
 for lack of comparability.
                                          14 - 248

-------
    TABLE 14-55.   EPIDEMIOLOGIC STUDIES SUGGESTING AN EFFECT OF PARTICULATE AIR
  POLLUTION AT CONCENTRATIONS AT OR NEAR THE U.S. AMBIENT AIR QUALUX,STANDARD

               AND  COMMENTS BY SHY313 ON THE REVIEWS OF THEM BY HOLLAND ET AL.301
  Author arrd
location of study
                              Findings
                                       Comments
               28
Lambert and Reid
 England
Sawicki181
 Cracow, Poland
                       A gradient of respiratory
                        symptom prevalence corre-
                        sponded with the pollu-
                        tion gradient.   Data were
                        derived from a self-
                        administered questionnaire
                        sent to a national proba-
                        bility sample.   Prevalence
                        ratios are adjusted for
                        smoking and age.

                       Prevalence of chronic
                        respiratory disease was
                        significantly greater in
                        residents of a high air
                        pollution area (annual
                        average particulates, 170
                        ug/m  (smoke, BS) vs.
                        those in a low pollution
                        area (annual avg.: 90
                        u/m ).  Data were strati-
                        fied for smoking and age.
                            Holland et al.  for unexplained
                             reasons discount the correspond-
                             ence of the symptom and air
                             pollution gradients.  Particu-
                             late levels range frorruless than
                             100 ug/m  to 200+ ug/m  (smoke,
                             BS).
                            Holland et al.  state that
                             differences are not adjusted
                             for occupational and social
                             class, but they fail to provide
                             evidence that these factors are
                             confounding variables in this
                             study.  The reviewers admit that
                             the strong differences are
                             unlikely to be explained away by
                             one confounding factor, but the
                             use of these data is discounted
                             in their final assessment.
Holland etal
 and Bennett et
 Kent, England
               al.
Within urban areas, air
 pollution levels were
 associated with lung
 function of children
 ages 5-14 years.  Effects
 were adjusted for social
 class, family size and
 previous history of
 bronchitis.  Smoke levels
 (BS)3were less than 100
 ug/m  in both urban areas.
Holland et al.  (1) reject the
 association with air pollution
 because the lung function effect
 was "inconsistent" across the mix
 of urban and rural study areas.
 However, urban-rural differences
 are to be expected, and, within
 the urban stratum, the air pollu-
 tion effect could not be accounted
 for by other risk factors.
                                           14 - 249

-------
     TABLE 14-55.   EPIDEMIOLOGIC STUDIES SUGGESTING AN EFFECT  OF  PARTICULATE  AIR
   POLLUTION AT CONCENTRATIONS AT OR NEAR THE U.S.  AMBIENT  AIR QUALIJX,STANDARD
                                 ,313
               AND  COMMENTS  BY  SHYJAJ  ON  THE  REVIEWS  OF THEM  BY  HOLLAND  ET AL.
                                                      301
   Author and
location of study
       Findings
           Comments
Tessier et al.
 Bordeaux, France
            98
Irwig et al.
 10 areas of England
An association was found
 between absenteeism due
 to respiratory disease
 among schoolchildren ages
 6-11 years and short-term
 levels in air pollution
 less than 100 ug/m
 (smoke level by method
 similar to BS).
Investigators reported a
 statistically significant
 relationship between the
 frequency of chest colds
 during 1972-1973 and air
 pollution measurements
 taken in November, 1973,
 after allowing for
 differences in the
 distribution of age,
 sex and social class.
Socioeconomic and other factors
 were not Included in the analysis
 However, these risk factors are
 unlikely to be determinants of
 temporal variations in disease
 frequency among the same group
 of children.  Likewise, there
 is no evidence for an effect
 of meteorologic factors and
 temporal variations in absen-
 teeism, as Holland et al.
 allege.

Holland et al.  state that the
 effect of smoking in the home
 was not considered but offer
 no evidence that this factor
 was a confounder.  Reviewers
 state that a second report
 from this study indicated no
 relationship with air pollution
 but they fail  to provide details
 on this study.
                                           14-250

-------
Meeting, the Rapporteur, and members of the WHO Secretariat; and, it was
determined that the Task Group experts' opinions of the Holland Report con-
tents were such that the Task Group's views, as expressed in the now published
                  312
1979 WHO document,    remained unaltered.   See Appendix 3C for further information
regarding this matter.
     One other important consideration should be noted in regard to the recently
                         301
published Holland Report.     That concerns the fact that Holland and colleagues
apparently failed to apply the same standards of review to the British air
quality measurement data (critically appraised in Chapter 3 of this document
and summarized earlier in this chapter) and study designs employed by British
epidemiologists in evaluating quantitative air pollution/health effects relationships
of the type assessed in their report.     This possible flaw in their appraisal,
especially in view of their dismissal of results of various American or other
studies on the basis of criticisms of errors in their pertinent methodologies
and aerometry data need to be further evaluated (together with other points
noted above) since it may raise questions regarding  their review and its
conclusions.  Full judgement by the scientific community regarding such questions
remains to be more completely formulated and voiced; pertinent comments on
views expressed in the Holland Report    are, therefore, invited as input in
order to assist in the evaluation of its potential usefulness as it might bear
on the present review of health criteria for sulfur oxides and particulate
matter.
                                   14-251

-------
14.7  REFERENCES

 1.     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.

 2.     Ministry of Health.  Mortality and Morbidity During the  London Fog  of
       December 1952.  London, Her Majesty's Stationery Office.  1954.

 3.     Waller, R. E., and B. T. Commins.  Episodes of high pollution in London,
       1952-1966.  In:  Proc. Int. Clean Air Conf., Part I.  London, National
       Society for Clean Air.  1966.  p. 288.

 4.     Sugden, F. G.  Local authority problems in  an industrial area.   Royal
       Soc. Health J. (London) 87:209-214, 1967.

 5.     Weatherley, M. L., and R. E. Waller.  High  pollution  in  London,  December
       1975,  Atmos.  Environ., in press.

 6.     Martin, A. E.  Mortality and morbidity statistics and air pollution.
       Proc. R. Soc.  Med.  57:969-975, 1964.

 7.     Waller, R. E., P. J. Lawther, and A. E. Martin.  Clean air  and health
       in  London.  Ir\:  Proc. Clean Air Conf. , Part I.  London, National
       Society for Clean Air.  1969.  p. 71-78.

 8.     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.

 9.     Burgess, S. E., and C. W. Shaddick.  Bronchitis and air  pollution.   R.
       Soc. Health J. 79:10-24, 1959.

10.     Scott, J. A.    The London fog of December, 1962.  Med. Off.  109:  250-252,
       1963.

11.     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.

12.     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.

13.     Lawther, P. J.  Compliance with the Clean Air Act:  Medical aspects.
       J.  Inst. Fuel  36:341, 1963.

14.     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.  Ijn:  Proc. 1959  Int.  Clean Air Conf.   London, National
       Society for Clean Air.  1960.  p. 189.
                                     14-252

-------
15.     Kevany, J.,  M.  Rooney, and J. Kennedy.  Health effects of air pollution
       in Dublin.   Ir.  J.  Med.  Sci. 144:102-115, 1975.

16.     Hagstrom,  R.  M.,  H.  A. Sprague, and E. Landau.  The Nashville air pol-
       lution study.   VII.   Mortality from cancer in relation to air pollu-
       tion.   Arch.  Environ.  Health 15:237-248, 1967.

17.     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.                                                        ~~

18.     Sprague, H.  A.,  and R. M. Hagstrom.   The Nashville air pollution study:
       Mortality  multiple regression.  Arch. Environ. Health 18:503-507,
       1969.

19.     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.

20.     Burn,  J. L., and J.  Pemberton.  Air pollution bronchitis and lung
       cancer in Salford.   Int. J. Air Water Pollut. 7:5-16, 1963.

21.     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.

22.     Winkelstein, W., and  S. Kantor.  Stomach cancer.  Arch. Environ. Health
       14:544-547,  1967.

23.     Winkelstein, W., and  M. Gay.  Suspended particulate air pollution.
       Relationship to mortality from cirrhosis of the  liver.  Arch. Environ.
       Health  22:174-177, 1971.

24.     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.

25.     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.

26.     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.
                                    14-253

-------
27.    Lave, L. B., and B. P. Seskin.  Air Pollution and Human Health.  Baltimore,
       The Johns Hopkins University Press.  1977.

28.    Lambert, P. M., and D. D. Reid.  Smoking, air pollution and bronchitis
       in Britain.  Lancet K853-857,  1970.

29.    Sawicki, F.  Chronic non-specific respiratory disease 1n the city of
       Cracow.   X.  Statistical analysis of air pollution by suspended partic-
       ulate matter and sulfur dioxide.  Epidemiol. Rev.  23:221, 1969.

30.    Sawicki, F.  Chronic non-specific respiratory disease in the city of
       Cracow.   XI.  The cross-section study.  Epidemiol. Rev. 23:242, 1969.

31.    Sawicki, F-  Air pollution and prevalence of non-specific chronic
       respiratory disease.  I_n:  Ecology of Chronic Non-Specific Respiratory
       Diseases.  Z. Brzezinski, J. Kopczynski, and F. Sawicki. ed., Warsaw,
       Panstwowy Zaklad Wydawnictw Lekarskich.  1972.  p. 3-13.

32.    Petrilli, f. L., G. Agnese, and S. Kanitz.  Epidemiologic studies of
       air pollution effects in Genoa, Italy.  Arch. Environ. Health 12:733-740,
       1966.

33.    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.                                                  ~

34.    Neri, L. C., R. J. C. Pearson, W. Litven, and S. L. Green.  Prevalence
       of Chronic Respiratory Disease and Possible Determinants in the Cities
       of Ottawa and Sudbury, Ontario.  Report of Dept. of Epidemiology,
       Laboratory Center for Disease Control, Health Protection Branch, Health
       and Welfare Canada, Ottawa, Ontario.  1976.

35.    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.

36.    Cohen, C. A., A. R. Hudson, J. L. Clausen, and J. H. Knelson.   Respiratory
       symptoms, spirometry and oxidant air pollution in nonsmoking adults.
       Am. Rev. Respir. Dis. 105:251-261, 1972.

37.    Emerson, P. A.   Air pollution, atmospheric conditions and chronic
       airway obstructions.  J. Occup. Med. 15:635-638, 1973.

38.    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.
                                    14-254

-------
39.     Cederlof,  R.   Urban factor and prevalence of respiratory symptoms and
       "angina pectoris."  Arch.  Environ. Health 13:743-748, 1966.

40.     Hrubec, Z.,  R.  Cederlof, L.  Freberg, R. Morton, and G. Ozolins.  Respiratory
       symptoms in  twins.  Arch.  Environ. Health 27:189-195, 1973.

41.     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.

42.     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.

43.     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.

44.     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.

45.     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.

46.     Ferris, B.  G.,  Jr., H. Chen, S. Puleo, and R. L. H. Murphy, Jr.  Chronic
       non-specific respiratory disease in Berlin, New Hampshire, 1967-1973.
       A further follow-up study.  Am. Rev. Respir. Dis. 113: 475-485, 1976.

47.     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.

48.     Anderson,  D. 0.,  I. H. Williams, and B. G. Ferris, Jr.  The Chilliwack
       respiratory survey, 1963.    Part II.  Aerometric study.  Can. Med.
       Assoc. J.   92:954-961, 1965.

49.     Anderson,  D. 0., B. G. Ferris, Jr., and R. Zinkmantel.  The Chilliwack
       study.  Part III.   The prevalence of chronic respiratory  disease in  a
       rural Canadian town.  Can.  Med. Assoc. J.  92:1007-1016,  1965.

50.     Anderson,  D. 0., and B. G.  Ferris, Jr.  Air pollution  levels  and chronic
       respiratory disease.  Arch. Environ. Health 10:307-311, 1965.

51.     Fry,  J., J.  B.  Dillane, and L. Fry.  Smog:  1962 v  1952.   Lancet,  p.
       1326, 1962.

52.     Lawther, P.  J.   Climate, air pollution and  chronic  bronchitis.   Proc.
       R.  Soc. Med. 51:262-264, 1958.
                                     14-255

-------
53.     Lawther, P.  J.,  R.  E.  Waller, and M. Henderson.  Air pollution and
       exacerbations of bronchitis.  Thorax  25:525-539, 1970.

54.     Heimann, H.   Episodic air pollution in metropolitan Boston.  A trial
       epidemiologic study.   Arch.  Environ. Health 20:230-251, 1970.

5-5.     Cohen, A.  A., S. Bromberg, R. W. Buechley, L. T. Heiderscheit, and C.
       M. Shy.   Asthma and air pollution from a coal fueled power plant.  Am.
       J. Public Health 62:1181-1188, 1972.

56.     Kurata,  J. H. ,  M. M.  Glovsky, R. L. Newcomb, and J. G. Easton.  A
       multifactorial  study of patients with asthma.  Part 2:  Air pollution,
       animal dander and asthma symptoms.   Ann. Allergy 37:398-409, 1976.

57.     Derrick, E.  H.   A comparison between the density of smoke in the Brisbane
       air and the prevalence of asthma.  Med. J. Aust. 11:670-675, 1970.

58.     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.

59.     Waller,  R. E.,  and P.  J. Lawther.  Some observations on London fog.
       Br. Med. J.  1:1356-1358, 1955.

60.     Gregory, J.   The influence of climate and atmospheric pollution on
       exacerbations of chronic bronchitis.  Atmos. Environ. 4:453-468, 1970.

61.     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.

62.     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.

63.     Kalpazanov,  Y., M.  Stamenova, and G. Kurchatova.  Air pollution and  the
       1974-1975 influenza epidemic  in Sofia.  Environ. Res. 12:1-8, 1976.

64.     Kalpazanov,  Y., G.  Kurtchatova,  and M. Stamenova.  Die Verunreinigung
       der Atmospharenluft in der Stadt Sofia und die Grippenepidemie am  Ende
       1972.  Zeitschr. Gesamte Hyg. 9, 1976.

65.     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.

66.     Dohan, F.  C., and E.  W. Taylor.   Air Pollution and Respiratory Disease,
       A Preliminary Report.  Am. J. Med. Sci. 240:337, 1960.
                                    14-256

-------
67.     Dohan,  F.  C.   Air pollutants and incidence of respiratory disease.
       Arch.  Environ.  Health 3:387-395, 1961.

68.     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.

69.     Angel,  J.  H. ,  C.  M.  Fletcher, I. D. Hill, and C. M. Finker.  Respira-
       tory illness  in factory and office workers.  Br. J. Dis. Chest 59:
       66-80,  1965.                                                    ~~

70.     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.

71.     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.

72.     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.

73.     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.

74.     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.

75.     Van der Lende, R.  Epidemiology  of Chronic Non-Specific Lung Disease
       (Chronic Bronchitis).  Assen, Royal Van Gorcum, and Springfield,  111.,
       Charles C.  Thomas.  1969.

76.     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,   ^n:  Ecology  of  Chronic  Non-Specific  Respiratory
       Diseases.   Z.  Brzezinski, J. Kopczynski, and F. Sawicki, ed.,  Warsaw,
       Panstwowy Zaklad Wydownictw Lekarskick. 1972.  p.  27-33.

77.     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.
                                     14-257

-------
78.     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.

79.     Lawther, P. J., A. G. F. Brooks, P. W. Lord, and R. E. Waller.   Day-to-day
       changes in ventilatory function in relation to the environment.   Part
       I.  Spirometric values.   Environ. Res. 7:24-40, 1974.

80.     Lawther, P. J., A. G. F- Brooks, P. W. Lord, and R. E. Waller.   Day-to-day
       changes in ventilatory function in relation to the environment.   Part
       II.  Peak expiratory flow values.  Environ. Res. 7:41-53,  1974.

81.     Lawther, P. J., A. G. F. Brooks, P. W. Lord, and R. E. Weller.   Day-to-day
       changes in ventilatory function in relation to the environment.   Part
       III.  Frequent measurements of peak flow.  Environ. Res. 8:119-130,
       1974.

82.     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.

83.     Ramsey, J. M.  The relationship of urban atmospheric variables to
       asthmatic bronchoconstriction.  Bull. Environ. Contain. Toxicol.
       16:107-111, 1976.

84.     Spicer, W. S., and H. D. Kerr.  Effects of environment on  respiratory
       functions, weekly studies on young male adults.  Arch. Environ.  Health
       21:635-642, 1970.

85.     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.

86.     Holland, W. W., D. D. Reid, R. Seltser, and R. W. Stone.   Respiratory
       Disease in England and the United States, Studies of Comparative
       Prevalence.  Arch. Environ Health 10:338-345, 1965.

87.     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.

88.     Toyama, T.  Air pollution and its health effects in Japan.   Arch.
       Environ. Health 8:153-173, 1964.

89.     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.
                                     14-258

-------
90.     Douglas,  J.  W.  B.,  and R.  E.  Waller.   Air pollution and respiratory
       infection in children.  Br.  J.  Prev.  Soc. Med. 20:1-8, 1966.

91.     Colley.  J.  R.  T.,  J.  W.  B.  Douglas, and D. D. Reid.  Respiratory disease
       in young adults:   Influence of early childhood lower respiratory tract
       illness,  social class, air pollution, and smoking.  Br. Med. J. 3:195-198,
       1973.

92.     Kiernan,  K.  E., J.  R.  T.  Colley, J. W.  B. Douglas, and D. D. Reid.
       Chronic  cough in young adults in relation to smoking habits, childhood
       environment and chest illness.   Respiration ^3:236-244, 1976.

93.     Burrows,  B., R. J.  Knudson, and M.  D. Lebowitz.  The relationship of
       childhood respiratory illness to adult obstructive airway disease.  Am.
       Rev.  Respir. Dis.  115:751-760,  1977.

94.     Burrows,  B., M. D.  Lebowitz, and R. J.  Knudson.  Epidemiologic evidence
       that childhood problems predispose to airway disease in the adult (an
       association between adult and pediatric respiratory disorders).  Pediat.
       Res.  11:218-220, 1977.

95.     Taussig,  L.  M.   Clinical  and physiologic evidence for the persistence
       of pulmonary abnormalities after respiratory illnesses in infancy and
       childhood.   Pediat. Res.  11:216-218, 1977.

96.     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.

97.     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.

98.     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.

99.     Kerrebijn,  K.  F.,  ARM.  Mourmans and K. Brersteker.  Study  of  the
       Relationship of Air Pollution to Respiratory Disease in Schoolchildren.
       Environ.  Res.  10:14-28, 1975.

100.    Watanabe, H.  Air pollution and  its effects  in Osaka, Japan.   Paper
       presented at the 58th Annual Meeting, Air Pollution Control  Associa-
       tion,  Toronto, Canada, June 20-24, 1965.  (Preprint).

101.    Holland,  W.  W., T.  Hal 11, A. E.  Bennett,  and A. Elliot.  Factors  influenc-
       ing the  onset of chronic respiratory disease.  Br. Med. J.  2:205-208,
       1969.
                                    14-259

-------
14SOXR/C    2-12-80
102.    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.

103.    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.

104.    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.

105.    Biersteker,  K.,  and P.  van Leeuwen.   Air pollution, bronchitis  preva-
        lence and peak flow rates  of schoolchildren in two districts of Rotterdam
        (Netherlands).   In:   2nd Int.  Clean Air Cong.  Proc. Washington,  D.C.,
        December  1970.   H.  M.  Englund and W.  T.  Berry (ed.). New  York,  Academic
        Press,  p.  209-212.

106.    U.S.   Environmental Protection Agency.   Health Consequences of Sulfur Oxides:
        A Report from CHESS, 1970-71.  EPA-650/1-74-004.  May 1974.

107.    U.S.   House of Representatives.  Committee on Science and Technology.  The
        Environmental Protection 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.

108.    House, D.  E. , J. F.  Finklea, C.  M. Shy, D. C. Calafiore, W. B. Riggan,
        J. W.  Southwick, and L. J.  Olsen.  Prevalence of chronic respiratory
        disease symptoms in adults:  1970 survey of Salt Lake Basin communities.
        In:   Health  Consequences of Sulfur Oxides:  A Report from  CHESS,  1970-1971.
        U.S.   Environmental Protection Agency.   Research Triangle Park, N.C.
        Publication  No. EPA-650/1-74-004.  May 1974.  p. 2-41 - 2-54.

109.    Goldberg,  H. E. , J.  F. Finklea,  C. J.  Nelson, W. B. Steen,  R. S.  Chapman,
        D. H.  Swanson, and A. A. Cohen.   Prevalence of chronic respiratory
        disease symptoms in adults:  1970 survey of New York communities.  Iji:
        Health Consequences  of Sulfur Oxides:   A Report from CHESS, 1970-1971.
        U.S.   Environmental Protection Agency.   Research Triangle Park, N.C.
        Publication  No. EPA-650/1-74-004.  May 1974.  p. 5-33 - 5-47.

110.    Hayes, C.  G., D.  I.  Hammer, C. M. Shy, V. Hasselblad, C. R. Sharp, J.
        P. Creason,  and K. E. McClain.  Prevalence of chronic respiratory
        disease symptoms in adults:  1970 survey of five Rocky Mountain  communities.
        I.n:   Health  Consequences of Sulfur Oxides:  A Report from  CHESS,  1970-1971.
        U.S.  Environmental Protection Agency.   Research Triangle Park, N.C.
        Publication  No. EPA-650/1-74-004.  May 1974.  p. 3-19 - 3-33.


111.   Finklea,  J.   F., J. Goldberg, V.  Hasselblad, C.  M. Shy. and C. G.  Hayes.
        Prevalence of chronic respiratory disease symptoms in military  recruits:
        Chicago induction center, 1969-1970.  In:  Health Consequences of
        Sulfur Oxides:  A Report from CHESS, 1970-1971.  U.S. Environmental
        Protection Agency.  Research Triangle Park, N.C.  Publication No.
        EPA-650/1-74-004.  May 1974.  p. 4-23 - 4-36.

                                   14-260

-------
112.    Colley,  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.

113.    Hammer,D.  I.   Frequency of lower respiratory disease in children:
       Retrospective  survey of two southeastern communities, 1968-1971.
       Ph.D.  Dissertation,  Harvard, Univ., 1976.

118.    Doll,  R. ,  and  A.  B.  Hill.  Mortality in relation to smoking:
       ten years'  observations of British Doctors.  Br. Med. J. 1:1399-1410;
       1460-1467,  1964.

119.    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.

125.    Cederlof,  R.,  R.  Doll, B. Fowler,  L. Friberg, N. Nelson, and V.  Vouk,
       eds.,  Air pollution and cancer.  Risk assessment methodology and
       epidemiological  evidence.  Report of a Task Group.  Environ. Health
       Perspect.  22:1-12, 1978.

126.    Waller,  R.  E.   The combined effect of smoking and occupational or urban
       factors in relation to lung cancer.  Ann. Occup. Hyg. 15:67-71,  1972.

127.    Higginson,  J.   Present trends in cancer epidemiology.  Proc. Can.
       Cancer Conf.  8:40-75, 1969.

128.    Pike,  M.  C., R.  J. Gordon, B. E. Henderson et al.  Air pollution.  In:
       Persons at High Risk of Cancer.  J.  F. Fraumeni, Jr. ,ed.  New York,
       Academic Press.   1975.  p. 225-240.

129.    Hammond, F.  C.   Smoking habits and air pollution in relation to  lung
       cancer.   In:   Environmental Factors  in Respiratory Disease.  D.  H. Lee,
       ed.  New York,  Academic Press.  1972.  p. 177-198.
130.    Ashley, D.  J.  B.   Environmental factors  in the  aetiology of gastric
       cancer.   Br.  J.  Prev. Soc. Med. 23:187-189, 1969.

131.    Mancuso, T.  F.,  E. M. MacFarlane, and J. D.  Porterfield.   Distribution
       of cancer mortality in Ohio.  Am.  J. Public  Health 45:58,  1955.

132.    Hoffman, E.  F.,  and A. G. Gilliam.   Lung cancer mortality.  Geographic
       distribution in the United States for 1948-1949.   Public Health  Rep.
       69:1033, 1954.

133.    Buell, P-, and J. E. Dunn.  Relative impact  of  smoking  and air pollution
       on lung cancer.   Arch. Environ. Health 15:291,  1967.

134.    Hammond, E.  C. ,  and D. Horn.  Smoking and  death rates -  report on 44
       months of follow-up of 187,783 men.   I.  Total  mortality.   II.   Death
       rates  by cause.   JAMA 166:1159-1294,  1958.
                                     14-261

-------
135.    Haenszel,  W.,  D.  B. Loveland, and M. G. Sirken.  Lung cancer mortality
       as related to residence and smoking histories.  I.  White males, J.
       Natl. Cancer.  Inst. 28:947, 1962.

136.    Haenszel,  W.,  D.  B. Loveland, and M. G. Sirken.  Lung cancer mortality
       as related to residence and smoking histories.  II.  White  females,  J.
       Natl. Cancer Inst.  32:803, 1964.

137.    Hammond, E. C.   Smoking habits and air pollution in relation to  lung
       cancer,  Iji:   Environmental Factors in Respiratory Disease, D. H.  K.
       Lee, ed.  Academic Press, New York, 9172.  pp. 177-198.

138.    Stocks, P.  Cancer and bronchitis mortality in relation to  atmospheric
       deposit and smoke.   Br. Med. J. 1:74, 1959.

139.    Menck, H.  R., J.  T. Casagrande, and B. E. Henderson.  Industrial air
       pollution:  Possible effect on lung cancer, Science. 183:210,  1974.

140.    Carnow, B. W., and P. Meier.  Air pollution and pulmonary cancer,  Arch.
       Environ. Health 27:207, 1973.

141.    Hitosugi, M.   Epidemiological study of lung cancer with special  reference
       to the effect of air pollution and smoking habits.  Inst. Public Health
       Bull 17:237, 1968.

142.    Eastcott, D.  F.  The epidemiology of  lung cancer in New Zealand, Lancet
       1:37, 1956.

143.    Dean, G.  Lung cancer in South Africans and British immigrants.  Proc.
       R. Soc. Med.  57:984, 1964.

144.    Reid, D. D., J. Cornfield, and R. E. Markush, et al.  Studies  of disease
       among migrants and native population  in Great Britain, Norway  and  the
       United States.  III.  Prevalence of cardiorespiratory symptoms among
       migrants and native-born in the United States.  Natl. Cancer  Inst.
       Monogr. 19:321, 1966.
145.    Selikoff, I.  J., E. C. Hammond, and J. Churg.  Absestos exposure,
       smoking, and neoplasia.  JAMA 204:106, 1968.

146.    Archer, V. E., and J. K. Wagoner.  Lung cancer among uranium miners  in
       the United States.   Health Phys. 25:351, 1973.

147.    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.

148.    Fasett, D. W.   Aldehydes and acetals.  In:  Industrial Hygiene and
       Toxicology.  Vol. 2.  F- A. Patty, ed.   Interscience, New York,  1963.
                                    14-262

-------
149.    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.

150.    McCarroll,  J. ,  and W.  Bradley.   Excess mortality as an Indicator of
       health effects  of air pollution.   Am. J.  Public Health 56:1933-1942,
       1966.                                                   ~~

151.    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.

152.    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.

153.    Glasser,  M. , and L. Greenburg.   Air pollution and mortality and weather,
       New York City,  1960-64.  Arch.  Environ.  Health 22:334-343, 1971.

154.    Ingram, W.  T.,  and J.  Golden.   Smoke curve calibration.  J. Air Pollut.
       Control Assoc.  23:110, 1973.

155.    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.

156.    Schimmel, H. , and T.  J. Murawski.   S02--Harmful pollutant or air quality
       indicator?   J.  Air Pollut. Control Assoc. 25:739-740, 1975.

157.    Schimmel, H. , and T.  J. Murawski.   The relation of air pollution to
       mortality.   J.  Occup.  Med. 18:316-333, 1976.

158.    Hodgson,  A., Jr.  Short-term effects of air pollution on mortality  in
       New York City.   Environ. Sci.  Technol. 4:589-597, 1970.

159.    Buechley, R. W., W. B. Riggan, W.  Hasselblad, and J. B. Van  Bruggen.
       SOp levels  and perturbations in mortality.  A study in New York-New
       Jersey metropolis.   Arch. Environ. Health £7:134-137, 1973.

160.    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.

161.    Corn,  M.   Dose to the respiratory tract from personal, occupational and
       community air pollutants.  Environ.  Lett. 1:29-39, 1971.

162.    Holland,  W.  W.,  and R. W. Stone.  Respiratory disorders in United
       States East Coast telephone men.  Am. J.  Epidemiol. 82:92-101,  1965.
                                    14-263

-------
163.    McCarroll, J.   Measurements of morbidity and mortality related to air
       pollution.  J.  Air Pollut.  Control Assoc.  17:203-209, 1967.

164.    Stocks, P.  Statistics of cancer of the lung.  J. Fac. Radiol.  London
       6:166-173, 1955.

165    Stocks, P.  Air Pollution and Cancer Mortality in Liverpool Hospital
       Region and North Walls.   Inter.  J. Air Pollut. 1:1-13, 1958.

166.    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.

167.    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.

168.    Bouhuys, A., G. J. Beck, and J.  B. Schoenberg.  Do present levels of
       air pollution outdoors affect respiratory health?  Nature 276:466-471.
       1978.

170.    Lebowitz, M. D.  A comparative analysis of the stimulus-response relation-
       ship between mortality and air pollution weather.  Environ. Res.
       6:106-118, 1973.

171.    Lebowitz, M., T.  Toyama, and J.  McCarroll.  The relationship between
       air pollution and weather as stimuli and daily mortality as responses
       in Tokyo, Japan, and with comparisons with other cities.  Environ. Res.
       6:327-333, 1973.

173.    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.

174.    Carnow, B. W., M.  H. Lepper, R.  B. Shekelle, and J. Stamler.  Chicago
       air pollution study.  Arch. Environ. Health 18:768-776, 1969.

175.    Jacobs, C., and B. Langdoc.  Cardiovascular deaths and air pollution in
       Charleston, South Carolina.  Health Services Reports  87:623-632, 1972.

176.    Yoshida, R., K. Motomiya, H. Saito, and S. Funabashi.  Clinical and
       epidemiological studies on childhood asthma  in air polluted areas in
       Japan.   I.n:  Clinical Implications of Air Pollution Research.  Acton,
       Massachusetts, Publishing Sciences Group, Inc., 1976.

177.    Mostardi, R. ,  and D. Leonard.  Air pollution and cardiopulmonary functions
       Arch. Environ.  Health 29:325-328, 1974.

178.    Sultz,  H., J.  Feldman, E. Schlesinger, and W. Mosher.  Arr effect of
       continued exposure to air pollution on the incidence  of chronic childhood
       allergic disease.   Am. J. Public Health 60:891-900, 1970.
                                    14-264

-------
179.    Ramaciotti,  D.,  M.  Bahy,  B.  Voinier,  and P.  Rey.   The SCL pollution
       level  and  the  incidence of bronchitis.   Medicine  sociale et preventive
       22:189-190,  1977.  (Iran.)

180.    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.

181.    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.

182.    Rudnik,  J.   Epidemiological  Study on  Long-term Effects on Health of Air
       Pollution.   Probl.  Med.  Wieku Rozwojowego 7a(suppl):1-159, 1978.

183.    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.

184.    Goldstein, I., and L.  Landowitz (Letter to editor).   J.  Air Pollut.
       Control  Assoc.  25:1195, 1975.

187.    Schimmel,  H.  Evidence  for possible acute health  effects of ambient air
       pollution  from time series analysis:   Methodological  questions and some
       new results based on New York City daily mortality,  1963-1976.  Bull.
       N.Y.  Acad.  Med.   54:1052-1108, 1978.

188.    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.

189.    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.

190.    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.

191.    Rail, D. P.   Review of  the Health Effects of Sulfur Oxides, Environ.
       Health Perspect. 8:97-121, 1974.

193.    U.S.  Environmental Protection Agency.  Scientific and Technical  Issues
       Relating to Sulfates.   Ad Hoc Panel of the Science Advisory Board.,
       Washington, DC,  1975.
                                    14-265

-------
194.    Boffey, P.  M.  Sulfur Pollution:  Charges that EPA Distorted the Data
       are Examined.  Science 192:352-354, 1976.

195.    Ferris, B.  G.  Effects of Air Pollution on School Absences and Differences
       on Lung Function in First and Second Graders in Berlin, New Hampshire,
       January 1966 to June 1967.  Am.  Review Respir.  Dis. 102:591-606, 1970.

196.    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-±64,
       1962.

197.    Wynder, E.  L., and G. B. Gori.  Contribution of the environment to
       cancer incidence.  An epidemiologic exercise.  J. Natl. Cancer Inst.
       58:825-830, 1977.

198.    Carnow, B.  W., and P. Meier.  Air pollution and pulmonary cancer.
       Arch.  Environ. Health  27:207-218, 1973.

199.    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.

200.    Stebbings,  J. , and D. Fogleman.   Identifying a susceptible subgroup:
       Effects of the Pittsburgh air pollution episode upon schoolchildren.
       Am. J. Epidemiol. 110:27-40, 1979.

201.    Firket, J.   Fog along the Meuse Valley.  Trans. Faraday Soc. 32:1192-1197,
       1936.

202.    Wilkins, E.  Air pollution aspects of the London Fog of December, 1952.
       Roy. Meterol. Soc. J. 80:267-271, 1954.

203.    Wilkins, E.  Air pollution and the London Fog of December, 1952.  J.
       Roy. Sanit. Inst. 64:1-21, 1954.

204.    Logan, W.   Mortality in the London fog incident.   Lancet  1:336-338,
       1953.

205.    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.

206.    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.

207.    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.
                                    14-266

-------
208.
209.
210.
211.
212.
213.
214.
215.
216.



217.


218.
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.
Cassell, E. J., M. D. Lebowitz,
Between Air Pollution, Weather,
Am. Rev. Res. Dis. 106:677-683,
and J.  R.  McCarroll.   The Relationship
and Symptoms in an Urban Population.
1972.
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. D.  A Critical Examination of  Factorial  Ecology  and  Social
Area Analysis for Epidemiological  Research.   Ariz. Acad.  of Science
12(2):86-90, 1977.

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.

Chapman, R. S., V. Hasselblad,  C.  G. Hayes,  J.  V.  R.  Williams,  and
D. I. Hammer.   Air Pollution  and Childhood  Ventilatory  Function.   I.
Exposure to Particulate Matter  in Two Southeastern Cities, 1971-72.   J_n:
Clinical Implications of Air  Pollution  Research.   A.  J.  Finkel  and
W. C. Duel, ed. , Publishing Sciences Group,  Inc.,  Acton,  MA,  1976.
pp. 285-303.

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.   ITI:   Clinical  Implications
of Air Pollution Research.  A.  J.  Finkel  and W.  C. Duel,  ed., Pub-
lishing Sciences Group, Inc., Acton, MA,  1976.   pp.  321-337.

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, 1973.

Stebbings,  J.  H., Jr.,  and D. G.  Fogleman.   Identifying a Susceptible
Subgroup:   Effects of the  Pittsburgh  Air Pollution Episode Upon School-
children.   Am.  J. Epidemiol.  110:27-40, 1979.

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.

Kagawa, J., and T. Toyama.  Photochemical Air Pollution.  Arch. Environ.
Health 30:117-122, 1975.
                                     14-267

-------
219.    Martin, A.  E.   Epidemiological studies of atmospheric pollution.  A re-
       view of British methodology.   Monthly Bulletin of the Ministry of Health
       and Public Health Laboratory Service, 20:42-49, 1961.

220.    Waller, R.  E.   Control of air pollution:  Present success and future
       prospect.   .In:   Recent Advances in Community Medicine.  A. E. Bennett,
       ed. , Edinburgh, Churchill, Livingstone, 1978.

221.    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.

222.    Glasser, M., and L.  Greenburg.  Air pollution and mortality and weather,
       New York City,  1960-64.  Arch Environ. Health 22:334-343, 1971.

223.    Pemberton, J.,  and C. Goldberg.  Air polution and bronchitis.  Br. Med.
       J. 2:557, 1954.

224.    Gorham, E.  Bronchitis and the acidity of urban precipitation.  Lancet
       2:691, 1958.

225.    Gorham, E.  Pneumonia and atmospheric sulphate deposit.  Lancet 2:287,
       1959.

226.    Hewitt, D.  Mortality in the London boroughs, 1950-52, with special
       reference to respiratory disease.  Br. J. Prev. Soc. Med. 10:45, 1956.

227.    Lepper, M. H. ,  N. Shioura, B. Carnow, S. Andelman, and L. Lehrer.
       Respiratory disease in an urban environment.  Arch.  Indust. Med. 38:36,
       1969.

228.    Watanabe, H. , and F. Kaneko.   Excess death  study of  air pollution.  lr\:
       Proceedings of the Second International Clean Air Congress.
       H. M.  Englund and W. T. Beery, ed., Academic Press,  New York, 1971.
       pp. 199-200.

229.    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.

230.    Report of the International Joint Commission, United States and Canada,
       on the Pollution of the Atmosphere  in the Detroit River Area.   Inter-
       national Joint Commission (United States  and Canada), Washington/
       Ottawa, 115 pp. 1960.

231.    Speizer, F. E.  , Y.  M. M. Bishop, and  B. G.  Ferris.   An epidemiologic
       approach to the study of the health effects of air  pollution.   Proc.
       4th Symp. Statistics and the Environment, Washington,  DC,  1977.
                                    14-268

-------
232.    Environmental  Protection Agency.   Air Quality Criteria for Sulfur Oxides.
       U.S.  Department of Health, Education, and Welfare, (Publ. AP-50),DC,
       1969.

233.    Environmental  Protection Agency.   Air Quality Criteria for Particulate
       Matter.   U.S.  Department of Health, Education, and Welfare, (Publ. AP-49),
       DC,  1969.

234.    ATS.   Epidemiology Standardization Project.  Am.  Rev. Res. Dis.
       118(6,pt.2),  1978.

235.    Cassell,  E.  J. , and M.  D.  Lebowitz.  The Utility of the Multiplex
       Variable  in Understanding Causality.   Perspect. Biol. Med. 19(3):338-341,
       1976.                                                       ~~

236.    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.

237.    Fox, J.  P. C.  E. Hall,  and L. R.  Elveback.  Epidemiology Man and Disease.
       The MacMillan Company Col 1ier-MacMillan, London, 1970.

238.    Friedman,  G.  D.  Primer of Epidemiology.  McGraw-Hill Book Company, a
       Blakiston Publication,  New York,  1974.

239.    Goldsmith, J.  R., and L. T. Friberg.   Effects of Air  Pollution on Human
       Health.   In:   Air Pollution .  II.  A. C. Stern, ed., Academic Press,
       New York,  1977.  pp. 458-610.

240.    Hill, A.  B.   The Environment and Diseases:  Associations and Causation.
       J_n:   Proceedings of the Royal Society of Medicine (Occ. Med.) 58:272,
       1965.

241.    Higgins,  I.  T.  T.  Epidemiology of Chronic Respiratory Disease:  A
       Literature Review.  EPA-650/1-74-007, U.S. Environmental Protection
       Agency, DC, 1974.

242.    Lillienfeld, A. M.  Foundations of Epidemiology.  Oxford University
       Press, New York, 1976.

243.    Macklem,  P.  T.  , and S.  Permutt.  The  Lung  in  the Transition Between
       Health and Disease.  Marcel Dekker,  Inc., New York,  1979.

244.    MacMahon,  B. , T. F. Pugh, and J.  Ipsen.   Epidemiology Methods.   2nd  Ed.
       Little, Brown and Company, Boston, Toronto, 1960.

245.    Rail, D.  P.   A Review of the Health  Effects of Sulfur Oxides.
       National  Institute of Environmental  Health Sciences,  NIH,  Research
       Triangle Park, NC, 1973, Environ.  Hlth.  Perspect. 8:97-m, 1974.
                                    14-269

-------
246.    Speizer, F. E.  An Epidemiclogical Appraisal of the Effects of Ambient
       Air on Health:  Participates and Oxides of Sulfur.  J. Air Pollut.
       Control Assoc. 19:647-655, 1969.

247.    Goldsmith, J.  R.,  and L. T. Friberg.  Effects of Air Pollution on Human
       Health.  I_n:   Air Pollution.  Vol. 2, A. C. Stern, ed. , Academic Press,
       New York,1977.  pp.  458-610.

248.    Higgins, I. T. T.   Epidemiology of Chronic Respiratory Disease:  A
       Literature Review.  EPA-650/1-74-007, U.S. Environmental Protection
       Agency, Washington,  DC, 1974.

249.    Lebowitz, M.  D.  Methodology of SOX/TSP Health Effects Research in
       Humans, EPA,  in press, 1980.

250.    World Health Organization.  Environmental Health Criteria for Sulfur
       Oxides and Suspended Particulate Matter.

251.    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 Association, 1978.

252.    Lipfert, F. W.  The association of air pollution with  human mortality:
       Multiple regression results for 136 U.S. cities, 1969.  Presented at the
       70th Annual Meeting, Air Pollution Control Association, Toronto, Canada,
       June 20-24, 1977.

253.    Lipfert, F. W.  The association of human mortality with air pollution:
       Statistical analyses by region, by age, and by cause of death.  Long
       Island Lighting Company, 1978.

254.    Crocker, T. D., W. Schulze, B. David, and A. V. Kneese.  Methods
       development for assessing  air pollution control benefits.  Vol. I:
       Experiments in the economics of air pollution epidermiology.
       EPA-600/5-79-001a, 19

255.    Schwing, R. C., and G. C.  McDonald.  Measures of association  of some air
       pollutants, natural  ionizing radiation, and cigarette  smoking with
       mortality rates.  Science  of the Total  Environment 5:139-169, 1976.

256.    Lave, L. B.,  and E.  P. Seskin.  Air pollution and human health.  John
       Hopkins University Press,  Baltimore, MD, 1977.

257.    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.

258.    Mostardi, R.  A., and R. Martell.  The effects of air  pollution on pul-
       monary functions in adolescents.  Ohio  J. Sci. 715:65-69,  1975.
                                    14-270

-------
259.    Waller,  R.  E.,  and B.  T.  Commins.   Episodes of high pollution in London,
       1952-1966.   In:   Proceedings of the International Clean Air Conference,
       Part I.   National  Society for Clean Air, London, 1966.  p. 288.

260.    Lawther,  P.  J.,  R.  E.  Waller, and M.  Henderson.  Air pollution and ex-
       acerbations  of  bronchitis.   Thorax 25:525-539, 1970.

261.    Waller,  R.  E.   Air pollution and community health.   J. Royal Coll.  Phys.
       London 5:362-368,  1971.

262.    Holland,  W.  W.,  D.  D.  Reid, R.  Seltser, and R. W. Stone.   Respiratory
       Disease  in England and the United States.  Studies of Comparative Pre-
       valence.   Arch.  Environ.  Health 10:338-345, 1965.

263.    Holland,  W.  W.,  and D. D. Reid.  The Urban Factor in Chronic Bronchitis.
       Lancet 1:445-448,  1965.

264.    Kagawa,  J.,  T.  Toyama, and M. Nakaza.   Pulmonary function tests in
       children exposed to air pollution,  ^n:  Clinical Implications of Air
       Pollution Research.  A.  J.  Finkel and W. C. Duel, ed., Publishing
       Sciences Group,  Inc.,  Acton, MA, 1976.   pp. 305-320.

265.    Fairbairn, A.  S.,  and D.  D. Reid.  Air pollution and other local factors
       in respiratory  disease.   Br. J. Prev.  Soc. Med. ^2:94, 1958.

266.    Mork, T.   A comparative study of respiratory disease in England , Wales,
       and Norway.   Norwegian University Press, Oslo, 1962.

267.    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.

268.    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.

269.    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.

270.    Bates, D. V.  Air pollution and chronic  bronchitis.   Arch.  Environ.
       Health 14:220,  1967.

271.    Bates, D. V.  The fate of the chronic bronchi tic:   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.
                                    14-271

-------
272.    Yashizo, T.  Air pollution and chronic bronchitis.  Osaka Univ. Med.
       J.  20:10, 1968.

273.    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.

274.    Fletcher, C. M., B. M. Tinker, I. D. Hill, and F. E. Speizer.  A Five-
       Year Prospective Field Study of Chronic Bronchitis.  In:  Proceedings
       at the llth Aspen Conference on Research in Emphysema.  PHS  no. 1879,
       U.S. Department of Health, Education, and Welfare, Washington, DC,
       June 1968.

275.    Ishikawa, S., D. H. Bowden, V. Fisher, and J. P. Wyatt.  The "emphysema
       profile" in two midwestern cities in North America.  Arch. Environ.
       Health 18:660, 1969.

276.    Fujita,  S., T. Motoichi, K. Shoji, Y. Ichiro, F. Takashi, S. Seigo,
       K. Tatsuo, and M. Michiko.  Studies on chronic bronchitis -  epidemio-
       logical  survey (2nd report).  Teishin Igaku 21:13, 1969.  English trans-
       lation no. 1734, APTIC no. 28558, EPA Air Pollution Technical  Infor-
       mation Service.

277.    Reichel, G.  Effect of air pollution on the prevalence of respiratory
       diseases in West Germany.  lr\:  Proceedings of the Second International
       Clean Air Congress, Washington, DC, 1970.

278.    Ulmer, W. T., G. Reichel, A. Czeike, and A. Leuschner.  Regional in-
       cidence  of nonspecific respiratory diseases.  IV.  Communication,
       Int. Arch. Arbeitsmed. 27:73, 1970.

279.    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.

280.    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.                                                          ~~

281.    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.

282.    Speizer, F. E., and B. G. Ferris, Jr.  Exposure  to  automobile  exhaust.
       II.  Pulmonary function measurements.  Arch.  Environ.  Health 26:319,
       1973b.                                                       ~~

283.    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.
                                     14-272

-------
284.    Prindle,  R.  A.,  G.  W.  Wright, R.  0.  McCaldin, S. C. Marcus,
       T.  C.  Lloyd,  and W.  E.  Bye.   Comparison of pulmonary function and
       other  parameters in two communities with widely different air pollution
       levels.   Am.  J.  Public Health 53:200, 1963.

285.    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.

286.    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.

287.    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.

288.    Schoettlin,  C.  E.,  and E.  Landau.   Air pollution and asthmatic attacks
       in the Los Angeles area.   Public Health Reports 76:545, 1961.

289.    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.

290.    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.

291.    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.

292.    Weill, H., M. M. Ziskind, V. Derbes, R. Lewis, R. J. M. Horton, and
       R. 0.  McCaldin.   Further observations on New Orleans asthma.  Arch.
       Environ.  Health 8:184, 1964.

293.    Carroll, R.  E.  Epidemiology of New Orleans epidemic asthma.  Am.  J.
       Public Health 58:1677, 1968.

294.    Phelps,  H. W.  Follow-up studies  in Tokyo-Yokohama respiratory  disease.
       Arch.  Environ. Health 10:143, 1965.

295.    Meyer, G. W.  Environmental respiratory disease  (Tokyo-Yokohama Asthma):
       The case for allergy.  In:  Clinical  Implications  of Air  Pollution
       Research.  A. J. Finkel and W. C. Duel, ed.,  Publishing Sciences  Group,
       Inc.,  Acton, MA, 1976.

296.    Glasser, M., L.  Greenburg, and F. Field.   Mortality  and morbidity during
       a period of high levels of air pollution.   New York, Nov.  23-25,  1965.
       Arch.  Environ. Health 15:684, 1967.
                                     14-273

-------
297.   Chiaramonte, L. T., J. R. Bongiorno, R. Brown, and M. E. Laano.  Air
       pollution and obstructive respiratory disease in children.  NY State
       J.  Med. 70:394, 1970.

298.   Rao, M.,  P.  Steiner, Q. Qazi, R. Padre, J. E. Allen, and M. Steiner.
       Relationship of air pollution to attack rate of asthma  1n children.
       J.  Asthma Res.  11:23, 1973.

299.   Ball, D.  J., R. Hume.  The relative importance of vehicular and domestic
       emissions of dark smoke in Greater London in the mid-1970s, the signi-
       ficance of  smoke shade measurements, and an explanation of the relation-
       ship of smoke shade to gravimetric measurements of particulate.  Atmos.
       Environ.  11:1065-1073, 1977.

300.   Aubrey, F., G.  W. Gibbs, and M. R. Becklake.  Air Pollution and Health
       in three urban communities.   Arch. Environ.  Health 34:360-368,
       Sept/Oct 1979.

301.   Holland, W.  W., A. E. Bennett,  I. R. Cameron, C. du V.  Florey,
       S.  R.  Leeder, R. S. F. Schilling, A. V. Swan, and R. E. Waller.
       Health Effects of Particulate Pollution:  Re-appraising the Evidence.
       Am. J. Epidemic!. 110(5):525-659, 1979.

302.   Brasser, L.  J., P. E. Joosting, and D. von Zuilen.  Sulfur Dioxide  -
       To What Level  is  it Acceptable?  Research Institute for Public
       Health Engineering, Delft, Netherlands, Report G-300, July 1967.

303.   Joosting, P. E.  Air  Pollution  Permissibility Standards Approached
       from the Hygienic Viewpoint.  Ingenieur, 79(50):A739-A747, 1967.

304.   Ware,  J., F. Speizer, et al.  Assessment of the Health  Effects of
       Sulfur Oxides  and Particulate Matter:  Analysis of the  Exposure-
       Response Relationship.  Research Triangle Park, NC, U.S.  Environ-
       mental Protection Agency, in press, 1980.

305.   Winkelstein, W.   Utility or futility of ordinary mortality statistics
       in the study of air pollution effects.  Proceedings of  the Sixth
       Berkeley Symposium on Mathematical Statistics and Probability, 1970.
       pp. 539-554.

306.   French, J.  G. , G. Lowrimore, W. C. Nelson, J. F. Finklea, T.  English,
       and M. Hertz.  The effect of sulfur dioxide  and suspended sulfates
       on acute respiratory  disease.   Arch. Environ. Health  27:129-133, 1973.

307.   National Research Council.  Airborne Particles.  National  Academy  of
       Sciences.   Washington, DC, 1978, Chapter  9,  Epidemiological  Studies on
       the Effects of Airborne  Particles on Human Health.   I.  T.  T.  Higgins and
       B.  G.  Ferris, Jr..  pp.  243-288.

308.   National Research Council.  Sulfur oxides.   National  Academy of  Sciences
       Washington, DC, 1978,  Chapter  7.  Epidemiological  Studies of Health
       Effects.  F. E. Speizer  and B.  G. Ferris, Jr..  pp.  180-209.
                                     14-274

-------
309.    HAS.   Proceedings of the Conference on Health Effects of Air Pollutants,
       prepared for the Committee on Public Works, U.S.  Senate, Committee Print,
       Serial  no.  93-15, U.S.  Government Printing Office, Washington, DC, 1978.

310.    WHO.   Air Quality Criteria and Guides for Urban Air Pollutants.  Re-
       port  of a WHO Expert Committee.   WHO Technical Report Series no.  506,
       Geneve, 1972a.

311.    WHO.   Health Hazards of the Human Environment, Geneva, 1972b.

312.    WHO.   Environmental Health Criteria (8):   Sulfur Oxides and Suspended
       Particulate Matter.  WHO, Geneva, 1979.

313.    Shy,  C. M.   Epidemiologic Evidence and the United States Air Quality
       Standards.   Am.  J.  Epidemiol. 110:661-671, 1979.

314a.   Ferris, B.  G. ,  Jr.   Health Effects of Exposures to Low Levels of
       Regulated Air Pollutants:  A Critical Review.  JAPCA 28:482-497,  1978.

314b.   Waller, R.  E.  Discussion of 314a.  I. T. T.  Higgins, R. E. Waller,
       R.  S.  Chapman,  and J. R. Goldsmith.  JAPCA 28:883-892, 1978.

315.    Biersteker, K.   Polluted Air Causes, Epidemiological Significance, and
       Prevention of Atmospheric Pollution.  Assen,  Netherlands, Van Gorcum
       and Co., pp. 21-23 (in Dutch), 1966.

316.    Watanabe, H.  Health effects of air pollution in Osaka City.  J.
       Osaka Life Hyg.  Assoc.  10:147-157(in Japanese), 1966.

317.    Toyama, T., H.  Kanyo, K. Makamura, J. Kagawa, S.  Yakura, S. Adachi,
       N.  Yamoto, F. Iriyama, F. Kumagaya, S. Osawa, and T. Nakamura.  Study
       on the prevalence of respiratory symptoms in a rural area  (Kashima,
       Ibaragi Pref.) in Japan.  J. Jpn. Soc. Air Pollut. 7:24-35  (in
       Japanese), 1966.

318.    Tani,  S.  Epidemiological Study on Chronic Bronchitis.  Japan. J.
       Public Health 22:431-438 (in Japanese), 1975.

319.    Yoshii, M.  , J.  Nonoyama, H. Oshima, H. Yamagiwa, and S. Taked.  Chronic
       pharyngitis in air-polluted districts of Yo  KKAICHI  in Japan.  Mie
       Med.  J. 19:17-27, 1969.

320.    Becker, W.  H., F. J. Schilling, and M. P. Ferma.  The effect  on health
       of the 1966 Eastern seaboard air pollution episode.  Arch.  Environ.
       Health. 16:414,  1968.

321.    Lindeberg, W.  Correlations between air pollutant concentrations  and
       death rates in Oslo.  In:  Air Pollution in  Norway.   III.   Oslo,
       Norway, Smoke Damage Council, 1968.
                                    14-275

-------
322.    Tessier, J. P., J. G. Faugere, P. Coudray et al.  Essai de correlation
       entre les donnees de la pollution atmospherique a Bordeaux et les
       absences scolaires des infants pour cause bronchorespiratoire.
       Bronchopneumologie 26:30-45, 1976.

323.    College of General Practitioners,  Brit. Med. J. 11:973  , 1961.

324.    Nose, Y. Jjr  Proceedings of the First  International Clean Air  Con-
       ference, Nat. Soc. Clean Air, London, England, p. 209, 1960.

325.    Takahashi, H.  Chest Dis. 8:1687, 1964.  (In Japanese)

326.    Bell, A., and J. L. Sullivan.  Air Pollution by Metallurgical In-
       dustries.  New South Wales Dept. of Public Health, Sydney,
       Australia, 1963.

327.    Shephard, R. J. , M. L. Thomson, G. C. Carey, and J. J. Phair.   Field
       testing of pulmonary dynamics.  J. Appl. Physiol. 13:189-193, 1958.

328.    Shephard, R. J., M. E. Turner, G. C. R. Carey, and J. J. Phair.
       Correlation of pulmonary function and domestic microenvironment.   J.
       Appl. Physiol. 15:70-76, 1960.

329.    Cornwall, C. J. , and P. A. B. Raffle.   Bronchitis—Sickness  Absence
       in London Transport.  Brit. J. Ind. Med. 18:24-32, 1961.

330.    Toyama, T.  Arch. Environ. Health 8:153, 1964.

331.    McCarroll, J. R. , and W. H. Bradley.  Excess mortality as an indicator
       of health effects of air pollution.  Am. J.  Pub. Health  56:1933, 1966.

332.    Scott, J. A.  Fog and atmospheric pollution  in London, winter 1958-1959
       Med. Officer (London) 102:191, 1959.

333.    Scott, J. A.  Fog and deaths in London, December 1952.   Pub.  Health
       Rep. 68:474-479, 1953.

334.    Colley, J. R. T., and W. W. Holland.  Social and Environmental  Factors
       in Respiratory Disease.  Arch Environ.  Hlth. 14:157, 1967.

335.    Howard, P.  The Changing Face of Chronic Bronchitis and  Airway
       Obstruction.  Br. Med. J. 2:89, 1974.

336.    Spicer, W. S., P. B. Storey, W. K. C. Morgan, H. D. Kerr, and
       N. E. Standiford.  Am. Rev. Resp. Dis.  86:705-712, 1962.

337.    Spicer, W. S.  Arch. Environ. Hlth. 14:185-188,  1967.

338.    Lebowitz, M. D., and B. Burrows.  Respiratory Symptoms  Related  to
       Smoking Habits In Family Members.  Chest Vol. 69:48-50,  1976.
                                    14-276

-------
                 Changes to References for Chapter 14 - PM/SO
     Certain Chapter 14 reference numbers represent studies deleted from earlier

drafts of Chapter 14 or designate studies now to be deleted in keeping with

changes in text noted earlier in Chapter 14 corrigenda comments.   Thus, the

following Chapter 14 reference numbers should be disregarded:   98; 108-111;

113-117;  120-124; 190; 212-214;  314;  342.

     References for studies cited in  Chapter 14 but not listed in the original

reference list, as noted in earlier corrigenda comments or text errata listings,

are as follows:


342.  Melia, R.  J. W. , C.  duV.  Florey, and A.  V. Swan.   The effect of atmo-
     spheric smoke and sulfur dioxide on respiratory illness among British
     schoolchildren:   A preliminary report.   Paper given at the Vllth Inter-
     national Scientific Meeting of the International  Epidemiological Association,
     Puerto Rico, 1977.

343.  Lawrence,  W. W.   Of acceptable risk, science and determination of safety.
     Los  Altos, William Kaufman, 1976.

344.  Warren Spring Laboratory.  The Investigation of Atmospheric Pollution
     1958-1966.  Thirty-second report.  Her Majesty's Stationary Office, London,
     1967.

345.  Warren Spring Laboratory.  National Survey of Smoke and Sulfur Dioxide,
     Instruction Manual.   Warren Spring Laboratory, Stevenage, England, 1966.

-------
339.    Cederlof,  R.,  and J.  Colley.   Epidemiologies! Investigations on Environ-
       mental  Tobacco Smoke.   JJK   R.  Rylander, ed. Environmental Tobacco
       Smoke.   Effects on the Non-smoker.  U. of Geneva.  1974.  pp. 47-49.
       (Scand.  J.  Resp.  Dis., Suppl.  91, 1974.)

340.    Schilling,  R.  S.  F. ,  A.  D.  Letai, S.  L. Hui, G.  J. Beck, J. B. Schoenberg,
       and A.  Bouhuys.  Lung Function,  Respiratory Disease, and Smoking In
       Families.   Amer.  J.  Epidemiol.  106:274-283, 1977.

341.    Riggan,  W.  B., J. B.  Van Bruggen, L.  E. Truppi, and M. B. Hertz.  Daily
       Mortality Models:  Air Pollution Episodes,  Paper given at the VHIth
       International  Scientific Meeting of the International Epidemiological
       Association,  Puerto Rico, 1977.
                                     14-277

-------
              APPENDIX 14-A

CONGRESSIONAL INVESTIGATIVE REPORT (1976)
  COMMENTARY ON U.S. EPA CHESS PROGRAM

-------
                                   APPENDIX A


              Congressional  Investigative Report (1976) Commentary
                            on U.S.  EPA CHESS Program

     As first discussed on p.  14-93 of this chapter,  the various epidemologic

studies carried out under the EPA CHESS Program (Community Health and Environ-

mental Surveillance System)  have engendered a great deal of controversy.   Most

controversial was a 1974 Monograph reporting on certain of these studies  and

entitled:  "Health Consequences of Sulfur Oxides:   A Report from CHESS, 1970-1971".

Subcommittees of the House Committee on Science and Technology later produced

a report on the Monograph, the CHESS Program, and EPA's air pollution programs

in general—a report entitled:  "The Environmental  Protection Agency's Research

Program with Primary Emphasis on the Community Health and Environmental Surveillance

System (CHESS): An Investigative Report."  This report, referenced throughout

this document as the Investigative Report or "IR (1976)," is a comprehensive

reference for qualifying the use of the CHESS Monograph, and the CHESS studies

generally. The full text of the IR (1976) is contained in an Addendum to the

CHESS Monograph, EPA-600/1-80-021, which is available from EPA as noticed in

the Federal Register of April 2, 1980, 45 FR 21702.

     Because of the controversy surrounding CHESS,  all references in this

document to CHESS have been very carefully considered.  An effort was made to

discuss only those studies which have undergone scientific peer review and

have been published in the open literature apart from, or in addition to,

official  EPA publications.  Further, in this chapter (14), each study has been

assessed on its own merits,  considering pertinent published criticisms and

qualifications.  Many such qualifications concern errors in aerometric measure-

ments, and these have been discussed at length in Chapter 3.  Other qualifications

-------
concern the analysis of CHESS data and the  conduct of epidemiology  generally;

these are

discussed as appropriate throughout this  chapter and further below.

     A proper evaluation of any CHESS study cited in this  document  should

include careful  reference to the entire IR  (1976).   To put the  evaluation  of

epidemiologic studies in context, however,  the following passage  from Section

VI A of the IR (1976) is presented.   Following that passage, critiques from

the IR (1976) which specifically address  studies cited in  this  chapter are

reproduced.  Finally, a review of CHESS air quality analysis procedures and

results is presented, based on Sections V and VI of the IR (1976).

Section VI A of the IR (1976) opens with  the following passage:




     A.  GENERAL PROBLEMS OF EPIDEMIOLOGIC  INVESTIGATIONS  OF POLLUTION EFFECTS

      Before  discussing  health  effects  problems  specific to  CHESS, some discussion
 of  general  difficulties  inherent to  pollution epidemiology  may be helpful.

      Exposure to suspect pollutants  is not  controlled  in  population  studies.
 Indeed with  current  technologies,  it is  not possible  to be  sure that  the
 correct  pollutant  is  even  being  measured.   Combinations of  pollutants  may  be
 more  harmful than  any single pollutant,  and the number ot studies needed  to
 investigate  such synergisms  (interactions)  increases  rapidly with the  number
 of  pollutants under  consideration. The analysis of  synergisms  is often impractical
 since sites  with the  needed  configurations  of pollutants  are seldom  at hand.

       Not  only  is  exposure  uncontrolled, it is  often  difficult to measure.
 Even  when  aerometric  measurements are  valid,  special  meteorologic conditions
 or  personal  habits may  cause a given subject to experience  pollution levels
 very  different  from  those  measured at  a  nearby  fixed  monitoring  station.
 These problems  are exacerbated in long term studies during  which the quality
 of  aerometric data  has  been  variable and individuals  have changed jobs and
 residences.  Aerometric methods  for  measuring hourly  or daily  pollution levels
 are often  less  reliable than required  for  studies  associating  pollution levels
 with  short-term health  effects.

      The health measurements are often subjective  responses to a questionnaire
 or  interview.   An  individual may give  one  answer on a self-administered
 questionnaire and  another  to a friendly  interviewer.  Other  factors,  such  as
 the public announcement of  a pollution alert, can  also influence subjective
 health measurements.   Some  health measurements, such  as pulmonary  function
 tests  or blood  analyses, are less influenced by poorly defined conditions
 surrounding  the measurements and are said  to be objective.   However, even
objective  endpoints  respond  to uncontrolled events  like an  undetected
 influenza  epidemic or high  pollen count.

-------
     Whether the health measurement is subjective or objective,  the response
is often affected by factors (covariates)  associated with the subject studied
and unrelated to pollutant exposure.   Whether the individual  smokes or is
subjected to cigarette smoke at home or work is  a covariate of dominant
importance in pollution studies.  Educational  attainment may affect responses
to questions about phlegm or pneumonia.   Occupation, age, sex, race, immunity
to influenza, allergy, access to air-conditioning and countless  other covariates
complicate the interpretation of epidemiologic data.   Epidemiologists treat
covariates in two ways.  They try to choose study populations which have
similar covariate characteristics so that health differences  between such
populations can be ascribed to pollution effects.   Alternatively,  they make
mathematical adjustments to nullify the effects  of covariate  imbalances.   Both
strategies have weaknesses, and neither works if the investigator  is unaware
of an important covariate or has failed to measure it.

     The epidemiologist has little control over  the subjects  studied.  He
cannot assign them at random to reside in polluted communities of  interest.
Thus, a clean town may contain many asthmatics because asthmatics  have wisely
chosen to live there rather than in a more polluted community.  This fundamental
problem of self-selection must qualify any conclusions obtained  from non-
randomized population studies:  it may be possible to demonstrate  temporal or
spatial associations between health and pollution measurements,  but a causal
relationship cannot be inferred on the basis of  a single epidemiologic study.

     Students of pollution counter these weaknesses in several ways.  One
strategy is to replicate an epidemiologic study  in a variety of circumstances
and serially in time.  If a consistent association between pollution and
health measurement is observed, it is held to be reliable since  covariate
imbalances and problems of self-selection are unlikely to affect all sites and
to persist over time.  Clinical studies, in which healthy volunteers are
subjected to controlled pollution exposures, and toxicological studies, in
which animals are subjected to various combinations and doses of pollutants,
complement information obtained from epidemiologic studies.  This  body of
information from clinical and toxicological studies and from several epidemiolgic
studies may substantiate an interesting association suggested by the health
and pollution measurements of a single epidemiologic study.

     In addition to these general issues, several questions directly pertinent
to the CHESS health measurements were examined,  namely:

     (1)  Was the health measurement a reliable and meaningful indicator of
public health?

     (2)  Was the statistical analysis sound and impartial?

     (3)  Were the methods used to ascribe specific health effects  to  specific
pollutants and to establish dose-response relationships  logically compelling?


     The following critiques from Appendix A, Part B, of the  IR {1976) may  be

helpful in assessing studies cited in this chapter.

-------
      No.l,  "Prevalence of chronic  respiratory disease symptoms  in adults:

                                                                                    212
1970  survey of  Salt Lake Basin Communities."   Reported by Chapman et  al.
                                   APPENDIX A
                                  !•*
            A  RECAPITULATION OF  THE  AEROMETRIC  AND METEOROLOGICAL,
              FINDINGS or THE INVESTIGATION AS  THEY  RELATE TO SPECIFIC
              SECTIONS OF THE CHESS MONOGRAPH AND THE HEALTH FINDINGS

                                   A. INTRODUCTION

              This section contains citations of errors and omissions found in a
            careful review of the CHESS Monograph which show that the use of
            aerometric and meteorological data in correlation with health effects
            end point measurements can easily mislead the reader of the CHESS
            document  into  inferences  which are not wholly or even partially
            supported  by the data in the report. Page, paragraph, and figure
            references are to the 1974 CHESS Monograph.
              Since an important application of the aerometric  data is to deter-
            mine  correlations with health  effects,  any errors  or overusage  of
            aerometric data based upon estimates or improper measurements will
            obviously reduce or negate  the value of any health effects correlations
            which are attempted. This misusage or overusage of aerometric data
            will be particularly  damaging as the extension of the conclusions is
            made in an attempt to discover possible threshold effects.

                                      B. CRITIQUE

            1. Prevalence  of Chronic  Respiratory Disease  Symptoms in  Adults:
                 1970 Survey of Salt Lake Basin Communities
              Observed  concentrations for  only  one year have  been used  to
            crudely estimate concentrations of sulfur  dioxide and suspended
            sulfates relating  to  a 4-7 year exposure. The 1971  observed annual
            average concentration of  sulfur dioxide  was used with the  1971
            emission rate from the smelter to obtain a ratio that was then mul-
            tiplied by  emission  rates for other  years to estimate concentrations
            for the other years. The.  estimated sulfur  dioxide concentrations
            were then used in a regression equation based on  a 1971 relationship
            to estimate suspended sulfate  concentrations. Possible  changes  in
            meteorological conditions  and  mode of smelter  operations  were
            neglected.  Acknowledgment is not given in  the discussion and sum-
            mary that the critical concentrations relating to health effects are
            nothing more than estimated concentrations.
              It is questionable whether or not long-term exposures  should  have
            been attempted for Magna, based on only one year's record of ob-
            servations  that are abnormal because of the smelter strike. It would
            certainly have been appropriate to have mentioned that only es-
            timated long-term data were available and indicated their degree of
            uncertainty in the discussion and summary.
                                          (85)

-------
                               86

  Further, we find many errors on Page 2-37, Table 2.1.A.14. It seems
that this table should have never been included in the report. Aside
from the misuse  of the diffusion model (discussed in Chapter IV) this
table lists suspended sulfate values for Magna for the years 1940-1970,
that are not the same as listed in Table 2.1.A.16, on page 2-39. The
values are estimated by a simple ratio from the smelter emission rates,
but this is not explained. On page 2-39 a regression equation is used for
the same purpose. All of the sulfate concentrations under the heading
CHESS are estimated observations except those for the year 1971.
This has not been properly indicated, e.g. by the use of parentheses.
  On pnges 2-37 emission rates are not sulfur dioxide rates as indicated
but emission rates in tons of sulfur per day. This means that the sulfur
dioxide emissions were twice the values listed. It also means that the
dispersion model estimates are incorrect. However, the listed estimated
concentrations in Magna and Kearns,  which are based  on a simple
ratio between observed concentrations in 1971 and some emission rate
for 1971, whatever it might be, are not changed.
  Note that the regression  equation  for suspended sulfates, Salt
Lake City, (pages 2-39) which is:

                     SS=0.101(TSP)-3.65

is quite different than that which can be obtamed from Table 2.1.4,
i.e.:
                     SS=0.065(TSP) + 1.93

  S02  exposures were derived by multiplying  the yearly smelter
Emission of S03  by the ratio  of the 1971 measured annual average
S02  concentration to the 1971  SOa emission rate (193  tons/day).
  Estimates of suspended  sulfates were derived from the estimates of
S02, using the  following regression equation for 1971:

                       SS=0.09 (S02)+6.66

  The annual  TSP exposures were derived by multiplying the yearly
smelter production of copper by the ratio of the 1971 measured annual
arithmetic  mean TSP concentration to the 1971 copper production
rate (260,000 tons/year).
  Smelter  emissions of sulfur dioxide in the early 1940's were roughly
three times greater than they were after  1956 although copper  pro-
duction has remained more or less constant. The method for estimating
suspended  sulfate, which is based on sulfur dioxide estimates leads to
very high values in the 1940's whereas the total suspended particulate
are estimated lower in 1940 than in 1971. The procedure used produced
very high ratios between SS and TSP for the earlier years. For example,
the 1940 ratio  (34.6/63) is 0.55. This ratio is so large that it is obviously
questionable.
  The audacity of the  estimates can be  seen in Figure 2.1.17. The
lowest value, which occured in 1971, is extrapolated all the way back to
1940, reaching unusually high annual average concentrations of more
than one part per million. Considering the effects of wind direction,
which would result in low concentrations much of the time because the
emeltcr stack  plume would not be blowing toward the town, such an
annual average would result in short-period concentrations many times

-------
                               87

the annual average. It is questionable that such high concentrations
ever occurred. If they did, they would be well-remembered, and living
conditions in Magnawould be different than in 1971. Such unreasonably
high estimates should have been further investigated  before being
presented.
  The grossness of the estimates made overrides other shortcomings
in this study pertaining to  exposure that might be mentioned. How-
ever, more carefully made estimates would have required considerably
more work,  including obtaining meteorological records and details of
smelter operations affecting plume behavior over the period of years
studied. Such a large effort may not have been worthwhile considering
the inexactness of some of the other aspects of the study. Nevertheless,
a study of this nature seems to call for actual observations, more ac-
curate estimates, or considerably less exactitude in its conclusions.
2. Frequency of Acute Lower Respiratory Disease in  Children: Retro-
     spective Survey of Salt Lake Basin Communities,  1967-1970
   The same comments apply to this study as for  the preceding study
on the prevalence of disease symptoms in adults. Inadequate recogni-
tion is given to the fact that only estimated concentration  data are
being used in the discussion and summary.
3. Aggravation of Asthma  by  Air Pollutants:  1971  Salt Lake Basin
     Studies
   In this study, daily entries in a dairy were used to determine weekly
asthma attack rates.  A statistical relationship was  then determined
between the attack rates (weekly) and observed air pollution concen-
trations (averaged weekly). Participants lived within a  2-mile radius
of air monitoring stations.
   Daily exposure of asthmatics in a community such  as Magna, which
is close to the smelter, are poorly characterized by a single monitoring
station. On a given day, one side of the community could be much more
affected by  the smelter stack plume than the other, and high concen-
trations from looping or fumigation  might affect one neighborhood
but  not others. The study inadequately assesses the effects of peak ex-
posures and episodes.
   This report does not make clear that the minimum  temperatures
used were from the Salt Lake City airport. The assumption seems to
have been made that temperature was uniform over the entire study
area. This is not true because  of the differences in elevation and the
effects of  the mountains, and the lake. Perhaps the differences  were
not  important, but they should have been considered. It is not  clear
why days were stratified by minimum rather than mean temperature.
   Minimum temperatures  occur during the  early morning wnen peo-
ple are generally indoors and perhaps in bed. When  temperatures are
low, windows are generally closed. Also, lower minimum temperatures
are  correlated with other meteorological phenomena that could also
affect asthma attack rates, e.g., lower humidity and lower wind speed.
Further there may be a correlation with wind direction. A lower than
average minimum temperature probably is also associated  with a
strong temperature  inversion  which would be  conducive to  lofting
the  smelter stack plume. Because of the  many questions raised, the
findings pertaining to temperature merely suggest further study and
have no general application.

-------
                               88

  Near the middle of the left hand column, page 2-89, the following
sentence  appears. "The shut-down of operations by the strike was
accompanied by a pronounced improvement in air quality and a reduc-
tion in asthma attack rates that occurred sooner and were larger than
seasonal reductions  observed in the more distant study communities
some 2 weeks later." Here there is a lack  of appreciation of the natural
climatic differences  that exit in the Salt Lake Basin. Some effects of
summer weather  could easily be delayed two weeks before reaching
Ogden. The average date for the last killing frost in Ogden is about
May 6, whereas the average date  of the last killing frost at Saltair
(the climatic station nearest to Magna  with  a long record)  is about
April 12.
  On Page 2-76 (near middle of page, right hand  column)  the smelter
is not "5 miles north of Magna."
  On page 2-81 the first graph in Figure 2.4.1 is incorrectly drafted.
After the 17th week the broken line should be solid and the solid line
broken. The temperature curve should  appear as  in  the graph for
the high exposure community.
  Figure 2.4.2, page 2-81, shows a weakness in the argument that the
sulfur  dioxide concentrations are responsible  for the  asthma attack
rate. In the High Exposure Community the attack rate starts up at
the 18th week as  the  sulfur dioxide concentrations approach zero, or
near zero, and remain very low for about six  weeks. It is noted that
this same graph shows the highest SO2 peak occurring at the 9th week,
which  seems to begin  about May 9. The graph on page 2-16 seems to
show the peak in April.
  In Figure 2.4.4,  page 2-82, with respect  to  the High  Exposure
Community, it may be noted that the sulfate concentrations are not
particularly well-correlated with the sulfur  dioxide  concentrations
plotted in  Figure 2.4.2, on the preceding page.  The  highest sulfate
reading occurs in the 3rd week, whereas  the  sulfur  dioxide levels
build up to a peak in the 9th week.
  On page 2-87, left hand column, it is stated that a threshold concen-
tration of  1.4 /ig/m'  was calculated for suspended sulfates  for the
higher temperature  range. In Figure 2.4.4 all of the  plotted concentra-
tions  are greater than  this value. Considering the background of
suspended sulfates generally observed, this low threshold  value seems
to have no practical  significance.
  The third paragraph that appears in  the right hand column, page
2-89, probably applies to  Magna, however,  this is not  made  clear.
There  is  a possibility that the paragraph could be given  broader
interpretation than  actually intended since the  last three sentences
seem to refer to conditions in urban areas generally. The paragraph
probably  should  have been divided into two  separate  paragraphs.
However, the main fault with the paragraph is  that important con-
clusions are drawn that are not supported by information presented
elsewhere in the report. It  says "excess asthma  attributable to  sulfur
dioxide might be expected 5 to 10 percent of summer days", "total sus-
pended particulates could occur on up to 5 percent of summer days and
30  percent of fall and winter days", and "excesses due to  suspended
sulfates are likely to occur on 10 percent of fall and winter days and
90  percent  of summer days." Assuming that the stated  relationships

-------
                               89

between  concentrations and temperature  are  true, the report does
not explain how the percentages of days  were obtained. The study
covered, only 26 weeks, but these conclusions apply to an entire year.
The percentages given seem to be rough estimates since they appear to
be given only  to the nearest 5 or 10 percent. The percentages might
have been obtained from daily values  for the minimum temperature,
pollutant concentrations and asthma attack rate; but it is not clear
how they were obtained.
  Presumably daily average concentration  levels of specific pollutants
were used in the construction of the "hockey stick" curves shown on
pages 2-86 and 2-88.  The discussion implies  that "24-hour levels"
were used, but the precise nature of the air quality data used in the
threshold analyses is not made clear.
  There could be various reasons not  explored by the study  why the
thresholds for asthma attacks  were lower on warmer  days. One of
these is that there may be more plume looping on warmer days. This
might  result  in  localized,  short-period,  high  concentrations,  but
relatively low  average  concentrations.
  The validity of scientific work can be tested  by the repeatability of
results. In this and the other CHESS  studies  there  were factors
affecting asthma attack rates  that were  not  considered and whose
effects are unknown. Such factors are:  time spent outdoors, percentage
of time windows are open, temperature change, relative humidity, etc.
The incompleteness 01 the study and the lack of understanding of the
causes of the asthma attacks suggest  that it might be  repeated with
significantly different results.
  Short-term  exposures  to concentrations much higher than average
annual or weekly concentrations could have occurred in the commu-
nities  studied  that were near large sources of air  pollution  such as
smelters. There exists the possibility that asthma attacks could be
triggered by brief-duration high concentrations. Such exposures could
have been  determined only inadequately  by the procedures used in
the study.  The report does not make clear why more  attention was
not devoted to peak concentrations.
4. Human  Exposure to Air Pollutants in  Five Rocky Mountain Com-
     munities, 1940-1970
  On  pages 3-7  through 3-12 beginning with the second  columnj
paragraph near middle of page, which begins  "By comparing .  . .".
There  is not  a simple relationship between average daily pollutant
emissions and  average annual pollutant  concentrations because  the
receptor area is often now downwind.  Also, some consideration should
have been given to determining if the years for which data are available
were representative meteorologically.
   (Page 3-11) Second paragraph, left hand side of page. Information
obtained during this investigation indicates that the ratio 1.63±0.21
should be 1.42±0.21. (The value 1.63 is the upper limit of this ratio.)
   (Page 3-12) Emission ratios of particulate  and  sulfur dioxide for
1971 are omitted from  this report. Therefore, it is not possible to
verify  the ratios given here.
   (Page 3-12) According to information obtained during this investi-
gation, the two values for TSP listed as  99.5 for  the years  1971-70,
should be 98.1 for both years.

-------
      No.  7,  "Prevalence of  chronic respiratory disease  symptoms  in  military

                                                                          212
recruits:   Chicago induction center."   Report by  Chapman et  al.
                                            92

             ties  where certain health effects were observed, the source of the
             suspended sulfftte is inadequately determined. The study findings are
             much too incomplete to call for the stringent control of suspended
             julfates as has been done on page 3-51.
             7. Prevalence of Chronic Respiratory Disease Symptoms  in Military
                  Recruits: Chicago Induction Center (Paragraph 4-ty
               Exposure estimates in this study are extremely crude.  In the sum-
             mary the following statement is made, "Available evidence indicates
             that exposures lasting  12  years or  more to ambient  air  pollution
             characterized  by elevated  annual average  levels  of sulfur dioxide
             (96  to 217  nz/m3), suspended particulates (103 to 155 Mg/m') and
             suspended sulfates  (14  ^ig/m') were  accompanied by significant in-
             creases  in the frequency of chronic  respiratory  disease  symptoms."
                The 96 Mg/m3 value is the average urban core value for 1969-70,
             which ranges from 54 to  138 Mg/ms, whereas the 217 Mg/m' is an average
             value for five  suburban communities for the. year 1969.  Going  back
             12 years  concentrations were much  higher.  During the  period  1960
             "through  1965, the lowest value was 222, and there was a nigh of 344
             in 1964.  For the five  suburban  communities there was data only for
             one pther year. It averaged 183 ^g/m!. The 14 Mg/m1 concentration for
             sulfates is for a period of 7 years, not 12 as stated. It basically repre-
             sents data for the Chicago core,area, with some scattered observations
             from East Chicago and Hammond, Ind.  The average concentrations
             for the city  should be somewhat less  than in  the core area. Use of the
             core area value would generally result in  an  overestimate.
                It is difficult to characterize exposures lasting 12 years for the entire
             Chicago area. Either this  should  have  been  done in  very general
             terms, nonquantitatively, or a greater effort should have been made
             to present more representative estimates.
                The assumption is being made that sulfate observations made at a
             central  urban  location in Chicago, averaged with a few  observations
             from East Chicago and Hammond, Ind. are generally representative of
             the entire Chicago area.
                (Page 4-8) Referring  to the Chicago area the following statement is
             made: "Each sampler location, identified  by  a station name in
             Figure 4.1.2, represents the -central business-commercial  district of
             that particular area." This statement is not true. Practically all, if
             not all the samplers are located on the roofs of school buildings  in an
             effort to obtain  representative community values:  They were not
             located  deliberately  in  business commercial  districts  and  do not
             slightly overestimate area-wide concentrations as suggested.
                (Page 4-23) In reading this paper about the prevalence  of chronic
             respiratory disease symptoms in military recruits, questions  arise about
             the actual locations from which the men  came and the local pollution
             levels to which they might have been exposed. Some rural occupations
             result in high exposures to dusts, plant allergens, etc.
                (Page 4-35)  (Summary) The 12-year  value for suspended sulfates
             should be 16 micrograms per cubic meter, not 14, as stated. Also,  it
             appears  that the  concentrations of sulfur didxide and suspended par-
             ticulate  are for only the period 1969-1970 and not for 12 years as
             is stated. (See Table 4.1.A.6)

-------
      No.  8,  "Prospective Surveys  of Acute Respiratory Disease  in Volunteer

Families:   Chicago Nursery  School  Study,  1969-1970."   Report by Finklea et  al.117
                                            93

             8. Prospective Surveys of Acute Respiratory Disease in Volunteer Fam-
                  ilies: Chicago Nursery School Study, 1969-1970
               On page 4-41, in Table 4.3.1, it is not clear where the sulfur dioxide
             data for the years 1959-63 come from. The Chicago network, which
             would have provided community data, was not operating effectively
             until  1964.
               On the same page the suspended sulfate data are probably repre-
             sentative for the core area but are high to be used as an average for the
             city as a whole.
               A serious weakness in this study is that the communities are ranked
             Intermediate,  High, and Highest  according to a ranking that was
             determined  by suspended particulate values, whereas the most im-
             portant finding  pertains  to sulfur  dioxide. Referring back to Table
             4.I.A.I, it can be'seen that a considerably different ranking would have
             resulted  if the  communities  had  been ranked according to sulfur
             dioxide concentrations. In Table 4.3.1, it may be noted that during
             the study that the "High" community had the lowest concentration
             of sulfur dioxide.
               Also note in Table 4.I.A.I that the Highest communities include1
             GSA, which happens to be on the  south  edge of  the Chicago Loop
             area.  This station  probably  contributed considerably to the high
             concentration of sulfur dioxide attributed to the Highest community
             during 1969-1970, yet it is very nonrepresentative of a nursery school.
             Also, note that  the Highest stations include Carver, which for some
             reason ranks highest because of suspended particulate concentrations
             whereas the sulfur dioxide concentrations are relatively low.
               Sulfates are not considered in the summary of this study, which
             seems to focus on sulfur dioxide without quantitative considerations of
             suspended sulfate levels.
                (Page 4-54) In the first paragraph of the Summary, the following
             statement appears: "It is  also possible that more recent lower  air
             pollution levels contributed to increased respiratory illness." On page
             4-51  the following statement is found.  "Acute respiratory morbidity
             was significantly lower among families living in neighborhoods where
             sulfur dioxide levels had been substantially decreased."  These  two
             statements  are  contradictory and require  clarification.  The first
             statement is remarkable. It can be  interpreted  to mean that some air
             pollution is good for you. Did the authors intend to say this? Such an
             important finding is inadequately  supported by the contents of the
             report.
             9. Human Exposure to Air Pollution in Selected New York Metro-
                  politan Communities, 1944-1971
               An overusage of estimated data can be found on page 5-19. The
             following two  statements appear:  (Left hand  column,  middle para-
             graph) "Measured values for suspended sulfates for 1956-1970 were
             available from the Manhattan 121st Street Station, and these values'
             were  used for citywide  values."  (Last  paragraph  on page)  "The
             observed annual ratios of suspended sulfate to  dustfall for New York
             City were used to estimate the suspended sulfate levels in Queens and
             Bronx."

-------
      No.  10, "Prevalence of  Chronic Respiratory Disease  Symptoms  in Adults
                                                                          212
1970  Survey of  New York Communities."   Report by  Chapman et  al.
                                           94

             10. Prevalence of Chronic Respiratory Disease Symptoms in Adults:
                  1970 Survey of New York Communities
               Three communities were compared: Riverhead, Long Island, a low
             exposure community, Queens, an intermediate exposure community,
             and the Bronx,  a high  exposure community. Parents of all children
             attending certain elementary schools located within  1.5 miles of an
             air monitoring station in each community were asked to participate
             in the study. Each child was given a questionnaire to be filled out by
             bis parents and returned.
               Regarding  exposure,  were  the concentrations measured  at the
             monitoring  stations  generally  representative?  Assuming  a  person
             remains reasonably near the station, in this case within 1# miles, and
             breathes the outside air, the station measurements would be generally
             representative for  long-term average  exposure. Maps of  annual
             concentrations which are for sulfur dioxide and suspended particulate
             matter, show reasonably uniform  concentrations across  the study
             areas. However,  as has been mentioned in  the report (5.1) Human
             Exposure to Air Pollution Selected New York  Metropolitan Com-
             munities, 1944-1971,  by Thomas D. English, et al., the Queens Com-
             munity lies about 1 mile west of the John F. Kennedy International
             Airport. The effect of  this airport and the various other possible
             sources of  air pollution  that could have  affected  particular local
             areas were not determined.
               The  fact that the CHESS monitoring sites were the same  as used
             in the  city air pollution control programs suggests that the sites
             were picked and are being used because they seem to be generally
             representative.
               More important than the representativeness  of  the monitoring
             site locations in this  study is the proper interpretation of the effects
             of the  greatly reduced  pollution levels during the period 1969-1971.
             It is not meaningful to draw conclusions from sulfur dioxide exposures
             ranging from 144 to 404 Mg/m' and sulfate exposures ranging from
             9-24 jig/m3, as was done in this  study. The implication is that nealth
             effects  can be caused by the lowest concentrations mentioned,  and this
             is not shown in  the study. Also,  it is stated that annual sulfur dioxide
             levels of 50 to 60 Mg/ms (accompanied by annual average  suspended
             sulfate levels of about 14 ng/nr and  annual arithmetic mean total
             suspended particulate levels of about 60 to 105 ng/ms) could be assoc-
             ciated  with such effects. These are  levels-that were measured in 1971,
             whereas in the study there seems to have been no way to have differ-
             entiated between the effects of pollution in  1971, or that might have
             occurred during some earlier time.  I\ is not reasonable to infer that
             lower pollution levels axe responsible for the observed health effects.

-------
      No.  11, "Prospective  Surveys of  Acute  Respiratory Desease  in Volunteer

Families:   1970-1971  New York  Studies."   Reports by  French  et al,306

               214                      212
Hammer et al,     and  Chapman et al.
           11. Prospective Surveys of Acuie  Respiratory Disease in Volunteer
                 Families: 1970-1971 New York Studies
              In this study families were telephoned once every two weeks and
           questioned about possible health effects. The families resided within
           1  to 1.5 miles of the air monitoring stations, i
              In the  discussion it is stated  that acute lower respiratory disease
           morbidity can be attributed to exposures  to 2 to 3 years involving
           annual average sulfur dioxide levels of 256 to 321 yg/nr  (accompanied
           by elevated  annual average  levels of total suspended  particulate of
            97 to  123  Mg/m* and  annual average suspended  sulfate levels of
            10 to 15 Mg/nr). These values are average values for the period 1966-
            1970, a five year period, and not period of 2 to 3 years as indicated.
            Also, they are the averages for the Bronx and Queens, respectively,
            and therefore do not represent a range of concentrations that would
            have occurred in any particular community, as implied. For example,
            the sulfur dioxide concentrations in the Bronx ranged from 184 to
            472 Mg/m3 and in the Queens from 131 to 420 Mg/m3, during the five
            year period. Three year averages are 174 to 247 Mg/ni', and two year
            averages, lower still.
              On  page 5-16 the dustfall concentrations shown  in Figure 5.1.21
            seem to be greater than would be obtained from the data presented in
            Figure 5.1.16.
              On  page  5-36  (Table 5.2.1) the values in this table seem to come
            from Table  5.1.A.8. The  values  in the column headed 1949-58 are,
            except for dustfall, for  shorter time periods. For example, the values
            for Queens come from data for the years 1956-58.
              On page 5—45 (Summary) we find that since the concentration data
            base comes from Table  5.1.A.8, the long term exposure values repre-
            sent a period of less than  20 years.
              Further,  it is  stated that  there is  a distinct possibility that in-
            creased susceptibility to acute lower respiratory illness is  maintained
            or induced  by exposures involving  annual  average  sulfur  dioxide
            levels of  51  to 63 Mg/m'  (accompanied by annual average total sus-
            pended particulate levels  of 63 to 104  Mg/m3 and annual average sus-
            pended sulfate levels of 13 to 14 Mg/ms). i'he 51 to 63 ^g/'m3, is a range
            resulting from two different analyses of  samples  (see puge 5-53).
            It represents uncertainty in measurement techniques rather than  a
            range  of exposure  as  would  be interpreted.  These  concentrations
            and the suspended sulfate concentrations of 13 to 14 Mg/mS happen to
            have occurred in the Intermediate I  and  the Intermediate II com-
            munities  during  1971. This particular study as conducted could  not
            have differentiated  between  the effects of these levels of pollution
            and the effects of higher levels that occurred earlier.
              Only average annual concentrations were considered and not peak
            or episode concentrations.

-------
      No.  12, "Aggravation  of Asthma by Air  Pollutants:   1970-1971 New  York

Studies."   Reports by Finklea et al.
           It. Aggravation of Asthma by Air  Pollutants: 1970-1971  New York
                 Studies
             Panelists who lived within a 1.5 mile radius  of three monitoring
           stations in communities identified as Low, Intermediate I, and Inter-
           mediate II, because of  their average air pollution concentrations,
           recorded asthma attacks each day in a diary for a penod lasting 32
           weeks, October 1970-May 1971. From a statistical association between
           asthma attack rates, 24-hour average concentrations from the moni-
           toring stations, and daily minimum temperatures from airpdrts near
           the study  communities, it was  concluded  that 24-hour suspended
           eulfate levels of 12 /*g/m» on cooler days (Tmln  equal  to 30  to 50 )
           and 7.3 Mg/m' on  warmer days (Tinln greater than 50°F) were thresh-
           olds for the induction of excessive asthma attacks. No firm  evidence
           could be found to associate  elevations in sulfur  dioxide  (100 to 180
           ng/m1 on 10 percent of days) with excessive asthma attack rates on
           either cold or warmer days.
                Regarding exposure levels, there is much less assurance that daily
              average levels throughout a community would be more or less uni-
              form than would be the case with annual average levels. More moni-
              toring stations might have been operated, or mobile stations used,
              to determine how pollution exposure varied from location to location.
              The determination of such differences in air pollution concentrations
              might have  been important, but probably more important is that the
              other factors (in addition to the observed air pollutants) that could
              have caused or contributed to the asthma attacks were not examined.
              It would  not be worthwhile to refine the information on the distri-
              bution of the air pollutants studied, unless a greater effort were made
              to study all  of the various possible causes of the asthma attacks more
              thoroughly.
                The study focused  on the effects  of minimum temperature. The
              possible effects of other meteorological variables could also have been
              explored.  Of particular interest would be  the effects of sudden, large
              temperature changes.
                It  is not  made clear why minimum instead of average, or even
              maximum,  temperatures were  picked  for  correlation.  Generally
              there would be less  actual exposure to minimum temperature, which
              usually occurs about sunrise, than to warmer temperatures. Asth-
              matics would generally be expected to protect themselves from colder
              temperatures, staying indoors and keeping windows  closed, whereas
              on warmer days they might be more subject to exposure to outdoor
              air with its assortment of possible allergens. There are diverse reasons
              why temperature might be an important factor determining asthma
              attack rates. No attempt was made in  the  study to provide an
              explanation.

-------
   It is expected that there would be noticeable temperature differences
 between  Riverhead (the Low community)  and Queens  (the Inter-
 mediate I, community). Although it is stated that the temperatures
 come  from nearby airports, the temperature curves plotted in Figure
 5.4.1  seem  to be identical  for both communities,  it  may be noted
 that u different curve is plotted for the low community Figure 5.6.2,
   (Figure 5.4.4) Although at a glance it appears that for the Inter-
 mediate  community  that the "Attack  Rate"  and the "Suspended
 Sulfate"  curves are similar, close inspection  shows that  more often
 than not, they are out of phase. Between the 2nd  and 3rd week the
 attack rate (AR) curve continues down as the suspended sulfate (SS)
 curve starts  up, between  the 10th and llth wee"k  the AR-curve
 continues down after the SS-curve starts up, between the 14th  and
 16th week the AR-curve goes up while the SS-curve continues down,
 between  the  19th and'20tn week the AR-curve starts up while the SS-
 curve continues down,  and again on the 27th week the AR-curve
 rises a week before an increase in the suspended sulfate  concentrations.
 In all, three  of the five increases in attack rate precede, rather than
 follow, increases in suspended sulfate concentrations.


 IS.  Frequency and Severity of CardiopuLmonary Symptoms in Adult
       Panels. 1970-1971 New York Studies (Paragraph 5.6).
   Symptom  diaries were maintained daily  for the 32-week period
 October  8, 1970 through May 22,  1971, by four panels, depending
 on state of health. The panelists were distributed in three communities


and lived within 1.5  miles  of  air pollution monitoring stations. It
was concluded that elderly panelists in the low exposure community
reported higher symptom rates on days when sulfate levels exceeded
10 /ig/ni5.  There seemed to  be good evidence of a threshold effect
between 6 and 10 Mg/rna, with a greater morbidity excess on wanner
days.
  Since suspended  sulfates  seem to be more uniformly distributed
than a pollutant such as sulfur dioxide, the concentrations determined
by monitoring should be generally representative of outdoor exposure
ard in most  cases  indoor and  outdoor average  exposures would  be
expected  to be similar. The question not answered  by this study is
whether or not the panelists are also being exposed to some other
causative  agent, or stress factor, that might nappen  to  correlate with
the sulfate concentrations. It,  and not  the suspended sulfate con-
centrations, might be the cause of the observed health effects.
  (Page 5-91) (Figure 5.5.3) The low value of sulfur dioxide that
began  at  the 19th week and continued until  the 24th  week are sus-
pected of  not  being true values. Near the end of the last  paragraph
on the preceding page it is  suggested that meteorological conditions
may have been responsible. A  careful  study of the meteorological
conditions and fuel usage would  be necessary to determine if these
might  have caused the  persistent  low concentrations. However, a
scanning  of the  daily local  climatological data shows no  obvious
reason  for the reported low values.
  Furthermore,  the minimum temperature curve for the  Low com-
munity in Figure 5.5.2 is not the same as given in Figure 5.4.1.
  The  New York Department of Air Resources  also reported  a large
drop in concentrations following the mid-winter peakjat the  Queens
(Intermediate  I) monitoring station, but reported values were never
as lort-, and a period of low values was not followed by a rise as shown
in the  Figure.  Further, the low values shown,  which  are about 25
Mg/m1,  or  .01  ppm  or less, are  quite low for the New York  metro-
politan area. Average weekly low values two or three times this value
would  generally be expected for a comparable period.

-------
      No.  14, "Ventilatory  Function  in School Children:   1970-1971 New York

                                     ?i ^
Studies."   Report by  May et al.



             14. Ventilatory Function  in  School Children:  1970-1971 New  York
                   Studies (Paragraph 6.6).
               Pulmonary tests were  made in three elementary schools in  com-
             munities with different air pollution levels, and there were four rounds
             of testing, November-December 1970, January 1971, February-March
             1971, ana April 1971. The children lived within 1.5 miles of a particular
             air monitoring station. The Queens monitoring station is on top of a
             school where the testing was done. However, the Bronx station is on
             top of a "court house in the center of a busy commercial area" (page
             5-6) and may not be close to the school. For  the Riverhead  com-
             munity it is not made clear whether or not the school and the monitor-
             ing station are at the same location or near each other. It is assumed
             that the schools in  Riverhead and the Bronx were within 1% miles of
             the monitoring stations, but this is not actually stated.
               It was concluded that 9 or more years exposure to annual sulfur
             dioxide levels  of an estimated concentration of 131  to 435 Mg/m3
             (accompanied by suspended  particulate  levels  of  about 75 to 200
             fig/m8) and suspended sulfate levels of about 5 to  25 /jg/m1 can be
             associated with a  small but significant impairment in ventilatory
             function. These values are from Table 5.6.2, and are the extreme high
             and low values listed. There is an implication here that the low con-
             centrations,  131 ng/m* for  sulfur dioxide and 5 /jg/m* for suspended
             sulfates represent threshold values. Actually they are only annual
             average concentrations for the years 1969 and  1970.  The observed
             health effects may have been the result of exposure to much, higher
             concentrations in other years, or to some other cause.

-------
No.  15, "Ventilatory  Function  in School Children: 1967-68.
          Testing in Cincinnati  Neighborhoods.   Reported by  Shy  et al.
                 15. Ventilatory Function in School Children: 1967-68 Testing in Cin-
                      cinnati Neighborhoods (Paragraph 6.1).
                   This study included a pair of public elementary schools in each of
                 six neighborhoods differing in socioeconomic  level, race, or pollution
                 exposure. All children in one or two classrooms of the second grade of
                 the elementary schools were asked to participate in the study to achieve
                 sample sizes of 60 to 75 children in each-of the six study sectors,
                 Ventilatory performance as measured by a spirometer was obtained 12
                 times from each child: once weekly in the months of November 1967
                 and February and May 1968. The tests were administered on Tuesday
                 and Wednesday mornings.
                   Air monitoring stations were placed in locations within three blocks
                 of each school  to provide samples representative of the air quality in
                 the  neighborhood served by the school. No  information is reported
                 on the distances of the homes of the  children  from the  school. Ap-
                 parently it was assumed that the home environment and the school
                 environment were  the same. Indoor soiling index and sulfur dioxide
                 observations were taken in the schools, but results are not reported.
                 It is reported that it was determined that indoor and outdoor sulfur
                 dioxide, soiling index,   and suspended particulate levels  measured
                 over the  24-hour  or 4-hour period directly preceding pulmonary
                 function tests did not consistently correlate with the test values.
                   Details of this lack of correlation are not given, but it was concluded
                 that "ventilatory  performance of children thus did not appear  to be
                 acutely affected by variations in pollutant levels on the day of  the
                 test."  ^Possible exposures over intermediate periods, say three days or
                 one week,  prior to testing were not considered. Conclusions seem to be
                 based  on possible long-period exposures, probably over a lifetime.
                   Concentrations of sulfur dioxide were low (less than 52 Mg/ro*) io all
                 areas,  so  health  effects were attributed to particulate pollutants
                 independent of atmospheric levels of gaseous  sulfur dioxide.
                   Average sulfate levels during the period of  the study were observed
                 to be between 8.9 and 10.1 jig/m8, in the polluted lower middle white
                 community, but previous average exposure was estimated to be 10.7
                 to 12.1 Mg/m!, based on the National Air Surveillance Network station.
                 The average suspended sulfate level in the clean white sectors was 8.3
                 Mg/m8, a relative difference of 13 percent. (The largest differences in
                 area exposure  were in  the  concentrations of suspended particulates.
                 Levels of total suspended particulates were J31 us/in* in polluted  sec-
                 tors and 61 to 92 Mg/ni* in clean sectors.
                   In reading this paper one wonders  about  the psychological  inter-
                 action between the children and the team members administering the
                 tests, who could anticipate the outcome of the experiment. The curves
                 for the black  children  in Figure 6.1.3, are  particularly interesting.

-------
SUMMARY ASSESSMENT OF CHESS POPULATION STUDIES

The 1976 Investigative Report (IR) on page 76 states:

          No formal methods are used to link specific  pollutants with
     specific health effects in the CRD, LRD, ventilation, and ARD studies.
     If a demonstrated health difference between communities cannot be
     explained in terms of imbalances in known covarieates, it is generally
     ascribed to pollution.  It is not possible to know which specific
     pollutants, if any, or what concentrations of any suspect pollutants,
     were responsible for the health effects.  The health effects data
     provide at most a rough guide for making general  judgments about
     probable health effects in other communities with similar pollutant
     sources, meteorology and population composition.

          The methodology used in the panel studies (asthma and cardio-
     pulmonary) attempts to disentangle the effects of the several pollutants.
     The multiple regression and relative risk calculations are interpreted
     as implicating...

          ...these formal methods do not provide logically compelling
     evidence that SS, or indeed any of the measured pollutants is of
     dominant importance.  The remarks are meant to aid in the assessment
     of the validity of the conclusions presented in the Monograph and to
     assist researchers performing similar studies and encountering
     similar difficulties.  This endeavor was greatly  assisted by hindsight.

Other  specific criticism of the 1974 CHESS studies have been that:

1.  Since ARD incidence has not been related to smoking habits consistently

all of the results must be suspect.  The results from  studies of ARD

have been inconsistent and the reason is not clear.

2.  Since increases in some adverse effects, e.g., LRD have not always

been consistent with the indicated pollution gradient  shown by multiple

study communities the data are not valid.

3.  Because the arbitrary scores developed to indicate LRD severity or

ARD severity seem sometimes not to represent a consistent gradient, the

entire system is suspect.  An accurate gradient may not be expressed by

an increasing numerical score, though the lowest scores represent less

severe illness than do the highest.

4.  Because consideration was not always given to exogenous smoking and

thus secondary exposure, or because ethnic or religious factors were

not considered in the analyses, the results are suspect.

-------
5.   Panel  study comments:

     a.   Many relevant factors,  including  medication  (steroids),  humidity,

     exercise, daily temperature changes,  nitrogen dioxide  levels,  and

     exposure to smokers at home or work were not evaluated.

     b.   The overreporting of asthma attacks on weekends  would  tend to

     invalidate results.  Higher reported  rates of asthma attacks occur

     on  weekends when pollution  levels generally are  somewhat lower.

     c.   The underreporting of attacks as  the length  of subject participation

     grew longer.

     d.   Reporting of attacks on heavy consecutive days suggests  a  lack  of

     association with pollution.  In many  individuals the occurrence  of

     an  asthma attack can be triggered by  many stimuli.

     e.   Daily measurements of air pollution are so poor  that they  cannot

     be  correlated with daily changes in symptom aggravation.

     f.   Failure to consider such factors  as pollen density,  indoor pollutant

     concentrations, location where episodes began, and medication  taken

     by  study subjects, cases doubt on the validity of the  data collected.


Comments for the future contained in the IR (1976) on page  16 included:

     "The overall impression left with the review groups  was  a  general
awareness of many of the problems we found in the air quality health
effects  research area.

     Specifically, questions such as the following must be  resolved for
future epidemiological studies:

     (1)  How do CRD  questionnaire responses change on serial  administration
in an area with unchanging pollution patterns?

     (2)  What is the sensitivity of the self-administered CRD questionnaire
compared with its use in an interview?

     (3)  What is the nature of the statistical dependence of-ARD *
attack rates, and what formal statistical  methods are appropriate to the analysis
of relative attack rates?

-------
     (4)  What can be done to tighten the eligibility requirements
for asthma and cardiopulmonary panels?

     (5)  How can the statistical analysis of asthma and cardiopulmonary
panels be improved?

     (6)  What combination of CHESS health measurements is most
appropriate to long-term serial  surveillance?

     (7)  What combination of CHESS health measurements is appropriate
to intensive studies of specific pollution hazards?"

     It is apparent from previous comments in this chapter and this section

that the Investigative Reports'  comments (IR, 1976) apply to all  past related

epidemiologic studies.  Yet, even the Committee indicated that the health

effects were there.  Some sense can be made from previous findings as well

as for planning future studies.

-------
        Section  IV  of the 1976  Congressional
        Investigative Report  (IR) concerning
        CHESS air quality measurements is  as
        follows:
       IV. CHESS AEROMETRIC MEASUREMENTS

                        A. INTRODUCTION

  As pointed put in the introduction, the attainment of precise, reli-
able, reproducible, and real time air quality measurements in the  field
(e.g., SO: and particulates) was a critical element of the CHESS pro-
gram.  This chapter provides a  critical review of  the  aerometric
measurement aspects of CHESS.
  However, before reporting on this  review two facts about CHESS
aerornetry should be mentioned. First, the methods used in CHESS,
especially in 1970-71, were probably as good as any available. Second,
quality control procedures  were slowly introduced into the CHESS
program. EPA cannot be criticised, and is not criticised in this report,
for using the best available  methods.  However, EPA can be criticized
for not pursuing a vigorous program of quality control throughout
CHESS. The  review reported  here  showed that CHESS did not
employ well-established quality control measures. The quality control
prop-am described in Appendix A of  the Monograph  was not carried
out.  A thorough quality  control program would  have discovered, for
example, the temperature effects on the method  used  to measure SO:
(described below). It would also hnve placed bounds  on the validity
of the data and precluded ovcrinterpretations.
  In the design and implementation of any measurement sj'stem, the
single most important consideration  is the end user of the data pro-
duced  by that measurement system.  In the  simplest  of all measure-
ment processes,  an individual scientist conducting his own research,
both measures the parameters of interest and uses the resultant  data
to draw conclusions about his experiment. In  such a  process the
individual involved has at his disposal all of the information contained
in the data, especially that concerned  with the limitations of the  data
and  the constraints under  which  they  should be used. In this  type
of situation, few formal  qualifications of the  recorded data ore neces-
sary since those'qualifications are implicit in the  mind of the scientist.
  In  larger programs however, the measurement process and the
utilization  process are quite often compartmentalized such that one
group of scientists is responsible for the collection, quality assessment
and storage of the measurement data,  and a second, usually nonrelated,
group  of scientists is responsible for the synthesis of all pertinent
information into a  final  set of  conclusions.  In  this type  of systems
research, the determination  of the fundamental quality 01 the measure-
ment data and transmittauce of that  quality  assessment are the single
most important  qualifier in the process of going from observation to
understanding.
  The CHESS program, as designed and implemented by the Envi-
ronmental  Protection Agency, is  a classic example of the  large sys-
tems  approach   to  research.  The  epidemiological   measurements
were designed, conducted, and stored by one group of scientists; the
                              (25)
     77-530—78	3

-------
                               26

fccromctric measurements were designed, conducted  and stored by a
second group of scientists.  The desired end product, a correlation of
health effects with atmospheric pollution was then derived from these
two independent sets of data accumulated in a large data storage net-
work.  It is important to reemphasize here that in such a research
program it is incumbent upon the measurement personnel to transmit
to the data user all of the information containea in the resultant data,
especially that relative to accuracy and precision. In order to under-
stand  the problems encountered in a large research  program such as
CHESS, it is necessary to understand the types of measurements that
were made.
  The assessment of atmospheric pollution exposure received by  a
defined population can be  derived from one of two broad classes of
measurement. The first is  a measurement that yields an "index" of
pollution. The second  is a  measurement that yields quantitative in-
formation about a specific pollutant as it is found in the atmosphere.
  A pollution index is a measure of the relative level of  pollution which
contains little or DO information as to the specific chemical or physical
properties of that pollution.* These indices can be useful in assessing
short-term trends of atmospheric quality in well-defined and  limited
geographic regions. They cannot be used to deduce information about
the source or  chemical nature of the material being measured. They
also cannot be used to  assess long-term  trends  of pollution  burden
since gradual changes  in  pollution sources will distort the  quan-
titative aspect of the index.  Most importantly, they cannot be used to
correlate  atmospheric  pollutant levels among  diverse  geographic
areas. Here again, the  difference in chemical and physical makeup of
the pollutants being measured distort  the quantitative aspect of the
index.
  An example of a measurement thnt gives a pollution index is the
dustfall observations as  applied in CHESS. In this method, an open
topped cylinder called a dustfall bucket is used to collect any pnr-
ticulate matter that falls  out,of the  atmosphere.  This  collection  is
carried out over a long time period,  usually one month; and the total
dry weight of material  collected is used to estimate pnrticulate burden
of the atmosphere during that time  period. A detailed description of
this process is given later in this Chapter. This measurement falls in
the index class because nil  solid material, regardless of its derivation
or chemical nature, is included in the final quantitative result.
  The second class of  pollution measurement is that which contains
information both  on the  specific species  of  pollutants and  on the
atmospheric  concentrations of those  pollutants.  In  this tvpe  or
measurement the sigruil that is measured is derived from a process or
  Rroperty which is specific to the pollutant of interest and which corre-
  ites  directly with the concentration of that pollutcnt in the atmos-
phere. An  example of  this  type of method is  the West-Gaeke proce-
dure for the measurement  of  atmospheric sulfur dioxide. In this pro-
cedure, air is bubbled through an absorbing solution at a known rate.
The solution is specific for  the r.bsorplion of SO2 from the air.  After  a
known duration of sampling, the quantity of SO; which was absorbed
from  the  air  is  quantitatively determined  by  the formation of  a
 • N.B. This Imlct 1« not the kind of "nlr qmlity Inrtri" oflrn uwl pnpnlvly fin ridlo broadcast* rtr 1
to »drlv clllims of Ihr rclid*. urfjunlitv of * city. 6ucb popular air quiLty Indicti *rr ujually »m»«l at
by combioint raeuuiemeouof Mrcral poUuUnU.

-------
                               27

colored chcmicnl complex of S02. If carefully carried out, the procedure
pives  an accurate value for the S02 concentration. The procedure is
described in detail later in this Chapter.
  Measurements such  as the  West-Gneke  procedure,  which  are
specific  and quantitative,  can be  used  to  compare atmospheric
pollutant burdens across diverse  geographic areas and through long
time periods. They can also be used to assess short-term variations in
pollutant levels  provided  that sufficient  sensitivity  exists in  the
method to  obtain a meaningful signal for the short time period used.
In conducting a program such as CHESS, vrhere an attempt is made
to relate health effects to pollution burdens, only those measurements
that fall in the  second  class, specific and quantitative, can  properly
be used  to  assess the relation  between health effects and pollutant
burden.
  In this chapter, an attempt will be made to evaluate the method-
ology used  to  measure  aerometric  parameters and  to  assess  the
validity of the resultant data. The review will encompass procedures
used in the field  situation, the quality control exercised over the proce-
dures, and the data storage and retrieval  network. Conclusions will
be drawn as to the adequacy of  the measured pollution levels to assess
exposures received by specific CHESS population groups.

         B. REVIEW or CHEMICAL AND PHYSICAL METHODS

1. THE WEST-GAEKE METHOD FOR  THE MEASUREMENT OF AMBIENT SOj
a. Description, of the Method
  The West-Gacke colorimetric procedure for S05 determination is
the designated Reference Method (Federal  Register, S6, No.  84, 61CS,
April 30, 1971).* Atmospheric SO2 is collected bv bubbling air through
a solution of potassium tetrachloromercurate (TCM). The product of
the reaction between S02  and  TCM is  the nonvolatile  dichloro-
sulfitomercurate that is then determined quantitatively bv reaction
with  formaldehyde  and  pararosanilino  hydrochloride, followed  by
photometric measurement of the resulting intensely colored  para-
rosaniline methyl sulfonic acid.
b. Description of the Field Apparatus and Sample Collection
  Outside air is drawn through a sample line at the rate of 200  nil
rnin"1, then through  a 6-inch long  glass bubbler stem (tip  diameter
of 0.025 in.) immersed  in  35  ml  (50 ml  after January,  1974)  of
0.1 M TCM solution  contained in a 32 mm diameter by 164  mm long
potypropylene sample container.  The  exhaust air  passed through a
glass wool moisture trap, then through ft hypodermic needle used as a
critical orifice to control the flow, tlirough another  moisture trap,  and
finally through  a vacuum pump. A sample consisted of a 24-hour
collection.  Collected  samples were stoppered,  and mailed  to EPA/
RTP for analysis.
e. Validity  as a Laboratory Procedure
  A collaborative study  by McKcc et al. (H.  C.  McKee, R.  E.
Guilder?, and O. Saenz,  Southwest Research Institute, S'WRI Project
21-2811, EPA contract  CPA 70^10) indicates  that "the method can-
 •AUercaUlr M« CFR Title 40, Fart SO. Apr?ndu A.

-------
                               28

not detect a difference smaller than 10 percent between two observa-
tions by the same analyst in the range of 0 to 1000 ^g m~5 A difference
of 20 percent or less may be detected above '^DO^g m~3, and a difference
of less  than  50 percent may  be  detected above lOO^g  m~V  For
analyses conducted by different laboratories on the some sample, "the
method cannot detect a difference of  less than 20  percent between
single-replicate observations of two laboratories in the range  of 0 to
1000 Mg m~3- At  a level of 100 /jg m~3, a difference of less than 100
percent is not detectable."  The  National  Primary Ambient  Air
Quality Standard for S02 is: For 24 hour average, 365 ^g/m*. For annual
average, 80 jig/m3.  Thus if the standard is met, most values  will be
around or below 80 Mg/m3, no more than one will be above  365 Mg/EQ3.
   Regarding the lower limit  of detection, the authors cited aoove
propose a value of 25 Mg ni~3 as a practical figure. "A single determina-
tion less  than this value is not  significantly  different from zero"
(Instrumentation  for  Environmental  Monitoring,  Air-SO,,  Instru-
mentation, Lawrence Berkeley Laboratories,  March 1972).
   It is therefore  evident that a single analysis is of little use, con-
sidering that the  expected concentrations of SO2 will usually be less
than the ambient air quality standard of 80  ^g m~3. Results should
be regarded as valid only in terms of the mean of multiple determina-
tions,  and only  when the  analytical method has  been followed
rigorously  by  experienced analysts.

                2. TOTAL SUSPENDED PARTICULATES

   Total suspended  particulates (TSP) were measured using the EPA
Reference  Method as specified in the Federal  Register (86  (84):
8191-8194, April 30, 1971$).
   Total suspended  particulates (TSP) were measured by drawing air
through a prcwieghed 8 x 10 inch  glass fiber  filter for a period of 24
hours.  The apparatus used for this procedure  was the standard High
Volume Sampler. At the end of the 24 hour time period, the filter was
reweighed, and the TSP computed on the basis of total air flow. The
ail- flow rate was approximately 60 ft'min""1 at the start, and must be
not Ie?s than 40 ft3uiin~l at the end for the measurement to be accept-
able. The average air flow rate was computed on the basis of a straight-
line interpolation  between beginning and ending flow rates.
   The  National Primary Ambient Air  Quality Standard for TSP is:
For 24 hour average, 260 pg/m*. For annual geometric mean, 75 ji£/m3.

                      8. SUSPENDED SULFATE

   Suspended sulfate was analyzed,  during the  CHESS program, using
portions of the TSP samples. From  the beginning  of  CHESS to
September 1971 the turbidimetric method of analysis was  used; then
the turbidimetric  method was dropped in  favor of the methylthymol
blue method, which was used throughout the remainder of the CILESS
program.
  The turbidimetric method consists of the water extraction of soluble
sulfates on the TSP filter, the addition of a barium chloride prepara-
tion to the extract,  and measurement of the resultant turbidity (from
           sco CFR Title 40, Part M, Appendix B.

-------
                                29

 the formation of insoluble barium sulfntc) with a spcctrophotometcrT>r
 colorimeter. Accuracy of the method is affected by the kind and con-
 centration of other ions present, as well as pH, conductance, tempera-
 ture, and bnrium concentration in the test solution.
   The methyl thymol blue method also utilizes the wafer extraction of
 soluble sulfates from the TSP. The filter extract is then passed through
 nn ion-exchange bed  to  remove interfering ions, and barium chloride
 is added under slightly acid conditions, forming barium sulfatc. Then
 the test mixture is made alkaline  and methyfthymol blue is added,
 which forms a  chclate  with the excess barium. The uncomplexed
 methythymol blue is  equivalent to  the amount of sulfatc present, and
 is measured spectrophotometrically. The metbylthymol blue procedure
 is automated (Technicon Autoanalyzer)  in all steps following water
 extraction of the TSP, end  this part of the procedure is reproducible
 within a ranee of 2 percent. Error in the determination of sulfate occurs
 predominant!}- in the steps preceding the methyl thymol blue method.

     4. DUSTFALL BTJCKET,  TAPE SAMPLER, CASCADE IMPACTOR,
                      AND  CYCLONE SAMPLER

   In addition to TSP measurements using  the Hi-Vol sampler, four
 other means of estimating particulate concentrations were used at
 various times.  The}'  are the  duslfall bucket, the tape sampler, the
 co.scade impactor, and the cyclone sampler.
   (a) The name "dustfall  bucket" is adequately descriptive.  It  is
 basically an  open-topped cylinder, with some protection against wind
 and rain loss, that is left out in the open, close to the ground or on a
 rooftop, for a month. At the end of that time the dry matter collected is
 weighed, and sometimes analyzed for trace metals. The dustfall bucket
 method is very crude and misses almost completely the very significant
 part of the aerosol, including the respirable aerosol, that does not settle
 rapidly. It must be considered here, however, because dustfall measure-
 ments were  extrapolated to obtain estimates of  suspended sulfates
 and sulfur  dioxide in Mew  York  City  during the  period 1949-5S
 ((Table 5.2.1, CHESS Monograph), and intermittently  in Chicago
 (Table 4.1.A.3), CHESS Monograph). Dustfall measurements  were
 used  as the basis for these extrapolations because there was no other
 basis for such estimates, but it must be remembered that the relation-
 ship between suspended sulfates and  dustfall is unknown, and that
 between sulfur  dioxide and  dustfall is another step  removed  from
 reality.
   (6) Coefficient of Haze (COH) is determined by the automatically
 operating tape sampler. It  is determined by measuring  the optical
 density of  an aerosol deposited on  n filter tape. The aerosol deposit
is obtained  by drawing air at a given flow  rate through white  filter
paper tape for a known period of time. If one could assume that the
composition  and physical characteristics of the aerosol  in a given
location did  not change with time—that only atmospheric loadings
would change—then the COH would give  a fairly good approximation
of the variations of particulate loading and visibility.
  However, this assumption is seldom justified, and even  at a given
location the  COH  only  roughly approximates  the  true  particulate
loading. The COH method is worthless, or nearly so, for comparisons
between  areas with dissimilar aerosols.  For  example, the aerosols

-------
                               30

collected at the Utah  sites  are primarily the light-colored alumir.o-
silicate dust, whereas  the aerosol collected within the inner core  of
large cities has  a predominantly sooty chnracter. For a  given  par-
ticulate lending the Utah aerosol will often have as little as one-tenth
the optical density of the urban aerosol.
   (c) The cascade impactor operates on the principle that  particles
in an air stream will tend to  follow a straight line when the air stream
is deflected, and thus  can be impacted  on  a surface in their path.
The cascade unpactor  consists of a series of parallel plates separated
by precisely  determined spaces.  Alternate plates contain a certain
number of "holes of a size that is decreased  as one goes through the
scries of plates from entrance to exit. Alternating  with the plates
containing the calibrated  holes are plates without holes. These  may
be coated with R medium for the trapping of impinged particles. Air
is drawn through the apparatus at a known rate, and tho particles are
collected in decreasing size fractious related to the decreasing size of
the holes in the plates.
   (d) The cyclone sampler is a device for the collection of the re=pi-
rable size fraction of an atmospheric particulute  loading.  It operates
on the principle that the inertia of individual particles will tend  to
keep the particles moving in a straight  line  when the air stream  in
which they are carried is deflected. By this means  the  larger size
particles are removed by impaction and settling, while the respirable
particles are carried along with the air stream and  are subsequently
collected on a filter.

   C. FINDINGS  AND EVALUATIONS OF MEASUREMENTS  AND  DATA
                           REDUCTION

   It is important to preface this evaluation of the CHESS air moni-
toring program with a statement of  the following  facts.  The inves-
tigative team  looked backward at the  program through a window in
time with all of the subsequent knowledge built up during that time.
More than  ten years  have  passed  since the  initial  planning of the
CHESS program and more  than six years have passed since the first
data were collected. During  that time there has been a vast  improve-
ment in  the understanding  of the methods  used  for pollution moni-
toring. Many  of the procedures used  in CHESS have subsequently
been  found to  contain serious errors. These problems  were often
uncovered as a direct result  of research and  quality control programs
ongoing within EPA. It would thus be unjustified to lay criticism  on
the principal?  in the CHESS program for using state of the .irt meas-
urement technology.
   On the other hand, some  serious oversights in scientific judgement
did occur. In the area of pollutant monitoring, these oversights could
have been completely avoided had proper attention been paid to even
rudimentary  quality control procedures. Throughout the  program,
much more emphasis was placed on the uninterrupted collection  of
data than was placed  on  the systematic evaluation of data quality.
The fiHd investigation  stage of this review identified numerous prob-
lems that resulted in the propagation of  unnecessarily large errors in
the aeromctric data. These  unevalu.itcd  errors persist even  today in
the data as it is stored in the CHESS computer  system. They could
have  been avoided or  easily discovered  and  quantified  hnd "a  well-

-------
f
                               31

designed quality control procedure been applied to the CHESS aero-
metric monitoring program. This statement is contrary to the state-
ment of the quality  control procedures  in  appendix A of the 1974
CHESS  Monograph. Appendix A  \vns  not a manual provided  to
CHESS  data gatherers, but was written lont:  after the data in the
1974  Monograph were  collected. However,  during  the field  investi-
gation of the CHESS monitoring contractors, it was found that the
quality control procedures as described in Appendix A of the CHESS
Monograph were routinely disregarded. In fact, for the first two years
of the program, virtually no EPA-direclcd  quality  control program
was implemented  at  any of the New York, Salt Lake City or Los
Angeles  CHESS monitoring sites.  Problems that were found in this
time  period were observed and documented by contractor personnel
and it was  mainly through their personal professional conduct that
any of the  field  problems were corrected.  Reasons  for this  rather
 TOSS oversight on proper data  management can only be  conjecture,
 nit it did appear that  inadequate staffing of the monitoring group,
coupled  with the intense pressure to get "the monitoring stations on
line and producing data, led to the situation described.
  In  fairness (regarding the time perspective mentioned earlier) the
problem of inadequate quality control on many large EPA programs
eventually was recognized internally  and in  1074 a  Quality Control
Branch was established  in the Quality Assurance  and Environmental
Monitoring  Laboratory. This brunch  was given the authority to im-
plement  proper quality  control  procedures on  all large atmospheric
monitoring  programs. Since  the formation of this group,  there has
been  a significant and  steady improvement iu quality assurance as
applied to air monitoring methods and data.
  In  this section, major emphasis will be  placed on review and evalu-
ation of  the  analytical methodology  used  in the CHESS program to
assess population  exposures to sulfur oxides  and  total  suspended
participates. Conclusions will be general to all data taken at "official"
CHESS  monitoring sites, regardless of location.  Where local  differ-
ences in procedures or rcsultont data did occur, these will be described
separately. Health studies, as described  in the 1974  CHESS Mono-
graph, that  used aerometric data derived from non-CHESS monitor-
ing sites  will be reviewed separately.

                        1. EULKUR DIOXIDE

  Atmospheric levels of S03 were determined  using the  EPA Ref-
erence Method, better known as the \Vest-Gacke or Pararosanaline
method.  The specific details  of this method are described  in the
procedures section of this chapter (Part B.I.). However, a few im-
portant  aspects of this method  will bo reiterated.  This reference
method is basically a laboratory method adapted for field use. It  is
a "wet chemical"  procedure relying on a gas-liquid phase chemical
reaction  between S02 and sodiuVa tetrachloromercuratc (TCM). To
accomplish this reaction, the SOj as a gas phase  pollutant, mu~t be
quantitatively absorbed  into  the  liquid  reuctnnt solution. This  is
accomplished" by bubbling ambient air  through the  solution at  u
controlled flow rate, thus, its description as a "bubbler method."

-------
                              32

  In an attempt to  stnndardize the methodology  nmi to eliminate
problems associated with intcrlaborutory errors, a CHESS policy was
instituted  whereby nil air sampling equipment was assemble;! nml
tested  at the central EPA research  laboratory und then  shipped  to
the contractors for field use. Also, bubbler tubes were prefillod with
the appropriate absorber solution, shipped to the contractor for their
daily monitoring use, and shipped back to the central laboratory for
chemical analysis. It  was this long distance shipment of the chemical
solutions that led to the first of a scries of field-use problems with the
procedure.  These problem areas will be summarized below with  an
attempt to evaluate their net effect on the resultant CHESS S02 tlritu.
Following this summary of individual problem areas,  nn  assessment
of the overall S02 data quality will be given.
a. Spillage  of Peagenl During Shipment
   The first field data were obtained in New  York City nr,d the Salt
Lake area  (Utah) in November, 1970. By mid-1971, field personnel
nt the Utah site reported to their CHESS field engineers  that sevpre-
spillnge was occurring during shipment. Many bubbler  tubes were
arriving partially filled with reagent and some were completely empty.
At the Salt Lake area  an attempt  was made  to refill with solution
from extra tubes those tubes that were low.  However, due to insuffi-
cient reagent, this was only partially successful.  This problem was
not officially recognized until October, 1972, at which time p.n internnl
EPA/CHESS memo was written outlining tho problem and suggesting
corrective action. The magnitude of the problem can be best n-ses=ed
bv quoting from the memo. "The present rcngent tubes for SO; and
Js'Oj leak during shipment.  . . .  The S0: leakage rate (was found to
be) 18% of the total  volume, 50% of the time. ... It follows there-
fore, that the resultant pollution data are unreliable." Recommenda-
tions were made in this memo as to possible corrective measures. These
recommendations were not instituted until March, 1973.
   During the subsequent years, many attempts were made to correct
this leakage problem. However,  none were wholly successful and ns
late as January 1975, another EPA memo described losses of solution
in SO; bubblers during shipment and suggesting appropriate corrective
action.
   The effects  of the reagent spillage problem on  the SO- data can
be only grossly estimated. Certainly, ninny samples were  totally lo-t.
These lost samples were not the major problem. Of more  signilirancr
was the undetermined amount of daily SOj data that were in error
due to the loss of sample by spillage and yet included in the network
system.
   If the reagent was partially lost  during shipment to the ?nmplin2
site and used as received,  fin increased concentration of TCM-SOj
complex would occur relative  to  normal sampling.  This potential
positive bias would be corrected by for the analvtical procet'ure u
-------
                               33

According .tt> the EPA Memo of October, 1972, onr> half of oil  SOj
datn taken between November,  1970 and  March, 1973 are  likely to
have been biased low by nn average of 17%. This problem  was  cor-
rected  after April,  1973.
b. Time Delay of the Reagent—S0< Complex
   The  Reference  Method as originally  described  in the Federal
Register, was to be conducted at 20° C. There was a known error in
the method associated with tune delay between sampling and analy-is
which  was dependent on temperatures. This error was derived from
the spontaneous decomposition over time of  the TCM-SOj  complex
as a function of temperature. The magnitude of the error anu its
exact dependence on temperature was  not known but a brief study
was conducted to determine its magnitude  by scientists of the CHESS
monitoring group in  November,  1971.  As a result  of this  study, a
correction factor of +1.5% per day was arithmetically applied to nil
CHESS SO; data to compensate for the time delay between sampling
nnd analysis.
   A more recent and comprehensive study has been carried out within
the Quality  Control Branch,  Environmental Monitoring Laboratory
at EPA on the effect of temperature on "The Stability of SOi Samples
Collected by the Federal Reference Method." This study indicated a
much more severe problem than was estimated by the original CHESS
study.  The evaluation was carried out over the range of 35 to  278
MS/m3 SO2 concentration.  The following findings  were presented in
the report:
       Over a normal range of temperature,  the rate of decav of the
    TMOSO2  complex increases five-fold for  every  10°C  increase
    in temperature, respectively.
       The rate of decay is independent of  SO: concentration.
       At 20, 30, 40, nnd 50° C the following SOj losses were observed:
    0.9, 5, 25, and 74% loss per day, respectively.
   This study makes abundantly clear a second and even more severe
error associated  with the  SOj measurements conducted by  CHESS.
During the summer months,  when the S0:  absorber solutions were
subjected to high and unknown temperatures between field sampling
nnd laboratory analysis,  significant degradation of  the samples did
occur. Estimates of time delay between sampling  and analysis range
from 7 to 14 davs. Estimates of summer temperature exposures range
from 25 to 40° C being most severe for the Utah CHESS sites. Thus,
CHESS SO; data can be estimated to  be  negatively biased, mainly
during the summer months. It would normally be difficult or impossible
to estimate the magnitude of the bias except to say that it is probably
large. However, simultaneous S0: measurements were taken by the
New York City Department of Air Resources and by the Utah State
Division of Health. These results were obtained by aa independent
method not susceptable to the temperature related error. A consistent
pattern emerged when side by side data are compared. From May to
October, the CHESS S0: data were lo\v with the largest error occurring
in the middle three summer months. The magnitude of the error varied
from month  to month and year to year, but the CHESS data were
consistently low and represented only n portion of the true ambient SOj
conceutration.

-------
                              34

c.  Concentration Dependence, oj Sampling Kfethod
  The SOj reference method was  subjected to a collaborative study
program in 1973. Four participating laboratories tested the 24-hour
•version of the Federal Reference Method. A previously unknown source
of error wns documented that npplics to the CHESS SO: data. It wr.s
found  that the 24-hour sampling  method does have i\ concentration
dependent  bin1;  which become^ significant nt the high eonr.pntm-
tion levels  (200Mg/m5). Observed values tend  to be  lower  than the
expected (known) S02 concentration  levels. This error source will yield
n negative  bias on the dnily CHESS S0: data when they exceed 200
Mg/ins and on nil monthly and yearly average datn.
d. Low flow correction
   The determination of atmospheric  S02 concentration was dependent
on, among other factors, the accurate measurement of nir that, passed
through the TCM solution. This flow wns controlled bv a critical flow
orifice in the form of a standard hypodermic needle. In practice, the
air flow  through the sampling system wns measured at the start and
end of each 24-hour sampling period. Tins was done to detect low
flow due to needle blockage. The Federal Register Method (Rpference
Method) calls  for an air flow of 200±20 ml/min. In field operation, the
CHESS procedure substantially broadened these tolerances. Replace-
ment needles  were  installed if the  initial air flow was greater than
220 ml/min which is consistent with  the Reference  Method; however.
needles were not replaced nor were samples voided until the measured
flow dropped below 100 inl'min. Integrated flows were calculated by
assuming a linear decrease in flow between the start and end of the
24-hour sampling period. If, however, the needle was partially blocked
near  either the beginning or the end of  the sampling period, the
linear flow correction would be in  error. Using the  Reference Method
flow tolerance, only small errors would be introduced by this correction
•(less  than  10%). Using the  CHESS procedure, however, errors  as
large as 50% could be introduced  ond not  detected.  These errors
would be random (either positive or negative) depending on when dur-
ing the sampling period the needle  blockage  occurred? Thus a larse
random  error  component wns added to the SO2 daily  data  but this
component was somewhat damped  statistically in  the  monthly  or
yearly averages.
   The  modification  of  flow tok>rancc by the CHESS  ncrometric
group is a procedure that would not have withstood the critical review
of a competent quality assurance program.
«.  Bubbler train leakage
   The West-Gaeke  method, as  described  in  the Federal RegUter,
employs a  vacuum  bubbler train. That i?, the sampled air i< drawn
through  the bubbler train by  a  vacuum pump  rather than  being
pushed through by a positive pressure pump. There are  many ad-
vantages to the vacuum procedure, most  important is  that the  air
does not come in contact with any internal pump mechanism. However,
there is a modest pressure differential between the atmosphere and the
internal  bubbler; thus nil  fittings and joints must be gas tight. The
bubbler train used in the CHESS program had two points where frequent
air leak problems were encountered.  One was  around the rubber
stoppers for the bubbler tube and moisture  trap and the other was the

-------
                               35

rubber  tubing used to hold the class assembly pieces together. Field
operators reported consistent problems with lenknge in the routine field
use of the bubbler train. In a severe leak situation, the samples were
voided  due to out of tolerance  (Low) flow rntes. There were many
cases however, where small leaks occurred  but the fmnl flow was
within  specifications so the sample  was included ns valid.  In cases
where the leaks  formed around the  rubber  stoppers,  no significant
error would be introduced  except due to the  linear flow correction as
applied to instantaneously developing leaks. This error is similar in
nnturc  to that discussed in the flow  section.  In the case of leeks  up-
stream  of the bubbler train, room air inslcnd of outside air  is drawn
through reagent. In normal situations, it hns ber-n observed that room
nir  is significantly less  polluted than outside  air. (See page C-C.
CHESS Monograph—comparison of school air to outside nir). This
effect may not ue as large for the small buildings used  to house CHESS
stations, but a somewhat decreased pollutant level would undoubtedly
be sampled. The absolute magnitude of this error cannot be fidcquntrly
assessed but it can be stated  that the error would be in a  negative
direction, that is, again to underestimate SO2 levels.

             2.  GENERAL ASSESSMENT OF CHESS SOj nATA

  The SOj data, accumulated at "official" CHESS  sites, followed a
remarkably uniform trend as the prosrom progressed. The method
Used was the EPA Reference Method wliich is specific for the  chemical
specie^, SO:. Thus, regional chanses in pollutant mix, i.e., the propor-
tion of  other pollutant species relative to SO:, hod minimal  effort on
the SO: data. However, the sum effect of the errors detailed  in this
section  did have a profound effect ou both the accuracy find the preci-
sion of  the data.
  Under  normal  circumstances,  n.  retrospective  evaluation of a
monitoring effort  that occurred a number of year;  in  thr  pa-t and
whirh had been terminated, could yield only the broadest of estimates
of  data quality.  Fortunntelv  for  this  review,  two  geographically
different locations with six different  monitoiing sites  were  involved
in the collection of simultaneous SOj data.  Further, the groups re-
sponsible  for the two data sets were managed independently and  the
methodology used was also independent. This fortunate circumstance
enabled the reviewers  to  acquire  n quantitative understanding of
absolute differences among data sets ns well as correlations with renvl aridiTietiicly and in
Salt Lake  City  they were quantified cond'ictiomctriedlly.  Neither
muthoil is  ns specific for  SOj as  H  the  R-fcrcncc  Method, that is,

-------
                               36

pollutants  that  are  in  a  significant ronmntrntion, relative to S0:
and that also oxidize to form nn acidic compound will be interpreted
as SOj. For tin"? reason, when the NYC Department of Air  Resources
initially brought to the attention of the CHESS Aerometric team the
large (fiscrepancy between their respective dnta, the discrepancy wai
dismissed as method bin< on the part of (he Now York method. An
EPA memo dated November 3, 1971 described n limited study into the
Reference  Method.  The conclusion reached  was "On  the basis of
(this study) ... I feel there is no sound bi^is for discrediting the
•EES (Environmental Exposure System) methodology."
   No further attempt was made to uncover the cixr.'-e of the discrep-
ancy in S03 data. Had the CHESS EES team obtained and compared
the Salt Lake Bnsin data, especially thnt from Magnu site, ft  disturbing
similarity would have been immediately apparent. This data confirmed
in detail  the discrepancies observed in New York. It is important that
the  Magna site  data were confirmatory since it \vns  in a region of
sincle source pollution, that from the nenrby  copper smelter. In  this
site very low levels of other pollutants existed  relative  to SO:, thus
the  peroxide method win capable  of giving rensonablv  reliable esti-
mates of the S0: concentration. Of equal importance the general  pol-
lutant mix was very different between  this rurnl smelter site and the
urban area of New York City. Despite these differences  the compari-
son  of side bv Fide Federal-State data indicate the same discrepancies
in both trends and absolute  concp.nlrafionv The following conclusions
as to SO; data validity can thus be reasonably drawn from  the review
of methodological errors and the comparison of existing side by  side
data.
   From November 1970 until December 1971 the S0: data generated
from CHESS sites using {lie modified Reference method were bia-pd
low by 50  to 100 percent in the High Exposure sites when compared
with existing State  S0: data.  Tims, the 1971 annual  average  SO;
exposure estimates of eOpg/m3 as reported for Muslin  in the CHESS
 monograph (page 2-24) arc more likely in the vicinity of  100 nz'
 Al-o, the same phenomenon occurred in New York and the reported
 values arc  also m ciinihi:- error.
   A confirming fact is that during cool months njtcr 1971 SOj dnta
 correlated  well both in trends  and ubsolut" corporations between
 State and Federal analyses. It thus seems likely that the  State data
 were reasonably accurate throughout that time'pcriod. However, one
 consideration' must  be  applied here: namely, that due to tlir Jiflrrcr.cr
 between the independent methods  an error bar of at  leant one hundred
 percent must be applied to the da'a ami rrpHcltli/ correct data cannot be
 drawn  from these obwnations. In  other words  where (wo  or  more
 independent observations are in disagreement by a significant amount
 it cannot be said  by inference nlon? thr.t one data >--et is more correct
 than the other. It is reasonable to t\ssumc, however, from  our review
 of nil State and Federal data in (he time period of 1970 through  1971,
 that the Federal SO: d.ita  ft- collected in the CHESS program were
 substantially low mid  went through an abrupt upward tran-:ition in
 concentration in December 1971  nt all CHESS sites ami Federal data
 taken  before that (ime may reasonably be c.xpcctcd to have a Ian:?,
 unknown negative bias.

-------
  In November 1971, the CIIESS monthly mean SO: data underwent
nn abrupt change in tlic po-itive direction. The cau-c of thi- change i<
not apparent. However, the result was profound. From tlmt time until
the conclusion of tlic CHESS program in July of 1975, the fall-winter
data were in very good agreement with other existing data end very
likely pave reliable estimates of fc>O: exposures.
  Throughout the entire  program, the CIIESS  SO: data  had  nn
associated negative bias during the summer months,  becoming mo-t
severe during  the  ho!te:-t periods  of July and August.  This error
usually reached fx niaximurn of CO  to SO pel cent imdcrci-timation oT
exposures nud was variable.  A- a result, even though  wintertime
monthly S0; averages appear valid from 1072-1975, annual average-;
of the snmc datu ure biasrd low due  to the inclusion of the summer
errors. The  best estimate of error in  the annual average data 1972-
1075 is approximately minus 15-20 percent relative.
  The individual  daily SO: levels, when  compared  to city or State
data or to replicate CIIESS measurements taken after 1C73 had ?-o
large a random error  component that they ore not useful to a--e~s
daily SO2 exposure (as attempted in the asthma panels). The  random
errors associated with the daily values were much larger than  the
differences observed over lime.
  Due to inherent methodological errors,  the following may  be con-
sidered as minimum differences between High and Ix>w SO: exposures
which  mrty  be considered  "real." These are b:i«ed on EPA's collab-
orative study of the reference method and used a 95 percent confidence
interval.
       Below  100  jig/m'  SO;,  ft difference of at least 50 yg,m3 is
    necessary to be statistically significant.
       Between 100 and 300 ^g/in3 S0:, a difference of at least 60 ^g/m:
    is nccc>«ary to be significant.
       Below  25 /jg/m3,  a single determination is not significantly
    different from zero.

                3. TOTAL  SUSPENDED PARTICVLATE

  The Hcfer'-nce  Method for  the determination of total suspended
participate mutter (TSP) is probably the simplest and mo^t reliable
method used  by CHESS.  It  has been  well studied and  most error
sources are known. However, it is a method that measures an arbitrary
and poorlv defined portion of the total atmospheric pnrticulatc burden
and the portion measured has unknown relevance to the human respir-
uble portion. The si?.c fraction measured is somewhat dependent on the
design of tlic shelter used for Hi-Volume sampler. The design and di-
mensions of the Reference Method shelter arc specified in the Federal
Register, thus the  portion of TSP that is collected by the  method
is generally  uniform. Best estimates  of particle size  range included
in the Reference Method  are  from 0.05  to  CO  pin diameter. Above
60 ttm  diameter, the particle fall velocity is too great to navigate  the
bend  nround the roof of the  shelter. Below 0.05  ^m the collection
efficiency  of the glass fiber filter used in the  method  diminishes.
  A  collaborative study was  conducted on  the Reference Method
using  12 different groups sampling ambient r.ir at a common location.
The results of this study indicate tlic method is capable of reproducible

-------
                               38

measurements with les? than 5 percent error nt  the 95 percent con-
fidence level. Also, the minimum detectable amount of TSP is approxi-
mately 2  jjg/m' (or  a 24-hour sampling period.  This *f.nsitivity is
more ihan sufficient for most 24-hour fSP measurements.
  Tlie TSP measurement method, as used in CHESS, had  one notable
difference  from the laboratory procedure which was  collaboratively
studied. The weighing procedure to determine TSP was performed at
EPA/RTP laboratory not by  the  CHESS contractors on site. This
necessitated the shipment  of  individual  filter samples through the
mail and  the  subsequent storages of the samples at EPA. During
laboratory reorganizations  nt RTP,  periods ns  long as 6 months
elapsed between actual field sampling and laboratory analysis.
  The following is  a summary  of individual errors and an assessment
of overall  TSP data quality.
Loss of partifulate matter before weighing
  In  the TSP methodology there were field-related procedures that
resulted in partial loss of  participate matter from  the  Hi-Volume
filter samples. Due to the exposed location of the Hi-Vol TSP samplers,
wind  and cold sometimes made it very difficult to remove the filter
paper from the apparatus without  lor.ing pnrt of the sample. No
estimate has been made of loss due to this problem; it would, of course
bias the reported  results only in the direction of lo\ver-than-actual
atmospheric loadings. This was not a constant problem among CHESS
sites.  It was noted by field operators us bcinj a particularly  severe
problem in the Salt Luke City urea during the winter months.
  Two other error sources  have been identified in the determination
of TSP, both  of which would  also produce  a low-side bias:  (1) the
shaking-off of particles from the filter during transit from the field
site to EPA/RTP, und (2) the evaporation of organic substances. In nn
attempt to quantify the mass loss during transit, David Ilinton, EPA/
RTP, made a  comparison of filters collected  in Utah, before and after
mailing from Salt Lake City to RTP (22). He found that  there was  a
overtime 4 percent loss. Carl  Broadhcad, of the  Utah  Division of
Heult.li, conducted  u similar  comparison;  however,  he  noted  nn
apparent loss of approximately 25%. This difference may, in part, be
due to the time of year the studies were conducted,  During the dry
summer months in the Salt Lake City area, much cf the TSP lending
is due to windborn crustal material (sand). This material is much more
easily lost in sample handling that is the finer anthropogenic particu-
late material.
  A final error source, one more difficult to assess, derives from wind
velocity versus collection efficiency. On days  with relatively high wind
(>15 mph), the Hi-Vol sampler is more susceptible to the inclusion
of large diameter  participate  material.  To  compound this problem,
the design of the shelter makes the magnitude of the error dependent
on the wind direction relative to the orientation of  the  shelter. The
main  result of this problem is that two side  by side Hi-Vol samplers,
oriented 00 degrees relative to each other, will produce  dissimilar
measurements  with  the discrepancy increasing  as  the  daily wind
velocity increases.
  The "overall  effect of the summed errors with  the Ili-Vol TSP
measurement is a slight  negative bins. This bias  may be ns smalPns
10% or may be ns large as" 30%. Side by side data from New York

-------
                               39

nnd Sr.lt Luke  indicate that this assessment is  reasonable. Those
datu filso indicate tlint the TSP data were by far the best quality
data tak^n in the CHESS monitoring program. Differences measured
between High and Low sites urc probably reasonable estimates  of
the differences of  TSP exposures  ^s received by populations within
these areas. Some  local source variations undoubtedly did occur, but
average annual exposures worn reasonable.
   In any overall assessment of the  CHESS TSP data it should be
noted  that nil of the sources of errors mentioned  previously related
almost exclusively to the loss of large participate matter and mnst
likely that matter  is a-^ociated with crustal weathering. This material
is outside of the normal human rcspirable  size fraction  and by com-
  ?osition, it would be unlikely to be associated with aggravated health.
  has,  loss of that portion  of the total  material may  not  have  di-
minished the quality of data for heulth effects studies. It mav in fact
have  rendered  that data  a closer  estimate  of the resniruble TSP
exposure to which  the CHESS population groups were subjected.
   It has been suggested by some environmental scientists that when-
ever Hi-Vol measurements  are made for health related studies, the
filter pads  should  be "shaken out" much like  a housewife does when
shaking crumbs  from a used tablecloth. The resultant TSP  exposure
estimates derived  from such a  procedure  would then  more closely
relate  to the human rcspirable  size fraction of the total atmospheric
particulate  burden.  Although  never  actually  implemented, this
suggestion  indicates the general  level of dissatisfaction with the TSP
Hi-Vol measurement method.

                   4. TOTAL SUSPENDED SULFATE

   The  determination   of  atmospheric  sulfate  concentrations,  its
carried out in the CHESS program, was a methodological extension
of the  Hi-Vol TSP method. Thus,  all errors r.ssociated^with the TSP
method also affect the sulfale method. Sub^amples w.-re cut from the
exposed Hi-Vol filters and were analyzed for totr.l \vater soluble sulfate.
Methods available for sulfate analysis at th?  time of CHESS deter-
mined  all water-soluble sulfatcs  as a class rather than distinguishing
them by chemical  species. Two  different methods were available  for
total sulfate ond both were used in CHESS.  From  November 1970
until September 1971,  the  manual  turbidimetric method  was em-
ployed. From September 1971  until Julv 1975, the methj-lthymol
blue (MTB) method was used.  The methods are somewhat similar
and are described in detail above.
   The turbidimetric method is subject to interferences, many of them
being other common pollutants. In  arcus  like the Salt Luke Basin
where  the pollutants are dominated by a single source,  the procedure
may be adequate.  However, in  urban areas like Cincinnati or New
York City, where the pollutant mix is derived from many independent
sources and is variable even within the city, the method is capable of
only the crudest estimates of sulfate  levels. It  should not be thought
of as  an accurate  measurement of  atmospheric sulfate. Especially,
small differences between High and Ix>w  exposure commmiitio*, such
ns were reported in the Cincinnati Study in the CHESS Monograph
(page 6-5) cannot be identified n.s real  differences. When a realistic eTror
estimate is applied to the reported sulfate concentrations, the differ-

-------
                               40

encc becomes  statistically insignificant. Any correlation  of  CHEF'S
hc.ilth effects with sulfntc levels where the sulf;;tc data were obluined
using the turbidimctric method muM be carefully qualified.
  The MTI3 method is b;\-ically u better measurement method becnu-e
most of  the  neromctrir  interferences  luivc been eliminated by  its
revised methodology. The t\vo remaining interfcrents, phosphate nnd
barium, nrc not normnlly found  in  atmospheric con<.cntra!ion>  high
enough to cause inordinate problems. However, problems os§orinted
with the sampling aspect of the  melliod have been  documented ond
do impact on the "general CHESS sulfatr data c;unlity.
  First, problems associated with sidfnte blanks (the level of sulfnlo
on  tlie (liter pad ns manufactured) were reported  to be high nnd
variable. In the 1071-1073 time period, problems of variable blank*
within the EPA NASN  program  were documented. Tl.c general
blank level was equivalent to an atmospheric sulfalc concentration
of  1-2/ig/ni'. However, the majur  problem VMS  variability of the
blank among manufactured lots of  the filters. The blank level  ofr^n
varied by more than  100 percent  among  lots  so that routine ond
continuous blank assessment should have  been mandatory.
  No evidence of routine sulfate blank determination  was found in
the CHESS monitoring program until  1974.  From  that time period
on, adequate blank assessment and correction were applied to the  data.
From 1971 until 1974 however, the  blank contribution to the CHESS
sulfate data was not adequately assessed and consequently a. po.-itive
nnd highly variable bias of unknown magnitude wr.s included in the
data.
  Second, adsorption of atmospheric S0:  onto the fiberglass  filter
material  followed by spontaneous oxidation of the S0: to sullats had
been well  documented.  A  19GG  publication  by  R.  E.  Lee nnd
J. Wagman provided results of their invc>tigation of  the problem. The
conversion was clearly documented v.ilh severe eticcts (Icmor.stratrd
on four-hour samples. The conversion did appear to he an uctive-site
catalytic conversion that decreased in  magnitude ofler an initial
saturation  of sites.  Thus, 24-hour  samples  were  much les? affected
by  this problem thnn  were those taken for shorter time  intervals.
Even so, the paper by Lee and  Wr.gman,  presented data  in which
routinely 0.5 to 1 ^m3 oMhe  measured sulfate was  derived  Jrom
SOj  conversion  products. The maximum conversion  presented was
2.1pg;m3 derived from  SO;;  this  constituted a  10 percent positive
bias of the sulfate data. A more realistic overage bias  is likely in  the
5 percent range. However, there  is clear evidence that in regions of
high levels of SO:, relative to sulfatc, the positive measurement bias
becomes  much more severe.  Tin's is probably  the  caie in  the Salt
Lake Basin orea.
  The third nnd most  devastating problem  associated  with  the
CHESS sulfate data occurred when  the laboratory analysis of sulfates
was contracted to an outside firm. During  this  time period  (October
1972-June  1974) the reported sulfate data underwent  a sudden and
sustained decrease  in  apparent  «tino-.phcric  sulfalc  level.  Upon
investigation it was determined  that tlm  laboratory  nno'.vsis  of' all
sulfate data from nil CHESS sites were biased low by approximately
50  percent. Tho reason  for this negative  bias was nnd still i?  not
completely clear, but the continued dissemination  cf poor dnhi was
clearly due to  inadequate quality controls. An imcriiu EPA report

-------
                                41
on  n  retrospective quality  assurance  evaluation of CHESi  Sulfntc
Data states:
  A quality control protocol was designed for CHESS chemical an.Myfis but ha*
not been implemented ns per the contract .... The quality control protocol
•hould be implemented immediately.
  In n scries of following studios the roognitude of the ofTcctcil data
and of the error were documented and nn attompt was made to correct
and therefore recover the data. This type of procedure is difficult fit
best nnd impossible in most crises. The validity of this data corre< tion
was again  assessed  by the  EPA Quality Assurance Branch. Their
finding was:
  The basic question .  . .  is — How dow one make bad data good"1 Whatever is
tried will be attacked for a multitude of (ju-tihablc) reason;,. Using the c\i-nr.g
data set for relative pollution level ass«?ment will be acceptable, but statement-,
concerning absolute levels  will not be. It  would not be RISC to  submit tbe-:e
dnt.i to the NADB,1 but rather answer all requests for these data internally.
  Their statement  gives a reasonable assessment  of the  CHESS
sulfate data  between 1972  and 1974. The  assessment of  other year
CHESS sulfate data is more difficult.  No  comparative  sulfate duta
exists from  the local agencies as it did for S03 and TSP. Based on
the intrinsic  capabilities of  the methods, nnd the error assessment of
the field use  procedures, it can generally be stated that:
   1. From 11)70  to September  1971  the  sulfate data were obtained
using the  turbidimetric method. It should be  used only  as a sulfate
level indicator. Due to interferences, there will be severe problems if
an attempt is made to correlate sulfate levels in one part of the country
with  sulfate  levels in another.
  2. From October 1971  until October 1972,  the data are subject to
the following considerations:
       a. The data  are  likely biased in  the  positive direction from
    1-2 pg/m'. This bias ma}'  be more  Revere in ureas  of high  S0:
    concentration relative  to  sulfate.
       b. The random error component of the measurement is probably
    in  the   order of ±25% at an atmospheric  concentration of
    10  fig/m3
   3. From October 1972 until June 1974, all CHESS sulfate data were
biased negatively bv approximately  50% on an r.nnual average bn-i =
due to  improper  laboratory  analysis by the contractor.  These data
should be used only on an adjusted annual average basis  to establish
local  trends  within  site  locations. The unknown cause of the  bins
prohibits use of  the  data in shorter time structure  (i.e., day,  week,
month) increments.
  4. From July 1974 until July 1975, CHESS sulfate data underwent
a marked improvement nnd was somewhat better than that collected
in  the  1971-1972 era.  The  positive bias of  the data  is  probably
similar  to that of the earlier period but the random  error component
was improved due  to  improved  sulfate blanks on  the  TSP filters.

           D. THE  CHAMP AIR MONITORING PROGRAM

                         1.  INTRODUCTION
  Early in the execution of the CHESS prop-am iu 19G9, a number of
start members in  the air quality measurements organization of EPA
  ' Nitlooil Atromttrlc Do to Bank.
     77-590—70 - 1

-------
                               42

decided it was desirable, indeed imperative, to improve the efficiency
find  accuracy  of  short-term air Quality  duta  monitoring coverage.
EPA coined the term CHAMP (Community Health Air_Monitoring
Program)  for this  concept of a second generation automatic system of
nir  monitoring stations. Seven  prototype  stations  were  operated in
California from January,  1972  to  February 1974. The manpower
ceiling placed on EPA resulted in a decision to contract for the devel-
opment, installation, and operation of the CHAMP system. A  con-
tract for the development of the CHAMP system was  awarded in
February, 1973. The developmental monitoring system was to contain
the  newest technology in  monitoring  instrumcntotion.  Accurate
measurement of all critical air and liquid flows in the  system was
incorporated to enhance the accuracy of the system.  The development
continued to mid  1974 when the first station systems were installed
in the Los Angeles area for field evaluation.

                      2. BTSTEM DESCRIPTION

  The CHAMP air quality measurement system assembles the avail-
able discrete pollutant measurement devices and associated meteor-
ological instruments into  a complete svstem in an  air-conditioned
portable building. EPA specified the pollutants to  be measured  and
selected the instruments with the advice of the  CHAMP contractor.
All data are recorded  digitally in  a mini-computer integral to each
Rvstem. The data are checked and  stored on tape  nt each  CHAMP
site for transmittal to the  EPA/RTP Laboratory nt Durham, North
Carolina. SO;  and NOj, nnd TSP measurements" are also taken  peri-
odically using older  CHESS-type  bubblers  and  Hi-Vol  sampler
instruments described  previously for backup and  validation of the
CHAMP instruments. These bubbler and filter samples are sent to
the contractor's chemical laboratory in California for analysis.
  All  the CHAMP  systems measure  ozone, total gaseous sulphur
NO/N02,  TSP./RSP combinations,  temperature, wind direction and
velocity, and humidity. Selected systems also incorporate CO nnd hv-
drocarbon sampling. The CHAMP system while automatic in principle,
requires periodic calibration and servicing by an operator to maintain
a high duty factor and an acceptable quality of data (less than 15%
error band). The operator repairs and adjusts instruments as required,
checks for failures, and does periodic calibrations  and data verifica-
tions.  A quality  assurance  specialist continually spot-monitors the
CHAMP  sites  carrying-out calibration and quality checks.
  It  should be noted that the instrumentation of the  CHAMP
stations is not  completely uniform. Some stations do not have wind and
pressure instruments; not  all have CO  and hydrocarbon instruments.
  The manner in which meteorological data from the CHAMP stations
is being analyzed  and used has not been investigated. This is a subject
of interest depending on the future of the CHAMP program.
  CHAMP stations were  visited in Thousand  Oaks, California, nnd
Salt Lake City, Mugnn. nnd  Kenrns, Utah. The kind of meteorological
instruments in u«e appeared to be  appropriate nnd they  appear to b
-------
                               43

  There nrc at present 18 CHAMP stations on line at locations se-
lected by EPA; six in the Los Angles Basin, three in Birmingham,
Alabama, four in  New York City,'four in the Salt Lake  Valley, and
one at the EPA  Health Effects Research  Laboratory  at Research
Triangle Park, North Carolina.

           8.  FINDINGS  REGARDING THE CHAMP  PROGBAM

  As in the CHESS program, all the instruments incorporated in the
CHAMP station were developed by the manufacturer for laboratory
use. In fact, some non-commercial instruments were selected by EPA
to try to use the  most advanced technology. The CHESS experience
has demonstrated the need  for validation in field  use and the con-
tractor appears to be attempting to do this.
  There was apparently some attempt to standardize on one instru-
ment manufacturer for  ease of maintenance, etc. Bcndix ozone and
NOE instruments were employed. Flame photometric measurement
was  selected for  S03 EPA  apparently was interested in a pulsed
flouresccnce device but the equipment cost was too high for the budget.
The present instrument actually measures total gaseous  sulphur and
it is assumed  that this is SOj. (The onlv other  likely gaseous  sulfur
compound  H2S, does not seem to be widely present.) The rest of the
measurements appear to be well-validated. The  backup measurement
with bubbler  methods have validated N02, to the extent possible.
The TSP/Hi-Vol  measurements were apparently  validated at  the
beginning of the CHAMP program.  However, because  of the non-
linear calibration  character  of the flame photometric instrument in
the low concentration ranges of interest from 0 to 50 jig/M3, calibra-
tion and range setting  by the operator still results in  5%  to 159c
range of uncertainty in the total sulphur readings. Further, while the
"U'cst-Gacke bubblers used to check CHAMP S02 are stored at 70°
F at the sites, they are shipped to the contractor's facilities for analysis
without temperature  control and are subject  to the unpredictable
temperature dependent decay of solutions prior  to analysis. Thus, the
SO;  validation in  the CHAMP sj'stem may be in greater  error than
EPA expects.
  The execution  of the CHAMP  program  has yielded  validation
and  quality control of field measurements better than CHESS. How-
ever, there arc clearly numerous unresolved problems with the  opera-
tion which have led to delays in validating  the  data bank  and  which
require high level  attention  for resolution ocfore reliable quantitative
aeromelric dnta can be obtained.
  The data processing was 2,900 data-days behind at the time  of this
investigation  and no  date agreed on for  total backlog elimination.
Drift of zero selling and data span of instruments  have invalidated
pnrt of the earlier analyses. The  data are only  about GO percent
machine validated. Field operator problems have arisen  possibly due,
in part,  to a lack of standardized operating  procedures. Successful
operation  of  the  CHAMP  system requires well-trained instrument
technicians, and  peoplo of tlus high level of skill have not beeu em-
ployed  in  the past. Because of such  circumstances, the S0:  data
obtained  through 1975 have been  lost  and  apparently  are uot
recoverable.

-------
                              44

  Some months npo EPA  fouml  that  Mfrnificnnl data were lost  in
Irnusmitting  over  leased lines  lo  the  RTF  Inhorntory. Thus, the
primary data source is the datu tapes from the CHAMP site computer
which are mailed to RTF.
  The CHAMP contract is  up for renewal in November 197C and the
bids are beins solicited competitively. It is believed that nt this time
competitive bidding could be n destabilizing step iu this program nnd
could delay the achievement of reliable routine d:;ta gathering another
year. On the other hnnd there nre  obvious advantages to open com-
petitive bidding. When system development is more nearly complete,
it would  certainly  be  appropriate for competitive  bidding  to  be
adopted. The competition should include quality control considera-
tions. Unfortunately,  the  EPA quality n-surnncc group  was not
consulted on the renewal request for proposal, although that group did
participate in evaluating proposals received.

                          4. SUMMARY

  CHAMP appears to be an improvement in real time field measure-
ment of  air pollutants in comparison  with CHESS.  However, the
system is still not completely validated and  may not  be ready for
routine use for 6 to 12 months. Data should not be stored in  an ac-
cessible data  bank until it is validated.
  The present best estimate of expected accuracy is ±15 to 20^o  on
the CHAMP measurements. However,  this will be a significant im-
provement over previous CHESS  oerometric network mesuremcnt
systems when and if it is realized.

-------
      Section V  of the 1976 Congressional
      Investigative  Report (IR)  concerning
      CHESS air  quality analyses procedures
      and  results is  as follows;
      V. REVIEW OF CHESS AIR QUALITY ANALYSIS
                PROCEDURES AND RESULTS

                        A. INTRODUCTION

  This chopter presents the results of the investigative team's critical
review of the utilization of neromctric data in the analysis and data
modeling presented  in the CHESS Monograph.  The  citations  to
pages, fipures and  paragraph numbers nre to the 1974 CHESS Mono-
prnph. The findings nre highlighted in terms of examples  wherein
it appears that estimates  have been extended beyond the range of
credibility,  model* hnve been  misused,  or miscellaneous errors of
vnrious types  have occurred which lend lo  misinterpretation or over-
interpretation of data or results of analyses.

                  B.  USE OF ESTIMATED  DATA

  A serious weakness in the CHESS study  was acknowledged in the
Inst paragraph on page 7-9, which refers to the Salt Lake Basin stud}-
nnd the  Rocky Mountain stud}'. It is in part:
  Severn! factors should be remembered when interpreting the results of the
lower  respiratory disease  atudiei ... a majority of the  pollution  exposure
data in both studies were estimated from emissions data.
  This statement  applies to one of the most important And  contro-
versial paragraphs in  the  CHESS report,  also on page 7-9,  which
follows:
  It is interesting to  note th.it larcer increases in total lower respiratory disease
nnd two nf its component* were observed in the High pollution community of
the  Salt Lake Basin study thr\n in the corresponding communities in the Rocky
Mountain studv. Also,  the  mcnn  annual suspended sulfate concentration was
higher in  the High pollution community in  the Salt Lake Basin study than in
the  Rocky Mountain  study; the opposite was true for sulfur dioxide. This suggests
that increases in lower respiratory disease  frequency are probably associated
with suspended sulfatej rather than sulfur dioxide.
  The paragraph  summarizes the  argument that exposure  to sus-
Eended  sulfates over a  period  of years produces  significant  adverse
 ealtb effects.
  Analysis  of  the background material  leading to the conclusion
shows that it is derived from  an interpretation of the relationship of
four numbers  all of which are estimated values. The sulfur  dioxide
values' are estimated  from  smelter emissions and the sulfate  values
nre estimated  from estimates  of sulfur dioxide in one case and esti-
mates of suspended pnrticulate based on  smelter emissions in the
other, assuming no  difference in the ratio of sulfate  to suspended
particulate in  the  communities, Kellog" Idaho;  Helena-East Helena
nnd Anaconda, Montana; and Magna, Utah.
  The "High pollution community"of the Salt Lake Basin" is Mngna,
Utah. It is less clear what is meant by the words "than in the Rocky

-------
                                 46

Mountain study". However,  this  parngraph refers  to  the preceding
pnrngrapb of the CUESb report, which spooks of concentrations, "us
Tow as 7.2 ng/m' in the Rocky Mountain Study".
  From this it cnn be concluded that reference is being made to con-
centrations of sulfates in Anaconda, Monlnnn.
  A  comparison is  being  made,  therefore, between  average  sulfur
dioxide concentrntions nnd average sulfute concentrations in Mnpnn.
aud Anaconda. The  period of the  records  being compared covers the
yenrs 196S-1S70.
  From the preceding paragraph the values being compared may be
obtained.  They nre os follows:

           (Th> conccntutiofl v»lu«i iri |ivtn in microi'imt per cubic m»l«r. written it *\J-n'-\
                                                       Sulfur
Mifni [[[         ??         li 0
Anicondi [[[        177          ~i.l


   Because  of  the methods used  for  making estimates, the nb-oUifc
values of these concentrations arc questionable. The next four section-
discuss these estimates.

1. ESTIMATED  SULFUR  DIOXIDE  COXCEXTIIATIOX, 92  fiG/M* (MACNA)

   The concentration value 92 ^g/m5 for Mairnn can be obtained from
Table 2.1.A.14 or Table 2.1. A. 10.  It is bused on the following (siimaU'
    1970 ........................ „ ...........................          64
    lyes
      Average	     go
  Thesp estimates of annual sulfur dioxide exposures wero derived l,v
multiplying the yciirly smelter emission for sulfur dioxide by the ratio
of the  1971 measured  tinmml  average  sulfur  dioxide cou'centrution
(61.8 Aicr/m3) to the same year's sulfur dioxide emission rn.te (103 tons'
day). The  last chapter established  that these data could be oft' by
100 percent, probably on the low side.
                  61.8/193 =.320  (Mg/mJ)/(tons/dny)
  The emission rates used were ns follows (page 2-37):l

Year:
1970 	
1909 	
19CS 	 	
Tanil
ti-
(SO,)
T.I
"OO
	 2S1
  In  order to obtain the estimated sulfur dioxide concentrations, it
must be first assumed that the  meteorological conditions for each of
the years  19CS,  1909 nnd 1970,  were identical to those conditions in
 1 Tlir:c ralci of fmlwion »re off hy t factor of two. Tons of sulfur, no- 'ons of sulfur •Jit>\idi>. art li>t»'l
Th*;r ralurs corrccinl ihnulJ h» 52.'. 6H m-| V>2 Innn.M^v. llowcvfr. this d"r? not chin:.' t">c vinnivci of
tulfur dloxl't*- concriurniions. which "Irjwnrt on .1 mi" l^'.«rcn rnfi^ur*'!! I'd conctMuradons »nd I'-Tl

-------
                               47

1971. There was no pro-cntaiion, in  tlie  Monograph of the u«c of
climntolopicul  data to show that 1071 was i-iinilar to the other vonrs,
an  average  ycnr, or  a generally  representnlivc  year. Even If the
mctcorologinil condition* for nil four  years had be'cn identicn), there
H still a  problem because the yenr 197-1, on which the estimates ore
based is  not n normal year  for smelter operations. Emi^ions  were
zero,  or practically  zero for two weeks  dining July, and  nearly zero
for  FIN weeks in July nnd  August.  Therefore, the emi?sion,'coiicentrn-
tion ratio is deficient in showing  the effects of the  summer sermon,
•when wind direction frequencies from the smelter  to Mnpm might
hnvc  been less thnn during the remoinder of the year. This sug^e^
tlmt the  average concentration of sulfur dioxide in Mngnn is likely to
have been slightly over-estimated, but it supports rather than changes
the conclusion that nveragc concentrations of sulfur dioxide nre Ic-^
in Magna  than in  Anaconda.  Primarily this estimate is  criticized
because it is not supported by clhnatologicul  information.
  Also it should be realized that the method used for estimating the
annual average concentration can result in nn incorrect estimate if
there is a significant background of sulfur dioxide  from  a  source or
sources other  than the smelter. Multiplying the emission rnte of the
smelter by a factor assumes  that all  individual observational values
that make up the annual average can be multiplied by this same factor,
when actually only those values totr.lly resulting "from  the smelfr
emissions would be  effected. The Salt  Lake City airport wind ro^c
(Figure 2.1.2) is probably  not representative "for estimating the
percentage of time that Mngna is downwind from the smelter because
the smelter stack is  at the base of the Oquirrh  mountain range.
However, the frequency of  west northwest and northwest  winds at
the  airport  suegest  that  Magna. is  only  downwind  about  5C,'0
of the time. Allowing  for the effect  of calm and variable winds, it
seems unlikely that Mogna would be  under the  influence of the
smelter more  than  10% of  the  time. It follows then, sulfur dioxide
values for  only  these hours  would be affected. On  the other hand,
if the smelter  is the only significant source of sulfur dioxide, a* inny
be the case, then multiplying individual  observation values of zero
concentration  would yield only zero, and the procedure for estimating
yields a true result, assuming no  change  in meteorological or emission
conditions. Since the  sulfur dioxide  background in Magna is not
known, the error that  could  be  produced by background concentra-
tions  cannot  be determined. Probably  most of the sulfur dioxide
does come from the smelter, so this source of error  is not significant.

2. ESTIMATED SULFUn DIOXIDE CONCENTRATION, 177 Mg/m'  (ANACONDA)

  A paragraph in the right hand  column of page 3-12 explains how the
averaze concentration  of 177 jijr/m1 for sulfur dioxide was  estimated
for  Anaconda for the period 19GS-70 using sulfation plate  data and
emission  rates. However, the explanation is incomplete, because it
requires the 1971 emission rate of tho smelter, which has been omitted
from the Monograph. Thus, the validity of the entire procedure is im-
possible to verify. Table 3.1.2., wbich lists the emission rate? by year
begins with the year 1970. The ratio of 0.343±.233  (jig,ms)/(ton day)
was obtained  by a very dubious procedure. To begin with, sulfiition
plate  data are'of somewhat uncertain nature. The document "Air

-------
                                48

Quality Criteria for Sulfur Oxides", U.S. Department of Health, Educa-
tion and Welfare, Public Health Service, National Air Pollution Con-
trol Administration, Washington, D.C., January,  1969, pp  24-25
snys th.H sulfation  "candles"  (and  plates) give  only "an  empirical
estimate of the average concentration". It also says "results are influ-
enced by wind movement and  humidity" and that "the lead peroxide
candle  provides  intelligence on the  oxidiznble sulfur compounds in
the  atmosphere  which seldom can  be  directly related  to  iulfur
dioxide".
   The CHESS Monograph paragraphs refer to sulfotion plate data for
19C5. The sulfntion plate is a variation  of the lead peroxide candle.
Developmental work on  the  plate  was reported in  the  following
reference:  Huey, N.A.  "The  Lend  Peroxide  Estimation  of  Sulfur
Dioxide Pollution" J. Air  Pollution Control  Association, Vol.  18,
pp 010-611, Sept.  19CS. Consequently  it is unlikely that sulfatiou
plates were in use in Anuconda in 1965.*
   In order to determine sulfur dioxide from a lead peroxide candle or
plate nn empirical  relationship must be used. For example,  in  the
Helena Valley, Montana, Area Environmental Study, (EPA,  Office
of Air  Programs, Research  Triangle Park, North Carolina, January
1972) the sulfation  values were converted to sulfur dioxide values by
means  of the relationship: 1  mg S0} per 100 cm* per day is equivalent
to 0.035 ppin ?O2. In the history of  the  use of lead peroxide devices,
there has not been general agreement  as  to  what  ratio should  be
used, nnd a belief  prevails that sulfation condle or plate data  ore
conservative, i.e., that sulfur dioxide concentrations arc sometimes
higher than indicated. Further, more information  is needed concerning
the location of the  station,  or stations, in the  Anaconda  area,  where
the sulfation data were obtained. In order to validate the Anaconda
sulfur dioxide data  further work needs to be done.
   In 1965  the annual average concentration  of sulfur  dioxide  was
reported to be SO jig/in3 with an emi*sion rate  of 609 tons/day. Since
the 1971 emission rate is omitted from the report it cannot be compared
with the corresponding concentration of 2SG  jig/m1. Assuming that
the 1971 emission rate is also  on  the order of COO-700 tons/day, then
there seems to be too great a dilTerence between the  80 Mg;m5 con-
centration and the 2S6 jig/m1 concentration. (Center paragraph, right
hand side, page  3-12.)J
   The  ratio 0.343±.253  has n Inrge  error factor. The range is from
.090 to .597. If  the low value is  multiplied by the emissions for the
years 196S-1970, the following concentrations are obtained:

                               IToru per diy]

                                                  Table 31.?    New Ttlu»
        Ycu                                          (SOi) Montint
     IOT1	    Omitted
    l-.i	        MS        *.<
    15f*	    ...	        117        (tj
    11167	"		        148        44'J


      NOTE.—The nmiuion n( the 1771 »mi«Jon rite? m>Lu It Impossible to check tU« effect o( us>n( the
    new T&lue for 1971 on the esiirotleJ emiuon rtlei.
   •Tli» rhunlrnl rcartlon for "rnnill«" ind "plntcs" li tbt    .
  tArrorrtlnt 10 Inlormalion rrcfutly rrrrivrd from ihft Mnniint sine O'pirincil of Dtl'.lb»nd EnTiron-
 mtnlal Sclrnr'i, the emlulon rates lined lor tb« Antcondt imeller are low.

-------
                               49
Y«lr
IJ70 	 _ 	
1959 	
IK! 	

SO] (miuioni onccitilt'Oii
(tent fw t»i) Ul"1')
	 _ |J5
	 . . Ml,
	 	 _ . |67

$7
  The average of these values is 46  :g.'ms (MAGNA)

  The 15 Mg/m3 estimate is a double estimate since the  sulfur dioxide
concentration data on  which it is based is also estimated. The sulfate
value seems to be an average for the years 196S-1970.  It i.s obtained
by  using the following regression equation, which is found on page
2—39
                   Magna-SS=O.C9(SOj)-i-G.66

  This  equation is based on 1971 condition*:.
  It is  of interest to  note that with a zero concentration of sulfur
dioxide there would still be  6.66 pg/m3 of sulfate, or  approximately
half the average annual value reported on 1971, which was 12.4 yirTn1
Further, 44%'of the 15  Mg/m3 of interest for  the years 10GS-1970 is
\inrelatcd  to sulfur  dioxide  concentration^.  The  Figures  2.4.2 and
2.4.4 suggest some lack of complete con-elation between sulfur dioxide
and sulfate concentrations.
  During  the strike with zero sulfur  dioxide concentrations, there
still is  an appreciable amount of suspended sulfate. Also, a peak
value of sulfate occurred during  the third  week that docs not corre-
spond with sulfur dioxide value  behavior during the same  period.
Similarly,  the very  large rise in  sulfur dioxide  that  peaked in the
ninth week hardly  shows in the sulfate values.  Consequently, the
regression equation  can be  questioned because the  reason for the

-------
                               50

sulfate values is not understood. What is the physical source of the
sulfates?
  Since the sulfur dioxide concentrations used in the regression equa-
tion are themselves estimated, uncertainties in the  sulfur dioxide
estimates are compounded in the sulfate estimates. Further, *ince the
source of a considerable amount of  the sulfate seems to be not associ-
ated with the sulfur dioxide, it is not clear what effect the strike period
has on the  estimates.
  The CHESS report lists the suspended  sulfate concentration as
12.4 jjg/ni5  in  1971 and this is the basis for the estimate of 15 pg.'m'
for the  196S-1970 period.  Observations  of sulfate in Magna area
subsequent to 1971 support the argument that average annual con-
centrations are in the neighborhood of 15  yg/m3, or that they are sig-
nificantly higher than reported for  Annconda.
  On page  2-79, in Table 2.4.1, it may be noted that suspended sulfate
values for  the High communitv do not follow the sulfur dioxide con-
centrations, particularly for tfie Spring  and  Summer. Tlu's raises a
  3uestion about using sulfur dioxide as an indicator of  sulfatc, cs was
  one with  the regression equation on page 2-39. (Median values for
the High community are: Sulfur dioxide, Spring 64, Summer 9, whereas
for suspended sulfate they are 8 and  7, respectively.)
  Wind  blowing  from the smelter stack  to  Magna would generally
cross a portion of the Great  Salt  Lake  and, therefore, might carry
more moisture, thereby facilitating the conversion of sulfur dioxide
to sulfate.  Perhaps  this mechanism  helps  to account for the high
sulfate concentrations observed in Magna.

    4. ESTIMATED SUSPENDED  SULFATE CONCENTRATION, 7.2 Jlg/mS
                           (ANACONDA)

  The  7.2 Mg/m1 suspended  sulfate  value  can be obtained  from
Table 3.1.7,  page 3-12,  by taking an average of  sulfate values for
three years, as Follows:
Year:                                                        •*/">'
    1970	   8.9
    1969	   7.6
    1968	   5. 1

      Average		   7. 2

  These sulfate values are estimates,  based  on estimates of total sus-
pended particulate and an estimate of the ratio of suspended sulfate
concentration to total  suspended particulate concentration, based on
results from  East Helena and Helena, Montana, and  Magna,  Utah.
The same procedure was used for  Kellogg, Idaho.
  On page  3-11, in an attempt to explain how the  suspended sulfate
estimates were made for Kellogg, it i> stated that "Data observed for
Magna during the period January 1971-June 1972 indicated an average
ratio  of suspended  sulfate concentration  to total suspended  piu-
ticulute  of  0.159." Following  this is  the reference  number "22," re-
ferring to National Air Pollution Control  Administration  Publication
No.  AP-61,  "Characteristics of  Particulote Patterns  1957-1960."
This publication presents graphs of suspended particulate concentra-
tions for various cities over a ton year period. In it, suspended sulfates
are not mentioned, the time penod is wrong, and  there  are no data

-------
                                 51

for Mag-na; therefore,  it must be concluded  that  the reference is an
error.
  An obvious reference for this paper would  have been tH/> paper bv
Marvin  B. Hertz, et al., "Human Exposure to Air Pollution in Saft
Lake Communities, 1940-1971," however, it is not referenced. Perhaps
this was tho reference intended. Even so,  the  ratio 0.159 caunot  be
obtained from the Hertz paper.
  In the Hertz  paper, page 2-11, Table 2.1.2, which giro CHESS
1971 Annual Averages lor  Magna,  the  suspended sulfate concentra-
tion is 0.6 M?/rns and  the  total suspended particulate  concentration
is 53.9, which gives a ratio of 0.178. In Tables 2.1.5 and 2.1.A.16, the
following concentrations are given: TSP, 66 Mg/m1, SS,  12.4  it%!m3.
Here the ratio  is 0.188. Other ratios can be determined for various
time periods from Tables  2.1.A.4 and 2.1.A.5, but none of the^e  is
0.159.
  Note  (page  3-11) that  the unexplained  ratio 0.159  for Magna  is
used with  the 0.063 ratio  for East  Helena to  obtain the ratio 0.111
plus or minus 0.057 that is used  to estimate suspended  sulfate con-
centrations for Kellogg, and the 0.11 plus  or minus 0.06 ratio for
Anaconda  (page 3-13).
   (Pages 3-8 and 3-9)  Particulate emissions for East Helena are given
in two tables on pages that face each other. The headings of the second
column in Table 3.1.4  should be "Emissions, Tons/year," not "Emis-
sions, Tons/day."
  On page 3-7 it is stated that estimates of  stack emissions for both
particulate and sulfur dioxide for East Helena for the years 1941-1070
were provided  by Asarco.  Presumably the  data  in "Table 3.1.3  are
Asarco data.  The source of the data in  Tnble 3.1.4 is  not stated.
  The Office of Air Programs Publication No. AP-91, Helena Valley,
Montana,  Area Environmental Pollution Study, give* more informa-
tion about the  industrial complex at East Helena. This study was
conducted  during the  period  June. .10.69  through June  1970. The
table below is from this study.

                 [MISSIONS FROM CAST HELENA INDUSTRIAl COMPLEX
                              |Tom f»r tfjy|

                                          [Million:
    Comptnyandoptntion            JOi production            firUulitei production
                        KtduCKJ    Normal  Hjiimom   Rrtucid    Nofnul   Minmum
Awco:
Sintering 	 	 	


Subtotal ...__ __—.

Antcondi:
Miuillintout.4 	 — 	
Subtotil 	 	
AmtrlonChtmct: Pi|m«nt production.
Tolil
114 C
I 4
C)

193 0

13.0
C)
1) 0
C)
206.0
315 6
U 6
(i)

330 2

13.0
0)
13 0
C)
143 2
355 1
Z3 2
(i)

17! 3

13.0
C)
13 0
C)
191.3
0.1
C)
(*)

.3

o
1.0
1.0
C)
1.3
0.5
<')
(i)

.5

P)
1.0
1.0
0)
1.5
6.54-
(')
C)

.SJ-

o
1.0
1.0
<')
1.5 +
 I Tht ouUidi llcujj* of conctntritei conl-ibuttt I iiinficint but undfttimintd I mount of pirliculclti.
 1 Cmiiiioni ftfso ocrur during thf ill; cr-.*'6
-------
                               52

  It may be noted  that  ASARCO  is only one  of  several purticu-
late sources for the  East Helena  area. Fuming  and  other sh>g
processing  activities of the Anaconda Co.  ore estimated to produce
1.0 tons per day of participates, resulting in a normal total of 1.0tons
per day, not a rate in the neighborhood of 0.3 tons per day as Table
3.1.3  suggests.  Further,  the  total normal sulfur dioxide cmf^ion
rate in the preceding table  is 343.2 tons per day,  a  considerably
higher rate than is given in Table 3.1.2.  (i.e., 1969: 221  tons/day;
1970: 239 tons/day).
  On page 3-7, right hand side, is given an explanation of how the
data in Table  3.1.4 were used to ootain a ratio  of  total suspended
participate concentration to tons of  participate emitted  per any for
East Helena. However,  after  giving this explanation, the eUimntPs
of TSP in Table 3.1.5, that were used to make the suspended sulfatc
estimates were not obtained  by means of this ratio. They seem to
have been obtained from the particulate emission  data in Table 3.1.3,
using  the  factor 3S3.22  (^g/m')/(tons/dny). The derivation of  this
factor is not explained.  Tin: ratio thnt is explained never seems to
have been used. The suspended sulfate  estimates are obtained by
multiplying the total suspended particulate  concentrations by the
factor 0.063, which is explained on page 3-8.
   Both observed and estimated suspended participate concentrations
are given in Table 3.1.4 and 3.1.5. It may be noted that the estimated
TSP values are used to estimate the suspended sulfate concentrations
and not the observed values for  the years  1966 through  Ift69. In
1966, the observed value was 87 ng/m3, whereas  the estimated value
is 114.2 >ig/m'. No explanation is given for  rejecting  the observed
values.
   Data for Magna during the period January 1971-June 1972 indi-
cated  an average  ratio of suspended sulfate  concentration to  total
suspended particulate of 0.159. The available data  for East Helena
indicated a suspended sulfate to total  suspended particulate  ratio
of 0.063±0.022 jig/m3. For Kellogg, the assumption has been made.
that the ratio of suspended  sulfate  to  total  suspended paniculate
is the  average  of these values, or 0.111 ±0.057.  For Anaconda, this
value was rounded to 0.11 ±0.00. It is  multiplied by the estimated
concentrations of  total suspended particulate listed in Table 3.1.7,
to obtain the suspended  sulfate values for enrh year.
   The following table has been  prepared from the Helena  Valley
study, June through October 1969.

Slilion
1 	
2 	
3 	
4 . 	

Avtrije 	 	 	 	

Loctlion
Dffrtti
	 	 ]4
	 	 |05
	 11?
	 274



i
Milts
0 1
2 i
4
4 5




Mfticulitt
1D8
74
19
62

76


lulfile
3 S
3 7
4.4
2.9

3.4


Rltio
0 T32
.C5
.Ot9
.C-7

.OiD

 I With rtiprct Id Iht imtller itjck.

-------
                               53

  The data from station1; I and 3, the stations nearest the stack, were
used to  obtain a ratio range (6.037, pages 3-8), but for some curious
reason the available ratios from  the Helena  Valley study were not
used. The average ratio for stations 1 and 3 is 0.051.
  The ratio chosen for Enit Helena, 0.063 plus or minus OU22 Gig/m1)/
Gig/m3), is not significantly different from that which might have been
obtained had more use baen made of the Helena Valley study, but
there is no basis for the assumption that the ratio of suspended sulfate
to suspended particulate is similar in Magna, East Heleat,  Helena,
and  Anaconda.
  The dubious nature of using suspended particulate concentrations
to estimate suspended sulfate can be seen by comparing Figures 2.4.3
and  2.4.4. In the Low Exposure Community, the sulfate level remains
low  and nearly constant wlu'le  the suspended particulate concentra-
tions fluctuate.
  In the High Exposure Community, the highest concentration of
suspended particulate occurred on the fourth week whereas the peak
suliate value occurred on the third week. On the fourth week, sulfate
levels dropped. A corresponding  drop in the sulfate levels does  not
occur until the fifth week. Only during the last seven or eight weeks
do   suspended  particulate  and  suspended  sulfate  concentrations
fluctuate together.  There may  be some situations where suspended
5articulate and suspended sulfate concentrations are well correlated.
  ustification for assuming correlation in the Salt Lake Basin and the
Rocky Mountain communities is inadequately supported by scientific
evidence presented in the CHESS Monograph.
  Further, the 7.2  Mg/m3 suspended sulfate estimate  for Anaconda is
based on an estimate that comes from another estimate of suspended
particulnte values based on rates of emission from the smelter. During
the  period 1961-1962, the annual total suspended particulate concen-
tration was found  to be 84.5 Mg/m'. In 1971, the average suspended
particulate  level was observed to be 52  »jg/m3. By comparing  the
observed total  suspended particulate  concentration  with  the  por-
ticulate  emitted from the Anaconda plant, a ratio of 9.1±2.3  (Mg/m3)/
(ton/dnv) was determined. This rntio was  multiplied by the  particu-
lnte emission for Anaconda shown in Table 3.1.3 to estimate the total
suspended particulate concentrations for the years  1940-1970. This
ratio cannot be actually obtained from the data presented in the report
because particulate emissions for the year 1971 are not given, i.e.,
they ore not listed in Table 3.1.3.
   The basis for this ratio Is unfounded since there are sources for the
suspended particulate other  than the smelter emissions.
   Although there are no actual  sulfate observations from the  Ana-
conda area included in the CHESS report there  are some actual
observations of suspended sulfate versus total suspended  particulate
available for the year 1971, that were  obtained from the Montana
State Department  of Health  and Environmental  Sciences. These
suggest that annual average suspended sulfate levels in Anaconda are
in the neighborhood of  4 or 5 jig/m3, even  less &m tne estimated
value (7.2 Mg/m3).

-------
                               64

  There are also pronounced seasonal effects, with much higher values
in winter  than  in summer. The months of February ana April had
values of 7 and  9 Mg/m1 whereas the months of July and August have
values of less than 1 ug/m5. Local heating emissions and relative humid-
ity may be significant factors determining the  measured concentra-
tion as well as the smelter emissions.

6. ESTIMATES OF SUSPENDED PARTICULATE, SALT LAKE  BAEI.V BTUDY

  On page 2-23 it is stated that "the number  of sulfric  acid plants
utilizing sulfur  recovered from emissions have increased from one in
1940 to seven in 1971, and that  air pollution control device? in the
form of baghouses, scrubbers,  cvcloues,  and mist eliminators have
been installed.  Such changes in the smelter operations would greatly
effect the ratio of suspended particulate to tons of copper produced.
Therefore, aside from the fact  that there would be differences from
year to year because of meteorology, the procedure described in the
first paragraph, right band column, pngc 2-24, for  estimating sus-
pended particulate from copper production in tons for 1971, is highly
questionable.

        $. ESTIMATES IN THE CH1GACO AND NEW TORK STUDIES

   In the  Chicago and New York studies suspended sulfate concen-
trations were estimated  from suspended  particulate concentrations.
In Chicago, the estimates were used to fill in data for some years when
no data were available. In the New York study measured values for
suspended sulfates for 1956-1970 were available from the  Manhattan
121st Street station, and these  values were used as citywide values.
The observed annual ratios of suspended sulfate to dustfall for New
York City were used to estimate the suspended sulfate levels in Queens
and Bronx.  In Table 5.3.1 suspended sulfate levels for the Low Com-
munity (Riverhead) are  listed as about 10 jig/m1 for the years  1961
through 1970. The basis for this estimate is not given, although it was
probably  determined  from the 1971 concentration, which was  10.2
fg/m3.
   In summary, it  appears that some values,  on which are based
important conclusions that sulfates may  be  harmful to  health, are
estimated values.

          C. USE OF MATHEMATICAL DISPERSION  MODELS

  The dispersion model shown in  Figure 2.1.16  is incorrectly applied.
It was used in the Salt Lake Bnsin study to determine  sulfur dioxide
contours around the smelter source and to show that annual exposure
estimates obtained  from the ratio of 1971  observed nir quality to
1971 emissions were not unreasonably high or low. First, the contours
arc incorrect because the model used does not take into  account the
elevation  of the  terrain  and the wind direction frequencies for the
Salt Lake City airport,  which were  used  are  different from those
affecting  the smelter  plume, which originates at  the base of the
Oquirrh Mountains. Second, n dispersion model  is based on numerous
assumptions and applied in this way might be off by a  factor of two,
or more. It does not make sense to use a model  to check observations.

-------
                               55

The usual  npplicntion is  to ,opply observational data to calibrnte,
or verify, a model.  A model such  as the one used might have been
applied to  show some sort of relative distribution of concentrations
across  the  Salt Luke Volley, however, it should  not hav£ been used
to justify  estimates of concentrations  over  the period^940-1970.
(See Tables 2.1.A.14 and 2.1.A.16). Further, during this review of the
CHESS report it wns discovered that smelter emissions used  for the
model  estimates were tons of sulfur, not  tons of sulfur dioxide. There-
fore, the model estimate is only half what it should have b^£pn  Doub-
ling the emission rate  and reducing the wind  direction  frequency
somewhat with respect  to Magna  might result in an estimated con-
centration near that measured,  which was 61  Mg/™3.
  Apparently the dispersion model wns run only once  and then the
ratio between the emission at the smelter for  1971 and the calculated
concentration was applied  to emission values for the other years in
order to obtnin the other listed concentrations in the column  headed
"Diffusion  Model".  No nccount  is taken of the fact that meteorological
conditions,  or perhaps  stack conditions, were not the same for  all
yenrs.  More information should have been included in this report on
exactly whnt meteorological data were used in the model. The model
requires the use of  the  STAR  program, which is obtained  from the
National Climate  Center. Frequently  the  results of  running  this
program ore based  on data for  the year 1904, which is  the only ycnr
when wind  directions were punclW on  data  cards to the nearest 10
degrees each hour rather than  each 3-hours. Therefore, the model is
likely  to have incorporated meteorological data  for some year other
than 1971,  the year of the emission data. No attempts is made to
show that the year  for period)  of the meteorological data is average,
good or bod. Similarly there is  no attempt to show that 1971  was an
average yenr, yet all of the estimates are based on this assumption.
  Considering how  the model estimates  for the yenrs 1940-1970 were
obtained it is misleading to include them in the table, and they serve
little purpose since  the ratio for the year 1970 is repented throughout.
  On page  2-43, bottom of right  hand  column,  trie  following state-
ments  appear: "Estimates of sulfur dioxide,  total suspended partic-
ulates, and suspended  sulfate  concentrations in the High exposure
community for  1940-1970 and the Intermediate II exposure com-
munity for 1950-1970 were obtained by a mathematical  dispersion
model, which utilized emissions from the industrial source nnd exten-
sive local meteorological diUa,  and by observed  relationships among
pollutants.   Observed  suspended pnrticulate,  suspended sulfate,  and
sulfur  dioxide concentrations for 1970-1971 were  used to calibrate  the
models used to estimate exposure levels for previous yenrs." Tlu's is an
overstatement. The estimates were obtained  from simple rntios  and
the  application of ft regression  equation. See page 2-39. The model
was pnJy applied once to demonstrate that annual exposure estimates
obtained from a ratio were not  unreasonably high or low.
  In the Chicago study, another attempt was made to apply a dis-
persion model  (Figure  4.1.10). This model  pives a  false  picture of
pollution conditions that prevailed  in  the study area because it is
based  only on pollution sources within the  city limits of Chicago,
omitting effects of adjoining large industrial sources in Indiana and of
some suburban communities to  the southwest of the Loop area, which
have considerable air pollution.

-------
                              56

  Mnps recently published by the Chicago Deportment of Environ-
ment Control, for the years 1970 and 1975 clearly show that pollution
concentrations are  not simply Concentric around the urban core  fts
the model indicates.
  On page 4-8, it is stated Measured data from  the City netwprk,
from which the exposure estimates were made, were best supported
by the Mitre model. It is not clear why a greater use was not made of
the available actual measurements instead of the model estimates.
Also, it is not sufficiently clear why the model happens to be for the
year 1968.

-------
SUMMARY ASSESSMENT—METEOROLOGY AND POLLUTION MEASURES
     The Investigative Report (1976, 99-102) cited the following
problems with the environmental measures:
     1.  superficial and perfunctory treatment of meteorological
     information;
     2.  insufficient exploration of possible relationships between
     meteorological conditions and asthma attack rates;
     3.  failure to consider peak and episode concentrations;
     4.  use of a single monitoring station to determine the exposure of
     a community;
     5.  failure to establish similarity of exposure and stress factors
     between communitites in the same study, excluding the exposure
     to specific pollutants;
     6.  impreciseness of monitoring station locations;
     7.  inexact locations of residences of individuals studied.

-------
           APPENDIX  14-B

      ANALYSIS  OF  TEMPERATURE
       EFFECTS  ON  MORTALITY
(Appendix materials  to  be  inserted)

-------
          APPENDIX 14-C

 WHO TASK GROUP ON ENVIRONMENTAL
HEALTH CRITERIA FOR SULFUR OXIDES
AND SUSPENDED PARTICULATE MATTER

               AND

   TASK GROUP CONSIDERATION OF
         HOLLAND REPORT

-------
               WHO TASK GROUP ON ENVIRONMENTAL
               HEALTH CRITERIA FOR SULFUR OXIDES
               AND SUSPENDED PAR TICULA TE MA TTER
i  O
  I
Participants
Members"

Professor K.  Biersteker, Medical  Research  Division, Municipal Health Department,
      Rotterdam, Netherlands (Vice-Chairman).

Professor K. A.  BuStueva,  Department  of Community Hygiene, Central Institute for
      Advanced Medical Training, Moscow, USSR

Dr P. Camner, Department of Environmental Hygiene, The Karolinska Institute,
      Stockholm, Sweden

Professor L. Friberg,  Department of Environmental  Hygiene, The Karolinska Institute,
      Stockholm, Sweden (Chairman)

Mrs M. Fugas, Laboratory  for Environmental Hygiene, Institute  for Medical Research
      and Occupational Health, Zagreb, Yugoslavia

Dr R. 1. M. Horton, Health Effects Research Laboratory, US Environmental Protection
      Agency, Research Triangle Park, NC, USA

Professor S. Maziarka, National Institute of Hygiene, Warsaw, Poland

Dr B. Piinz, State Institute  for Protection of Air Quality and Land Usage, Essen, Federal
      Republic of Germany

Dr H. P. Ribeiro, Laboratory of Pulmonary Function, Santa Casa de Misericordia de Sao
      Paulo, Sao Paulo, Brazil

Dr T. Suzuki,  Institute of Public Health, Tokyo, Japan

Mr G. Verduyn, Institut d'Hygiene et d*Epidemiologie, Brussels, Belgium

Mr R. E. Waller, Medical  Research Council, Air Pollution Unit, St Bartholomew's Hospital
      Medical College, London, England (Rapporteur)

Mr D. A. Williams, Surveillance Division, Air Pollution Control Directorate, Environment
      Canada, Ottawa, Ontario, Canada
Representative* of other Organizations

Mr J. Janczak, Environment and Housing Division, United Nations Economic Commission
      for Europe, Geneva, Switzerland

Mr  D. Larrf, Division  of  Geophysics, Global Pollution and  Health, United Nations
      Environmental Programme, Nairobi, Kenya

Dr D. Djordevic, Occupational Safety and  Health Branch, International Labour Organisa-
      tion, Geneva, Switzerland

Mr G. W,  Kronebach,  Technical  Supporting Services Branch, World  Meteorological
      Organization, Geneva, Switzerland

Dr A. Berlin, Health Protection Directorate, Commission of the European Communities,
      Luxembourg

Mr J. A. Bromley,  Environmental Directorate, Organization for Economic Co-operation
      and Development, Paris, France
Secretariat

Professor B. G.  Ferris, Jr,  Department of Physiology,  Harvard  University School of
      Public Health, Boston, MA, USA (Temporary Adviser)

Dr  Y.  Hasegawa, Medical Officer, Control of  Environmental  Pollution  and  Hazards,
      World Health Organization, Geneva, Switzerland (Secretary)

Dr H. W. de Koning, Scientist, Control of Environmental Pollution and Hazards, World
      Health Organization, Geneva, Switzerland

Dr  B.  Marschall, Medical Officer, Occupational  Health, World  Health  Organization,
      Geneva, Switzerland

Dr  R. Masironi,  Scientist, Cardiovascular Diseases, World Health Organization, Geneva,
      Switzerland

Dr S. I. Muravieva, Institute of Industrial Hygiene and Occupational Diseases, Academy
      of Medical Sciences of the USSR, Moscow, USSR (Temporary Adviser)

Dr  V. B. Vouk,  Chief, Control  of Enviromental Pollution and Hazards,  World Health
      Organization, Geneva, Switzerland
               * Unable to attend:

               Professor M.  H. Wahdan, High  Institute of Public  Health, University of Alexandria,
                     Alexandria, Egypt

-------
o
I
ro
             ENVIRONMENTAL HEALTH CRITERIA FOR SULFUR
             OXIDES AND SUSPENDED PAR TICULA TE MA TTER
   A WHO Task Group on Environmental Health Criteria for Sulfur Oxides
 and Suspended Particulate Matter met in Geneva from 6 to 12 January 1976.
 The meeting was opened by Dr B. H. Dieterich, Director, Division of Environ-
 mental Health,  who welcomed  the participants and the representatives of
 other  international  organizations on  behalf of  the  Director-General.  Dr
 Dieterich briefly outlined the history and purpose of the WHO Environmental
 Health Criteria  Programme  and the  progress made in its implementation,
 thanks to the  active collaboration of WHO Member States and the support of
 the United Nations Environment Programme (UNEP).
   The Task Group reviewed and revised the second draft criteria document
 and made an evaluation of the health risks from exposure  to these substances.
   The first and second drafts  were prepared by  Professor B. G. Ferris, Jr,
 Harvard University School of Public Health, USA. The comments on which the
 second draft was based were received from the national focal points collabora-
 ting in the WHO Environmental Health Criteria Programme in  Belgium,
 Bulgaria, Canada, Czechoslovakia, the Federal Republic of Germany, Greece,
 Japan, New Zealand, Poland, Sweden, USA, USSR and  from the Food  and
 Agriculture Organization of the United Nations (FAO),  the United Nations
 Eduational Scientific and Cultural Organization (UNESCO), the United Nations
 Industrial Development Organization (UNIDO), the World  Meteorological
 Organization (WMO), the International Atomic Energy Agency (IAEA), and the
 Commission of European Communities (CEC). Comments were also received
 from Professor H. Antweiler and Dr B. Prinz (Federal Republic of Germany),
 Professor K. Biersteker and Dr R. van der Lende (Netherlands), Professor F.
 Sawicki (Poland), and  Professor W. W. Holland and Professor P. J. Lawther
 (United Kingdom).
   The collaboration of these national institutions, international  organiza-
 tions and  individual experts is gratefully acknowledged. The Secretariat also
wishes to  thank Professor B. G. Ferris,-Jr and Mr R.'E.  Waller for their in-
valuable assistance in the final stages of the preparation of the document.
   In view of the substantial amendments made to the document (particularly
within sections 2 to 5) since  the meeting of the Task Group, a revised version
 was circulated  to all members in February 1978. At the same time, copies of
 a newly-produced review of the health effects of particulate pollution (Holland
 et al., in press), that had been submitted for  consideration, were distributed
 to the members. Comments were sought on the draft of the criteria  docu-
 ment itself, and on any amendments or additions considered necessary in
light of the new report. These comments, together with others received from
the International Petroleum Industry Environmental Conservation Association,
and the International Iron and Steel Institute, were then considered by "a
small  group consisting  of  the  Chairman of the Task Group meeting, the
Rapporteur and some members of the Secretariat^ The alterations suggested
(mainly  within section  9) were circulated again  to the original members of
the Task Group prior to publication.
   The document has been based, primarily, on original publications listed in
the reference section. However, several recent reviews of health aspects of sulfur
oxides and suspended particulate matter have also been used including those
by  Katz (1969), Committee on the Challenges of Modern Society (1971),
Organization for Economic Cooperation and Development (1965), Rail (1974),
Task Group on Lung Dynamics (1966), Task Group on Metal Accumulation
(1973),  US Department  of Health, Education and  Welfare (1969a), US
Environmental Protection Agency (1974), World Health Organization (1976a),
and World Meteorological Organization (1974).
   The purpose of this  document is to review and evaluate available informa-
tion on the biological  effects of  sulfur oxides and suspended  particulate
matter including suspended sulfates and sulfuric acid aerosols, and to provide
a scientific basis for decisions aimed at the protection of human health from
the adverse consequences of exposure to  these substances in both occupational
and general environments. Although there  are various routes of exposure,
such as inhalation, ingestion (World Health Organization, 1971, 1974) and
contact with skin, attention in this report has been concentrated upon  the
effects of  inhalation of these substances, since this is the most important
route of exposure.  The discussion has also been limited  to sulfur dioxide,
sulfur trioxide, sulfate  ions, and particulate matter primarily resulting from
the combustion of  fossil fuels. The sulfate ion  has been considered in  the
variety of forms in which it occurs in the atmosphere, e.g., sulfuric acid and
various sulfate salts.
    The vast literature on these pollutants has been carefully evaluated and
selected according to its validity and relevance for assessing human exposure,
for understanding the  mechanisms of the biological action of the pollutants
and for establishing environmental health criteria, i.e.,exposure-efTect/response
relationships in  man.  Environmental  considerations haw been limited to
elucidating the pathways leading from the natural and man-made sources of
 these substances to the sites of toxic action in the human organism. The non-
human targets (plants,  animals, ecosystems) have not been considered unless
 the effects of their contamination were judged to  be of direct relevance to
 human health. For similar reasons, much of the published information on the
 effects of these pollutants on experimental animals has not been included.
    Details  concerning  the WHO Environmental Health Criteria  Programme

-------
                               GLOSSARY


AaDO.:   Alveolar-arterial difference or gradient of the partial pressure of
     oxygen.  An overall measure of the efficiency of the lung as a gas ex-
     changer.  In healthy subjects, the gradient is 5 to 15 m Hg (torr).

A/PR/8 virus:  A type of virus capable of causing influenza in laboratory
     animals; also, A/PR/8/34.

Abscission:  The process whereby leaves, leaflets, fruits, or other plant
     parts become detached from the plant.

Absorption coefficient:  A quantity which characterizes the attenuation with
     distance of a beam of electromagnetic radiation (like light) in a substance

Absorption spectrum:  The spectrum that results after any radiation has
     passed through an absorbing substance.

Abstraction:  Removal of some constituent of a substance or molecule.

Acetaldehyde:  CH..CHO; an intermediate in yeast fermentation of car-
     bohydrate anil in alcohol metabolism; also called acetic aldehyde,
     etha1dehyde, ethana1.

Acetate rayon:  A staple or filament fiber made by extrusion of cellulose
     acetate.  It is saponified by dilute alkali whereas viscose rayon remains
     unchanged.

Acetylcholine:  A naturally-occurring substance in the body which can
     cause constriction  of the bronchi in the lungs.

Acid:  A substance that  can donate hydrogen ions.

Acid dyes:  A large group of  synthetic coal tar-derived dyes which
     produce bright shades in a wide color range.  Low cost and ease
     of application are  features which make them  the most widely used
     dyes  for wool.  Also used on  nylon.  The term acid dye is derived
     from  their precipitation in an acid bath.

Acid mucopolysaccharide:  A class  of compounds composed of protein
     and polysaccharide.  Mucopolysaccharides comprise much of the
     substance of connective  tissue.

Acid phosphatase:  An enzyme  (EC 3.1.3.2) which catalyzes  the  disassociation
     of phosphate (PO.)  from  a wide range  of monoesters of orthophosphoric
     acid.  Acid phosphatase  is active  in  an acidic  pH  range.

Acid rain:  Rain having  a pH  less  than 5.6, the minimum expected  from
     atmospheric CO..
                                      G-l

-------
Acrolein:  CH2=CHCHO; a volatile, flammable, oily liquid, giving off
     irritant vapor.  Strong irritant of skin and mucuous membranes.  Also
     called acrylic aldehyde, 2-propenal.

Acrylics (plastics):  Plastics which are made from acrylic acid and are
     light in weight, have great breakage resistance, and a lack of
     odor and taste.  Not resistant to scratching, burns, hot water,
     alcohol or cleaning fluids.  Examples include Lucite and Plexiglass.
     Acrylics are thermoplastics and are softened by heat and hardened
     Into definite shapes by cooling.

Acrylic  fiber:  The generic name of man-made fibers derived from acrylic
     resins (minimum of 85 percent acrylonitrite units).

Actinic:  A term applied to wavelengths of light too small to affect
     one's sense of sight, such as ultraviolet.

Actinomycetes:  Members of the genus Actinomyces; nonmotile, nonspore-
     forming, anaerobic bacteria, including both soil-dwelling saprophytes
     and disease-producing parasites.

Activation energy:  The energy required to bring about a chemical reaction.

Acute respiratory disease:  Respiratory infection, usually with rapid
     onset and of short duration.

Acute toxicity:  Any poisonous effect produced by a single short-term
     exposure, that results in severe biological harm or death.

Acyl:  Any organic radical or group that remains intact when an organic
     acid forms an ester.

Adenoma:  An ordinarily benign neoplasm (tumor) of epithelial tissue;
     usually well circumscribed, tending to compress adjacent tissue rather
     than infiltrating or invading.

Adenosine monophosphate (AMP):  A nucleotide found amoung the hydrolysis
     products of all nucleic acids; also called adenylic acid.

Adenosine triphosphatase (ATPase):  An enzyme  (EC 3.6.1.3) in muscle
     and elsewhere that catalyzes the release  of the high-energy, ter-
     minal phosphate group of adenosine triphosphate.

Adrenalectomy:  Removal of an adrenal gland.   This gland  is  located near
     or  upon the kidney and is the site of origin of a  number of hormones.

Adsorption:  Adhesion of a thin layer of molecules to a  liquid or solid  sur-
     face.

Advection:  Horizontal flow of air at the surface or aloft;  one  of  the
     means by which heat 1s transferred from one  region  of the earth
     to  another.
                                     G-2

-------
Aerodynamic diameter:   Expression of aerodynamic behavior of an irregularly
     shaped particle in terms of the diameter of a sphere of unit density
     having identical  aerodynamic behavior to the particle in question.

Aerosol:   Solid particles or liquid droplets which are dispersed or sus-
     pended in a gas.

Agglutination:  The process by which suspended bacteria, cells or similar
     particles adhere and form into clumps.

Airborne pathogen:  A disease-causing microorganism which travels in the
     air or on particles in the air.

Air pollutant:  A substance present in the ambient atmosphere, resulting
     from the activity of man or from natural processes, which may cause
     damage to human health or welfare, the natural environment, or
     materials or objects.

Airway conductance:  Inverse of airway resistance.

Airway resistance (Rflw)'  The pressure difference between the alveoli
     and the mouth required to produce an air flow of 1 liter per second.

Alanine aminotransferase:  An enzyme (EC 2.6.1.2) transferring amino
     groups from  L-alanine to 2-ketoglutarate.  Also known as alanine
     transaminase.

Albumin:  A type  of simple, water-soluble protein widely distributed
     throughout animal tissues and  fluids, particularly serum.

                                                           0
                                                           ii
Aldehyde:  An organic compound characterized by the group -C-H.

Aldolase:  An enzyme (EC 4.1.2.7) involved in metabolism of fructose
     which catalyzes the formation  of two 3-carbon intermediates in the
     major pathway of carbohydrate  metabolism.

Algal bloom:  Sudden spurt in growth of algae which can affect water
     quality  adversely.

Alkali:  A salt of sodium or potassium capable  of  neutralizing acids.

Alkaline phosphatase:  A phosphatase (EC 3.1.3.1)  with  an optimum  pH  of
     8.6, present ubiquitously.

Allergen:  A  material that, as a result of coming  into  contact with  appro-
     priate tissues of an animal body, induces  a  state  of sensitivity result-
     Ing in various reactions; generally associated with  idiosyncratic
     hypersensitivities.

Alpha-hydroxybutyrate dehydrogenase:  An enzyme (EC 1.1.1.30),  present
     mainly in mitochondria, which  catalyzes  the  conversion of hydro-
     xybutyrate to acetoacetate  in  intermediate biochemical  pathways.
                                    G-3

-------
Alpha rhythm:  A rhythmic pulsation obtained in brain waves exhibited
     in the sleeping state of an individual.

Alveolar capillary membrane:   Finest portion of alveolar capillaries,
     where gas transfer to and from blood takes place.

Alveolar macrophages (AM):  Large, mononuclear, phagocytic cells found
     on the alveolar surface, responsible for the sterility of the lung.

Alveolar oxygen partial pressure (PA02):  Partial pressure of oxygen in the
     air contained in the air sacs of the lungs.

Alveolar septa:  The tissue between two adjacent pulmonary alveoli, con-
     sisting of a close-meshed capillary network covered on both surfaces
     by thin alveolar epithelial cells.

Alveolus:  An air cell; a terminal, sac-like dilation in the lung.  Gas
     exchange (O-XCCL) occurs here.

Ambient:  The atmosphere to which the general population may be exposed.
     Construed here not to include atmospheric conditions indoors, or in
     the workplace.

Amine:  A substance that may be derived from ammonia  (NH,) by the re-
     placement of one, two or three of the  hydrogen (H) atoms by hydro-
     carbons or other radicals (primary, secondary or tertiary amines,
     respectively).

Ami no acids:  Molecules consisting of a carboxyl group, a basic ami no
     group,  and a residue group attached to a central carbon atom.  Serve
     as the  building blocks of proteins.

p-Aminohippuric acid (PAH):  A compound used to determine renal plasma
     flow.

Aminotriazole:  A systemic herbicide, C.H^N., used in areas other than
     croplands, that also possesses some antithyroid  activity; also called
     amitrole.

Ammonification:  Decomposition with production of ammonia or ammonium
     compounds, esp. by the action of bacteria on nitrogenous organic
     matter.

Ammonium:  Anion (NH.) or radical  (NH.) derived from  ammonia by combination
     with hydrogen.  Present in rainwater,  soils and  many commercial ferti-
     lizers.

Amnestic:  Pertains to immunologic memory:   upon receiving a second
     dose of antigen, the host "remembers"  the  first  dose and responds
     faster  to the challenge.
                                    6-4

-------
Anaerobic:   Living, active or occurring in the absence of free oxygen.

Anaerobic bacteria:  A type of microscopic organism which can live in
     an environment not containing free oxygen.

Anaphylactic dyspneic attack:  Difficulty in breathing associated with
     a systemic allergic response.

Anaphylaxis:  A term commonly used to denote the immediate, transient
     kind of immunological (allergic) reaction characterized by contraction
     of smooth muscle and dilation of capillaries due to release of pharmacologically
     active substances.

Angiosperm:  A plant having seeds enclosed in an ovary; a flowering plant.

Angina pectoris:  Severe constricting pain in the chest which may be
     caused by depletion of oxygen delivery to the heart muscle; usually
     caused by coronary disease.
         o             _o
Angstrom A:  A unit (10   cm) used in the measurement of the wavelength
     of light.

Anhydride:   A compound resulting  from removal of water from two molecules
     of a carboxylic (-COOH) acid.  Also, may refer to those substances
     (anhydrous) which do not contain water in chemical combination.

Anion:  A negatively charged atom or radical.

Anorexia:   Diminished appetite; aversion to food.

Anoxic:  Without or deprived of oxygen.

Anthraquinone:  A yellow crystalline ketone, ^.HgO^ derived from
     anthracene and used in the manufacture of dyes.

Anthropogenic:  Of, relating to or influenced  by man.  An anthropogenic
     source of pollution is one caused  by man's actions.

Antibody:   Any body or substance  evoked by the stimulus of  an antigen
     and which reacts specifically with antigen in  some demonstrable way.

Antigen:  A material such as a  foreign  protein that,  as a  result  of
     coming in contact with appropriate tissues of  an animal, after  a  latent
     period,  induces a state of sensitivity and/or  the production of antibody.

Antistatic  agent:  A chemical compound  applied to  fabrics  to  reduce  or
     eliminate accumulation of  static electricity.

Arachidonic acid:  Long-chain fatty-acid which serves as  a precursor
     of prostaglandins.
                                     G-5

-------
Area source:   In air pollution, any small individual fuel combustion
     or other pollutant source; also, all such sources grouped over a
     specific area.

Aromatic:  Belonging to that series of carbon-hydrogen compounds in
     which the carbon atoms form closed rings containing unsaturated
     bonds (as in benzene).

Arterial partial pressure of oxygen (PaCL):   Portion of total pressure of
     dissolved gases in arterial blood as measured directly from arterial
     blood.

Arterialized partial pressure of oxygen:  The portion of total pressure
     of  dissolved gases in arterial blood attributed to oxygen, as
     measured from non-arterial (e.g., ear-prick) blood.

Arteriosclerosis:  Commonly called hardening of the arteries.  A condition
     that exists when the walls of the blood vessels thicken and become
     infiltrated with excessive amounts of minerals and fatty materials.

Artifact:  A spurious measurement produced by the sampling or analysis
     process.

Ascorbic acid:  Vitamin C, a strong reducing agent with antioxidant proper-
     ties.

Aspartate transaminase:  Also known as aspartate aminotransferase
     (EC 2.6.1.1).  An enzyme catalyzing the transfer of an amine group
     from glutamic acid to oxaloacetic, forming aspartic acid in the
     process.  Serum level of the enzyme is increased in myocardial in-
     farction and in diseases involving destruction of  liver cells.

Asphyxia:  Impaired exchange of oxygen and carbon dioxide, excess of
     carbon dioxide and/or lack of oxygen, usually caused by ventilatory
     problems.

Asthma:  A term currently used in the context of bronchial asthma in
     which there is widespread narrowing of the airways of the  lung.
     It  may be aggravated by inhalation of pollutants and lead  to
     "wheezing" and shortness of breath.

Asymptomatic:  Presenting no subjective evidence of disease.

Atmosphere:  The body of air surrounding the earth.  Also, a measure  of
     pressure (atm.) equal to the pressure of air at sea  level, 14.7  pounds
     per square inch.

Atmospheric deposition:  Removal of pollutants from the atmosphere  onto
     land, vegetation, water bodies or other objects, by  absorption,
     sedimentation, Brownian diffusion,  impaction,  or precipitation in rain.
                                    G-6

-------
Atomic absorption spectrometry:  A measurement method based on the
     absorption of radiant energy by gaseous ground-state atoms.   The
     amount of absorption depends on the population of the ground state
     which is related to the concentration of the sample being analyzed.

Atropine:   A poisonous white crystalline alkaloid, C,7H?^NOV from
     belladonna and related plants, used to relieve Spasms ind to dilate
     the pupil of the eye.

Autocorrelation:  Statistical  interdependence of variables being analyzed;
     produces problems, for example, when observations may be related
     to previous measurements  or other conditions.

Autoimmune disease:  A condition in which antibodies are produced against
     the subject's own tissues.

Autologous:  A term referring  to cellular elements, such as red blood cells
     and alveolar macrophage,  from the same organism; also, something
     natually and normally ocurring in some part of the body.

Autotrophic:  A term applied to those microorganisms which are able to
     maintain life without an  exogenous organic supply of energy, or which
     only need carbon dioxide  or carbonates and simple inorganic nitrogen.

Autotrophic bacteria:  A  class of microorganisms which require only
     carbon dioxide or carbonates and a simple inorganic nitrogen com-
     pound for carrying on life processes.

Auxin:  An organic substance that causes  lengthening of the stem when
     applied  in low concentrations to shoots of growing plants.

Awn:  One of  the slender  bristles that terminate the glumes of the
     spikelet in some cereals  and other grasses.

Azo  dye:  Dyes  in which the azo group is  the chromophore and  joins
     benzene  or napthalene rings.

Background measurement:   A measurement of pollutants  in ambient  air  due
     to natural sources;  usually taken in remote  areas.

Bactericidal  activity:  The process of killing bacteria.

Barre:  Bars  or stripes in a fabric, caused by uneven weaving,  irregular
     yarn or  uneven dye distribution.

Basal cell:   One of the innermost  cells of  the deeper epidermis  of  the
     skin.

Benzenethiol:   A compound of benzene and  a  hydrosulfide  group.
                                      G-7

-------
Beta (b)-lipoprotein:   A biochemical complex or compound containing both
     lipid and protein and characterized by having a large molecular
     weight, rich in cholesterol.   Found in certain fractions of human
     plasma.

Bilateral renal sclerosis:  A hardening of both kidneys of chronic
     Inflammatory origin.

Biomass:  That part of a given habitat consisting of living matter.

Biosphere:  The part of the earth's crust, waters and atmosphere where
     living organisms can subsist.

Biphasic:  Having two distinct successive stages.

Bleb:  A  collection of fluid beneath the skin; usually smaller than
     bullae or blisters.

Blood urea:  The chief end product of nitrogen metabolism in mammals,
     excreted  in human urine in the amount of about 32 grams (1 02.)
     a day.

Bloom:  A greenish-gray appearance imparted to silk and pile fabrics
     either by nature of the weave or by the finish; also, the creamy
     white color observed on some good cottons.

Blue-green algae:  A group of simple plants which are the only N--fixing
     organisms which photosynthesize as do higher plants.

Brightener:  A compound such as a dye, which adheres to fabrics in order
     to provide better brightness or whiteness by converting ultraviolet
     radiation to visible light.  Sometimes called optical bleach  or
     whitening agent.  The dyes used are of the  florescent type.

Broad bean:  The large flat edible seed of an Old World upright vetch
     (Vicia faba), or the plant itself, widely grown for  its seeds and
     for  fodder.

Bronchi:  The  first subdivisions  of the trachea  which conduct air  to
     and  from  the bronchioles of  the lungs.

Bronchiole:  One of the finer subdivisions of the bronchial  (trachea)
     tubes, less than 1 mm in diameter, and having no cartilage in
     its  wall.

Bronchiolitis:  Inflammation of the smallest bronchial  tubes.

Bronchiolitis  fibrosa obliterans  syndrome:  Obstruction of the  bronchioles
     by fibrous granulation arising from an ulcerated mucosa; the  condition
     may  follow inhalation of irritant gases.
                                     G-8

-------
Bronchitis:  Inflammation of the mucous membrane of the bronchial tubes.
     It may aggravate an existing asthmatic condition.

Bronchoconstrictor:  An agent that causes a reduction in the caliber
     (diameter) of a bronchial tube.

Bronchodilator:  An agent which causes an increase in the caliber (diameter)
     of a bronchus or bronchial tube.

Bronchopneumonia:  Acute inflammation of the walls of the smaller bronchial
     tubes, with irregular area of consolidation due to spread of the in-
     flammation into peribronchiolar alveoli and the alveolar ducts.

Brownian diffusion:  Diffusion by random movement of particles suspended
     in liquid or gas, resulting from the impact of molecules of the
     fluid surrounding the particles.

Buffer:  A substance in solution capable of neutralizing both acids
     and bases and thereby maintaining the original pH of the solution.

Buffering capacity:  Ability of a body of water and its watershed to
     neutralize introduced acid.

Butanol:  A four-carbon, straight-chain alcohol, C.hLOH, also known as
     butyl alcohol.                               * 3

Butylated hydroxytoluene (BHT):  A crystalline phenolic antioxidant.

Butylated hydroxyanisol (BHA):  An antioxidant.
14
  C  labeling:  Use of a radioactive  form of carbon as a tracer, often
     in metabolic  studies.
14
  C-proline:   An amino acid which has been labeled with radioactive carbon.

Calcareous:  Resembling or consisting of calcium carbonate  (lime),  or
     growing on limestone or  lime-containing soils.

Calorie:  Amount of heat required to raise temperature of 1 gram of
     water at  15°C by 1 degree.

Cannula:  A tube that is inserted into a body  cavity, or other tube
     or vessel, usually to remove fluid.

Capillary:  The smallest type  of vessel; resembles a  hair.   Usually
     in reference  to a blood  or lymphatic  capillary vessel.

Carbachol:  A  chemical compound (carbamoylcholine  chloride, C-H.-CIN-OO that
     produces  a constriction  of the  bronchi; a parasympathetic  stimulant
     used  in veterinary medicine and topically in  glaucoma.
                                     G-9

-------
Carbon monoxide:   An odorless, colorless, toxic gas with a strong affinity
     for hemoglobin and cytochrome; it reduces oxygen absorption capacity,
     transport and utilization.

Carboxyhemoglobin:  A fairly stable union of carbon monoxide with hemo-
     globin which interferes with the normal transfer of carbon dioxide
     and oxygen during circulation of blood.  Increasing levels of
     Carboxyhemoglobin result  in various degrees of asphyxiation, In-
     cluding death.

Carcinogen:  Any agent producing or playing a stimulatory role in the
     formation of a malignancy.

Carcinoma:  Malignant new growth made up of epithelial cells tending to
     infiltrate the surrounding tissues and giving rise to metastases.

Cardiac output:  The volume of blood passing through the heart per unit
     time.

Cardiovascular:  Relating to the heart and the blood vessels or the
     circulation.

Carotene:   Lipid-soluble yellow-to-orange-red pigments universally
     present the photosynthetic tissues of higher plants, algae, and the
     photosynthetic bacteria.

Cascade impactor:  A device for measuring the size distribution of particulates
     and/or aerosols, consisting of a series of plates with orifices of
     graduated size which separate the sample into a number of fractions
     of decreasing aerodynamic diameter.

Catabolism:  Destructive metabolism involving the release of energy and
     resulting in breakdown of complex materials in the organism.

Catalase:   An enzyme (EC 1.11.1.6) catalyzing the decomposition of hydrogen
     peroxide to water and oxygen.

Catalysis:  A modification of  the rate of a chemical reaction by some
     material which is unchanged at the end of the reaction.

Catalytic  converter:  An air pollution abatement device that removes
     organic contaminants by oxidizing them into carbon dioxide and
     water.

Catecholamine:  A pyrocatechol with an alkalamine side chain, functioning
     as a  hormone or neurotransmitter, such as epinephrine, morepinephrine,
     or dopamine.

Cathepsins:  Enzymes which have the ability to hydrolyze  certain proteins
     and peptides; occur in cellular structures  known as  lysosomes.

Cation:  A positively charged  ion.
                                    G-10

-------
Cellular permeability:   Ability of gases to enter and leave cells;  a
     sensitive indicator of injury to deep-lung cells.

Cellulose:   The basic substance which is contained in all vegetable
     fibers and in certain man-made fibers.  It is a carbohydrate and
     constitutes the major substance in plant life.  Used to make cellulose
     acetate and rayon.

Cellulose acetate:  Commonly refers to fibers or fabrics in which the
     cellulose is only partially acetylated with acetate groups.   An
     ester made by reacting cellulose with acetic anhydride with SO.
     as a catalyst.

Cellulose rayon:  A regenerated cellulose which is chemically the same
     as cellulose except for physical differences in molecular weight
     and crystal!inity.

Cellulose triacetate:  A cellulose fiber which is completely acetylated.
     Fabrics of triacetate have higher heat resistance than acetate and
     may be safely ironed at higher temperature.  Such fabrics have improved
     ease-of-care characteristics because after heat treatment during
     manufacture, a change in the crystalline structure of the fiber
     occurs.

Cellulosics:  Cotton, viscose rayon and other fibers made of natural fiber
     raw materials.

Celsius scale:  The thermometric scale in which freezing point of water
     is 0 and boiling point is 100.

Central hepatic necrosis:  The pathologic death of one or more cells,
     or of a portion of the liver, involving the cells adjacent to  the
     central veins.

Central nervous system (CNS):  The brain and the spinal  cord.

Centroacinar area:  The center portion of  a grape-shaped gland.

Cerebellum:  The  large posterior brain mass  lying  above  the pons and
     medulla and  beneath the posterior portion of  the cerebrum.

Cerebral cortex:  The layer of gray matter covering  the  entire surface
     of the cerebral hemisphere of mammals.

Chain  reaction:   A reaction that stimulates  its  own  repetition.

ChaJlenge:  Exposure of a test organism to a virus,  bacteria,  or other
     stress-causing agent, used in conjunction with  exposure  to  a  pollutant
     of interest, to explore possible  susceptibility brought  on  by the
     pollutant.
                                   G-ll

-------
Chamber study:  Research conducted using a closed vessel in which pollutants
     are reacted or substances exposed to pollutants.

Chemiluminescence:   A measurement technique in which radiation is pro-
     duced as a result of chemical reaction.

Chemotactic:  Relating to attraction or repulsion of living protoplasm
     by chemical stimuli.

Chlorophyll:  A group of closely related green photosynthetic pigments
     occurring in leaves, bacteria, and organisms.

Chloroplast:  A plant cell inclusion body containing chlorophyll.

Chlorosis:  Discoloration of normally green plant parts that can be
     caused by disease,  lack of nutrients, or various air pollutants,
     resulting in the failure of chlorophyll to develop.

Cholesterol:  A steroid  alcohol C-yH.gOH; the most abundant steroid in
     animal cells and body fluids.

Cholinesterase (CHE):  One (EC 3.1.1.8) of a family of enzymes capable
     of catalyzing the hydrolysis of acylcholines.

Chondrosarcoma:  A malignant neoplasm derived from cartilage cells,
     occurring most frequently near the ends of long bones.

Chromatid:  Each of the  two strands formed by longitudinal duplication
     of a chromosome that becomes visible during  an early stage  of cell
     division.

Chromophore:  A chemical group that produces color in a molecule by absorbing
     near ultraviolet or visible radiation when bonded to a nonabsorb-
     ing, saturated residue which possesses no unshared, nonbonding valence
     electrons.

Chromosome:   One of the  bodies (46 in man)  in the cell nucleus that is  the
     bearer and carrier  of genetic information.

Chronic respiratory disease (CRD):  A persistent  or  long-lasting intermittent
     disease  of the respiratory tract.

Cilia:  Motile, often hairlike extensions of a cell  surface.

Ciliary action:  Movements of cilia in the  upper  respiratory tract, which
     move mucus and foreign material upward.

Ciliogenesis:  The formation of cilia.
                                    G-12

-------
Citric acid (Krebs) cycle:   A major biochemical pathway in cells,  in-
     volving terminal oxidation of fatty acids and carbohydrates.   It
     yields a major portion of energy needed for essential body functions
     and is the major source of C02.   It couples the glycolytic breakdown
     of sugar in the cytoplasm witn those reactions producing ATP  1n the
     mitochondria.   It also serves to regulate the synthesis of a  number
     of compounds required by a cell.

Clara cell:  A nonciliated mammalian cell.

Closing volume (CV):  The lung volume at which the flow from the lower
     parts of the lungs becomes severely reduced or stops during expiration,
     presumably because of airway closure.

Codon:  A sequence of three nucleotides which encodes information  re-
     quired to direct the synthesis of one or more ami no acids.

Coefficient of haze (COH):   A measurement of visibility Interference in the
     atmosphere.

Cohort:  A group of subjects included in a test or experiment; usually
     characterized by age, class or other characteristic.

Collagen:  The major protein of the white fibers of connective tissue,
     cartilage, and bond.  Comprises over half the protein of the  mammal.

Collisional deactivation:  Reduction in energy of excited molecules
     caused by collision with other molecules or other objects such
     as the walls of a container.

Colorimetric:  A chemical analysis method relying on measurement of the
     degree of color produced in a solution by reaction with the pollutant
     of interest.

Community exposure:  A situation in which people in a sizeable area are
     subjected to ambient pollutant concentrations.

Compliance: A measure of the change in volume  of an internal organ  (e.g.
     lung, bladder) produced by a unit of pressure.

Complement:  Thermolabile substance present in serum that is destructive
     to certain bacteria and other cells which have been  sensitized  by
     specific complement-fixing antibody.

Compound:  A substance with Us own distinct  properties,  formed by  the
     chemical combination of two or more elements  in fixed  proportion.

Concanavalin-A:  One of two crystalline globulins  occurring in the  jack
     bean; a potent hemagglutinin.

Conifer:  A plant, generally evergreen, needle-leafed,  bearing naked seeds
     singly or  in cones.
                                    G-13

-------
Converter:   See catalytic converter.

Coordination number:   The number of bonds formed by the central  atom in
     a complex.

Copolymer:   The product of the process of polymerization in which two or
     more monomeric substances are mixed prior to polymerization.  Nylon is
     a copolymer.

Coproporphyrin:  One of two porphyrin compounds found normally in feces
     as a decomposition product of bilirubin (a bile pigment).  Porphyrin
     is a widely-distributed pigment consisting of four pyrrole nuclei
     joined in a ring.

Cordage:  A general term which includes banding, cable, cord, rope, string,
     and twine made from fibers.  Synthetic fibers used in making cordage
     include nylon and dacron.

Corrosion:   Destruction or deterioration of a material because of reaction
     with its environment.

Corticosterone:  A steroid obtained from the adrenal cortex.  It induces
     some deposition of glycogen in the liver, sodium conservation, and
     potassium excretion.

Cosmopolitan:  In the biological sciences, a term denoting worldwide
     distribution.

Coulometric:  Chemical analysis performed by determining the amount of a
     substance released in electrolysis by measuring the number  of
     coulombs used.

Coumarin:  A toxic white crystalline lactone (CgM-CO found  in plants.

Coupler:  A chemical used to combine two others in a reaction, e.g. to
     produce the azo dye in the Griess-Saltzman method for N0«.

Crevice corrosion:  Localized corrosion occurring within crevices on  metal
     surfaces exposed to corrosives.

Crosslink:   To connect, by an atom or molecule, parallel chains  in  a  complex
     chemical molecule, such as a polymer.

Cryogenic trap:  A pollutant sampling method in which a gaseous  pollutant
     is condensed out of sampled air by cooling (e.g. traps  in one  method
     for nitrosamines are maintained below -79 C, using solvents maintained
     at their freezing points).

Cuboidal:  Resembling a cube in shape.

Cultivar:  An organism produced by parents belonging  to different  species
     or to different strains of the same species, originating and  persist-
     ing under cultivation.
                                    G-14

-------
Cuticle:   A thin outer layer, such as the thin continuous fatty film
     on the surface of many higher plants.

Cyanosis:   A dark bluish or purplish coloration of the skin and mucous
     membrane due to deficient oxygenation of the blood.

Cyclic GMP:   Guanosine B'-phosphoric acid.

Cytochrome:   A class of hemoprotein whose principal biological function
     is electron and/or hydrogen transport.

Cytology:   The anatomy, physiology, pathology and chemistry of the cell.

Cytoplasm:   The substance of a cell exclusive of the nucleus.

Dacron:  The trade name for polyester fibers made by E.I. du Pont de Nemours
     and Co., Inc., made from dimethyl terephthalate and ethylene glycol.

Dark adaptation:  The process by which the eye adjusts under reduced
     illumination and the sensitivity of the eye to light is greatly in-
     creased.

Dark respiration:  Metabolic activity of plants at night; consuming oxygen
     to use stored sugars and releasing carbon dioxide.

Deciduous plants:  Plants which drop their leaves at the end of the grow-
     ing season.

Degradation (textiles):  The decomposition of fabric or  its components
     or characteristics (color, strength, elasticity) by means of light,
     heat, or air pollution.

Denitrification:  A bacterial process occurring in soils, or water, in
     which nitrate is used as the terminal electron acceptor and  is re-
     duced primarily to N-.  It is essentially an anaerobic process;  it
     can occur  in the presence of low levels of oxygen only if the micro-
     organisms  are metabolizing in an anoxic microzone.

De novo:  Over  again.

Deoxyribonucleic acid (DMA):  A nucleic acid considered  to be  the carrier
     of genetic  information coded in the sequence  of purine and pyrimidine
     bases (organic bases).  It has the form of a  double-stranded helix
     of a linear polymer.

Depauperate:  Falling short of natural development or  size.

Derivative spectrophotometer:  An instrument with  an  increased capability
     for detecting overlapping spectral lines  and  bands  and also  for
     suppressing instrumentally scattered light.
                                    6-15

-------
Desorb:   To release a substance which has been taken into another substance
     or held on its surface; the opposite of absorption or adsorption.

Desquamation:   The shedding of the outer layer of any surface.

Detection limit:  A level below which an element or chemical compound
     cannot be reliably detected by the method or measurement being used for
     analysis.

Detritus:  Loose material that results directly from disintegration.

DeVarda alloy:  An alloy of 50 percent Cu, 45 percent Al, 5 percent Zn.

Diastolic blood pressure:  The blood pressure as measured during the period
     of filling the cavities of the heart with blood.

Diazonium salt:  A+ch§mical compound (usually colored) of the general
     structure ArN?Cl , where Ar refers to an aromatic group.

Diazotizer:  A chemical which, when reacted with amines (RNhL, for example),
     produces a diazonium salt (usually a colored compound).

Dichotomous sampler:  An air-sampling device which separates particulates
     into two fractions by particle size.

Differentiation:  The process by which a cell, such as a fertilized egg,
     divides  into specialized cells, such as the embryonic types that
     eventually develop into an entire organism.

Diffusion:  The process by which molecules or other particles intermingle
     as a result of their random thermal motion.

Diffusing capacity:  Rate at which gases move to or from the blood.

Dimer:  A compound formed by the union of two like radicals  or
     molecules.

Dimerize:  Formation of dimers.

1,6-diphosphofructose aldolase:  An enzyme (EC 4.1.1.13) cleaving  fructose
     1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde-
     3-phosphate.

D-2,3-diphosphoglycerate:  A salt or ester of 2,3-diphosphoglyceric acid,
     a major  component of certain mammalian erythrocytes involved  in the
     release  of Op from HbO™.  Also a postulated  intermediate  in the bio-
     chemical patnway involving the conversion of  3-  to 2-phosphoglyceric
     acid.

Diplococcus pneumoniae:  A species of spherical-shaped  bacteria  belonging
     to the genus Streptococcus.  May be  a causal  agent  in pneumonia.
                                    G-16

-------
Direct dye:  A dye with an affinity for most fibers; used mainly when
     color resistance to washing is not important.

Disperse dyes:  Also known as acetate dyes; these dyes were developed
     for use on acetate fabrics, and are now also used on synthetic
     fibers.

Distal:  Far from some reference point such as median line of the body, point
     of attachment or origin.

Diurnal:  Having a repeating pattern or cycle 24  hours long.

Dl_co:  The diffusing capacity of the lungs for carbon monoxide.  The ability
     of the lungs to transfer carbon monoxide from the alveolar air into the
     pulmonary capillary blood.

Dorsal hyphosis:  Abnormal curvative of the spine; hunch-back.

Dose:  The quantity of a substance to be taken all at one time or in
     fractional amounts within  a given period; also the total amount of a
     pollutant delivered or  concentration per unit time times time.

Dose-response curve:  A curve on a graph based on responses occurring
     in a  system as a result of a series of stimuli intensities or doses.

Dry  deposition:  The processes  by which matter is transferred to ground
     from  the atmosphere, other than precipitation; includes surface ab-
     sorption of gases and sedimentation, Brownian diffusion and impaction
     of particles.

Dyeing:  A process of coloring  fibers, yarns, or  fabrics with either
     natural  or synthetic dyes.

Dynamic calibration:  Testing of a monitoring system  using  a continuous
     sample stream of known  concentration.

Dynamic compliance (C,.   ):  Volume change per unit of transpulmonary
     pressure minus tneypressure of pulmonary resistance during airflow.

Dynel:  A  trademark for a modacrylic staple fiber spun from a  copolymer
     of acrylonitrile and vinyl chloride.  It has high strength, quick-
     drying properties, and  resistance to  alkalies  and acids.

Dyspepsia:  Indigestion,  upset  stomach.

Dyspnea:   Shortness of breath;  difficulty  or  distress in breathing;  rapid
     breathing.

Ecosystem:  The interacting  system of a biological  community and  its
     environment.

Eddy:  A current of water or air running  contrary to  the main current.
                                    G-17

-------
Edema:   Pressure of excess fluid in cells, intercellular tissue or cavities
     of the body.

Elastomer:   A synthetic rubber product which has the physical properties
     of natural rubber.

Electrocardiogram:  The graphic record of the electrical currents that
     initiate the heart's contraction.

Electrode:   One of the two extremities of an electric circuit.

Electrolyte:  A non-metallic electric conductor in which current, is carried
     by the movement of ions; also a substance which displays these qualities
     when dissolved in water or another solvent.

Electronegativity:  Measure of affinity for negative charges or electrons.

Electron microscopy:  A technique which utilizes a focused beam of electrons
     to produce a high-resolution image of minute objects such as particu-
     late matter, bacteria, viruses, and DNA.

Electronic excitation energy:  Energy associated in the transition of
     electrons from their normal low-energy orbitals or orbitals of higher
     energy.

Electrophilic:  Having an affinity for electrons.

Electrophoresis:  A technique by which compounds can be separated from a
     complex mixture by their attraction to the positive or  negative
     pole of an applied electric potential.

Eluant:  A  liquid used in the process of elution.

Elute:  To perform an elution.

Elution:  Separation of one material  from another by washing or by dissolving
     one in a  solvent  in which the other is not soluble.

Elutriate:  To separate a coarse, insoluble powder from a finer one by
     suspending them in water and pouring off the finer powder from the
     upper part of the fluid.

Emission spectrometry:  A rapid analytical technique based  on measurement
     of the characteristic radiation  emitted by thermally or electrically
     excited atoms or  ions.

Emphysema:  An anatomic alteration of the  lung, characterized  by  abnormal
     enlargement  of air spaces distal to  the terminal  bronchioles, due
     to dilation  or destructive changes  in the  alveolar walls.

Emphysematous  lesions:  A wound or injury  to the  lung  as  a  result of
     emphysema.
                                     G-18

-------
Empirical  modeling:   Characterization and description of a phenomena
     based on experience or observation.

Encephalitis:   Inflammation of the brain.

Endoplasmic reticulum:   An elaborate membrane structure extending from the
     nuclear membrane or eucaryotic cells to the cytoplasmic membrane.

Endothelium:   A layer of flat cells lining especially blood and lymphatic
     vessels.

Entropy:   A measure of disorder or randomness in a system.  Low entropy
     is associated with highly ordered systems.

Enzyme:  Any of numerous proteins produced by living cells which catalyze
     biological reactions.

Enzyme Commission (EC):  The International Commission on Enzymes, established
     in 1956, developed a scheme of classification and nomenclature under
     which each enzyme is assigned an EC number which identifies it by
     function.

Eosinophils:   Leukocytes (white blood cells) which stain readily with the
     dye,  eosin.

Epidemiology:   A study of the distribution and determinants of disease
     in human population groups.

Epidermis:  The outermost living layer of cells of any organism.

Epididymal fat pads:  The fatty tissue located near the epididymis.  The
     epididymis is the first convoluted portion of the excretory duct
     of the testis.

Epiphyte:   A plant growing on another plant but obtaining food from the
     atmosphere.

Epithelial:  Relating to epithelium, the membranous cellular layer which
     covers free surfaces or lines tubes or cavities of an animal body,
     which encloses, protects,  secretes, excretes and/or assimilates.

Erosion corrosion:  Acceleration or increase in rate of deterioration
     or attack on a metal because of relative movement between a corrosive
     fluid and the metal surface.  Characterized by grooves, gullies, or
     waves in the metal surface.

Erythrocyte:   A mature red blood cell.

Escherichia coli:  A short, gram-negative, rod-shaped bacteria  common
     to the human intestinal tract.  A frequent cause of  infections  in
     the urogem'tal tract.
                                    G-19

-------
Esophageal:   Relating to the portion of the digestive tract between the
     pharynx and the stomach.

Estrus:   That portion or phase of the sexual cycle of female animals
     characterized by willingness to permit coitus.

Estrus cycle:  The series of physiologic uterine, ovarian and other
     changes that occur in higher animals.

Etiolation:   Paleness and/or altered development resulting from the
     absence of light.

Etiology:  The causes of a disease or condition; also, the study of
     causes.

Eucaryotic:   Pertaining to those cells having a well-defined nucleus
     surrounded by a double-layered membrane.

Euthrophication:  Elevation of the level of nutrients in a body of water,
     which can contribute to accelerated plant growth and filling.

Excited  state:  A state of higher electronic energy than the ground state,
     usually a less stable one.

Expiratory (maximum) flow rate:  The maximum rate at which air can be
     expelled from the lungs.

Exposure level:  Concentration of a contaminant to which an individual
     or  a population is exposed.

Extinction coefficient:  A measure of the space rate of diminution, or
     extinction, of any transmitted light, thus, it is the attenuation
     coefficient applied to visible radiation.

Extramedullary hematopoiesis:  The process of formation and development
     of  the  various types of blood cells and other formed elements  not
     including that occurring  in bone marrow.

Extravasate:  To exclude from  or pass out of a vessel into the tissues;
     applies to urine, lymph,  blood and similar  fluids.

Far  ultraviolet:  Radiation in the range of wavelengths from  100  to 190
     nanometers.

Federal  Reference Method (FRM):  For NO-, the EPA-approved analyzers  based
     on  the  gas-phase chemiluminescent measurement principle  and  associated
     calibration procedures; regulatory specifications prescribed in  Title
     40, Code of Federal Regulations, Part  50, Appendix F.

Fenestrae:   Anatomical aperatures often closed by a  membrane.

Fiber:   A fine, threadlike  piece, as of cotton,  jute, or  asbestos.
                                     G-20

-------
Fiber-reactive dye:   A water-soluble dyestuff which reacts chemically
     with the cellulose in fibers under alkaline conditions;  the dye
     contains two chlorine atoms which combine with the hydroxyl groups of
     the cellulose.

Fibrin:   A white insoluble elastic filamentous protein derived from fibrino-
     gen by the action of thrombin, especially in the clotting of blood.

Fibroadenoma:  A benign neoplasm derived from glandular epithelium, in-
     volving proliferating fibroblasts, cells found in connective tissue.

Fibroblast:  An elongated cell with cytoplasmic processes present in
     connective tissue, capable of forming collagen fibers.

Fibrosis:  The formation of fibrous tissue, usually as a reparative or
     reactive process and not as a normal constituent of an organ or
     tissue.

Flocculation:  Separation of material from a solution or suspension •
     reaction with a flocculant to create fluffy masses containing * -„
     material to be removed.

Fly ash:  Fine, solid particles of noncombustible ash carried out of a
     bed of solid fuel by a draft.

Folded-path optical system:  A long (e.g. 8-22 m) chamber with multiple
     mirrors at the ends which can be used to reflect an infrared beam through
     an ambient air sample many times; a spectrometer can be used with such
     a system to detect trace pollutants at very low levels.

Forced expiratory flow (FEF):  The rate at which air can be expelled from
     the lungs; see expiratory flow rate.

Forced expiratory volume (FEV):  The maximum volume of air that can be
     expired in a specific time interval when starting from maximal
     inspiration.

Forced vital capacity  (FVC):  The greatest volume of air th-t can be
     exhaled from the  lungs under forced conditions after  ; /,'xvi'jm
     inspiration.

Fractional  threshold concentration:  The portion of the concentration
     at which an event or a response begins to occur,  expressed  as  a
     fraction.

Free radical:  Any of  a variety of highly-reactive atoms  or molecules
     characterized by  having an unpaired electron.

Fritted bubbler:  A porous glass  device  used  in  air pollutant  sampling
     systems to introduce small bubbles  into  solution.

-------
Functional residual capacity:   The volume of gas remaining in the lungs
     at the end of a normal expiration.   It is the sum of expiratory
     reserve volume and residual volume.

Gas exchange:  Movement of oxygen from the alveoli into the pulmonary
     capillary blood as carbon dioxide enters the alveoli from the blood.

Gas chromatography (GC):  A method of separating and analyzing mixtures
     of chemical substances.   A flow of gas causes the components of a
     mixture to migrate differentially from a narrow starting zone in a
     special porous, insoluble sorptive medium.   The pattern formed by
     zones of separated pigments and of colorless substances in this
     process is called a chromatogram, and can be analyzed to obtain the
     concentration of identified pollutants.

Gas-liquid chromatography:  A method of separating and analyzing volatile
     organic compounds, in which a sample is vaporized and swept through
     a column filled with solid support material covered with a nonvolatile
     liquid.  Components of the sample can be identified and their con-
     centrations determined by analysis of the characteristics of their
     retention in the column, since compounds have varying degrees of
     solubility in the liquid medium.

Gastric juice:  A thin watery digestive fluid secreted by glands in the
     mucous membrane of the stomach.

Gastroenteritis:  Inflammation of the mucous membrane of stomach and
     intestine.

Genotype:  The type of genes possessed by an organism.

Geometric mean:  An estimate of the average of a distribution.  Specifically,
     the nth root of the product of n observations.

Geometric standard deviation:  A measure of variability  of a distribution.
     It is the antilogarithm of the standard deviation of the logarithms
     of the observations.

Globulins (a, b, q):  A family of proteins precipitated  from plasma  (or
     serum) by half-saturation with ammonium sulfate, or separable by
     electrophoresis.  The main groups are the a, b,  q fractions, differ-
     ing with respect to associated lipids and carbohydrates and  in  their
     content of antibodies (immunoglobulins).

Glomular nephrotic syndrome:  Dysfunction of the  kidneys characterized
     by excessive protein  loss  in the urine, accumulation of body fluids
     and alteration in albumin/globulin ratio.

Glucose:  A sugar which is a principal source of  energy  for  man and  other
     organisms.

Glucose-6-phosphate dehydrogenase:  An enzyme (EC  1.1.1.49)  catalyzing
     the dehydrogenation of glucose-6-phosphate  to  6-phosphogluconolactone.
                                    G-22

-------
Glutamic-oxaloacetic transaminase (SCOT):  An enzyme (EC 2.6.1.1) whose
     serum level increases in myocardial infarction and in diseases in-
     volving destruction of liver cells.  Also known as aspartate
     aminotransferase.

Glutamic-pyruvic transaminase (SGPT):  Now known as alanine aminotransferase
     (EC 2.6.1.2), the serum levels of this enzyme are used in liver function
     tests.

Glutathione (GSH):  A tripeptide composed of glycine, cystine, and glutamic
     acid.

Glutathione peroxidase:  An enzyme (EC 1.11.1) which catalyzes the destruction
     of hydroperoxides formed from fatty acids and other substances.
     Protects tissues from oxidative damage.  It is a selenium-containing
     protein.

Glutathione reductase:   The enzyme (EC 1.6.4.2) which reduces the oxidized
     form of glutathione.

Glycolytic pathway:  The biochemical pathway by which glucose is con-
     verted to  lactic acid in various tissues, yielding energy as a
     result.

Glycoside:  A type of chemical compound  formed from the condensation of
     a  sugar with another chemical radical via a hemiacetal linkage.

Goblet  cells:   Epithelial cells that have been distended with mucin and when
     this is discharged as mucus, a goblet-shaped shell remains.

Golgi apparatus:  A membrane system involved with secretory functions
     and transport in a cell.  Also known as a dictyosome.

Grana:  The lamellar stacks of chlorophyll-containing material in plant
     chloroplasts.

Griege  carpet:  A carpet in its unfinished state, i.e. before it has
     been scoured and dyed.  The term also is used for woven  fabrics
     in the unbleached and unfinished state.

Ground  state:   The state of minimum electronic energy of a molecule or
     atom.

Guanylate cyclase (GC):  An enzyme (EC  4.6.2.1) catalyzing the trans-
     formation  of guanosine triphosphate to guanosine 3':5'-cyclic  phosphate.

H-Thymidine:  Ihymine deoxyribonucleoside:  One of the  four major  nucleosides
     in DMA.    H-thymidine has been  uniformly labeled with tritium, a  radio-
     active form  of hydrogen.

Haze:   Fine dust, smoke or fine vapor reducing transparency of  air.
                                    G-23

-------
Hemagglutination:   The agglutination of red blood cells.   Can be used as
     as a measurement of antibody concentration.

Hematocrit:  The percentage of the volume of a blood sample occupied by
     cells.

Hematology:  The medical specialty that pertains to the blood and blood-
     forming tissues.

Hemochromatosis:  A disease characterized by pigmentation of the skin
     possibly due to inherited excessive absorption of iron.

Hemoglobin (Hb):  The red, respiratory protein of the red blood cells,
     hemoglobin transports oxygen from the lungs to the tissues as oxy-
     hemoglobin (HbO«) and returns carbon dioxide to the lungs as hemoglobin
     carbamate, completing the respiratory cycle.

Hemolysis:  Alteration or destruction of red blood cells, causing hemoglobin
     to be released into the medium in which the cells are suspended.

Hepatectomy:  Complete removal of the liver in an experimental animal.

Hepatic:   Relating to the liver.

Hepatocyte:  A  liver cell.

Heterogeneous process:  A chemical reaction involving reactants of more
     than  one phase or state, such as one in which gases are absorbed  into
     aerosol droplets, where the reaction takes  place.

Heterologous:   A term referring to donor and recipient cellular elements
     from  different organisms, such as red blood cells from sheep and
     alveolar macrophage from rabbits.

Hexose monophosphate shunt:  Also called the phosphogluconate  oxidative
     pathway of glucose metabolism which affords a total combustion  of
     glucose independent of the citric acid cycle.   It is  the  important
     generator  of NADPH necessary for synthesis  of fatty acids  and  the
     operation  of various enzymes.  It serves as a source  of  ribose  and
     4- and 7-carbon sugars.

High-volume sampler  (Hi-vol):  Device for taking a sample  of  the  particulate
     content of a large amount of-air, by drawinq  air  through  a fiber filter
     at a  typical rate of 2,000 m 724 hr (1.38  m /min),  or as  high  as 2,880
     mV24 hr (2 in /min).

Histamine:  An  amine derived from the amino acid,  histidine.   It is a
     powerful stimulant of gastric  secretion and a constrictor of bronchial
     smooth muscle.  It is a vasodilator and causes  a  fall  in blood
     pressure.

-------
Homogenate:  Commonly refers to tissue ground into a creamy consistency
     in which the cell structure is disintegrated.

Host defense mechanism:   Inherent means by which a biologic organism
     protects itself against infection, such as antibody formation,
     macrophage action,  ciliary action, etc.

Host resistance:  The resistance exhibited by an organism, such as man,
     to an infecting agent, such as a virus or bacteria.

Humoral:  Relating to the extracellular fluids of the body, blood and
     lymph.

Hybrid:  An organism descended from parents belonging to different
     varieties or species.

Hydrocarbons:  A vast family of compounds containing carbon and hydrogen
     in various combinations; found especially in fossil fuels.  Some
     contribute to photochemical smog.

Hydrolysis:  Decomposition involving splitting of a bond and addition
     of the H and OH parts of water to the two sides of the split bond.

Hydrometeor:  A product of the condensation of atmospheric water vapor (e.g.
     fog,  rain, hail, snow).

Hydroxyproline:  An amino acid found among the hydrolysis products of
     collagen.

Hygroscopic:  Pertaining to a marked ability to accelerate the condensation
     of water vapor.

Hyperplasia:  Increase in the number of cells in  a tissue or organ ex-
     cluding tumor formation.

Hyperplastic:   Relating to hyperplasia; an  increase in  the number  of
     cells.

Hypertrophy:  Increase in the size of  a tissue element, excluding  tumor
     formation.

Hypertension:   Abnormally elevated blood  pressure.

Hypolimnia:  Portions of  a lake below  the thermocline,  in which water
     is stagnant and  uniform  in temperature.

Hypoxia:   A  lower than normal amount  of oxygen  in the  air, blood  or  tissues
                                    G-25

-------
Immunoglobulin (Ig):   A class of structurally related proteins consist-
     ing of two pairs of polypeptide chains.   Antibodies are Ig's and
     all Ig's probably function as antibodies.

Immunoglobulin A (IgA):   A type of antibody which comprises approximately
     10 to 15 percent of the total amount of antibodies present in normal
     serum.

Immunoglobulin G (IgG):   A type of antibody which comprises approximately
     80 percent of the total amount of antibodies present in normal  serum.
     Subfractions of IgG are fractions G,, and Sy-

Immunoglobulin M (IgM):   A type of antibody which comprises approximately
     5 to 10 percent of the total amount of antibodies present in normal
     serum.

Impaction:  An impinging or striking of one object against another;  also,
     the force transmitted by this act.

Impactor:  An instrument which collects samples of suspended particulates
     by directing a stream of the suspension against a surface, or into a
     liquid or a void.

Index of proliferation:   Ratio of promonocytes to polymorphic monocytes
     in the blood.

Infarction:  Sudden insufficiency of arterial or venous blood supply
     due to emboli, thrombi, or pressure.

Infectivity model:  A testing system in which the susceptibility of
     animals to airborne infectious agents with and without exposure to air
     pollutants is investigated to produce information related to the
     possible effects of the pollutant on man.

Inflorescence:  The arrangement and development of flowers on an axis;
     also, a flower cluster or a  single flower.

Influenza A-Aaiwan Virus:  An infectious viral disease, believed to
     have originated  in Taiwan, characterized by sudden onset, chills,
     fevers, headache, and cough.

Infrared:  Light  invisible to the human eye, bgtween  the wavelengths
     of 7x10   and 10  m (7000 and 10,000,000 A).

Infrared  laser:  A device that utilizes the  natural oscillations  of  atoms
     or molecules to  generate coherent electromagnetic  radiation  in  the
     infrared region  of the spectrum.

Infrared  spectrometer:  An  instrument for measuring  the  relative  amounts
     of radiant energy in the infrared region of the  spectrum as  a  function
     of wavelength.
                                    G-26

-------
Ingestion:   To take in for digestion.

In situ:   In the natural or original position.

Instrumental averaging time:   The time over which a single sample or
     measurement is taken, resulting in a measurement which 1s an average
     of the actual  concentrations over that period.

Insult:  An injury or trauma.

Intercostal:  Between the ribs, especially of a leaf.

Interferant:  A substance which a measurement method cannot distinguish
     completely from the one being measured, which therefore can cause some
     degree of false response or error.

Interferon:  A macromolecular substance produced in response to infection
     with active or inactivated virus, capable of inducing a state of
     resistance.

Intergranular corrosion:  A type of corrosion which takes place at and
     adjacent to grain boundaries, with relatively little corrosion of
     the grains.

Interstitial edema:  An accumulation of an excessive amount of fluids
     in a space within tissues.

Interstitial pneumonia:  A chronic inflammation of the interstitial tissue
     of the lung, resulting in compression of air cells.

Intraluminal mucus:  Mucus that collects within any tubule.

Intraperitoneal injection:  An injection of material into the serous
     sac that lines the abdominal cavity.

In utero:  Within the womb; not yet born.

In vitro:  Refers to experiments conducted outside the living organism.

In vivo:   Refers to experiments conducted within the living organism.

Irradiation:  Exposure to any form of  radiation.

Ischemia:  Local anemia due to mechanical obstruction (mainly arterial
     narrowing) of the blood supply.

Isoenzymes:  Also called  isozymes.  One of a group of enzymes that  are
     very similar in catalytic properties, but may be differentiated  by
     variations in physical properties, such as  isoelectric point  or
     electrophoretic mobility.  Lactic acid dehydrogenase  is  an  example
     of an enzyme having many isomeric forms.
                                   G-27

-------
Isopleth:  A line on a map or chart connecting points of equal value.

Jacobs-Hochheiser method:   The original Federal Reference Method for NOp,
     currently unacceptable for air pollution work.

Klebsiella pneumoniae:  A species of rod-shaped bacteria found in soil,
     water, and in the intestinal tract of man and other animals.  Certain
     types may be causative agents in pneumonia.

Kyphosis:  An abnormal curvature of the spine, with convexity backward.

Lactate:  A salt or ester of lactic acid.

Lactic acid (lactate) dehydrogenase (LDH):  An enzyme (EC 1.1.1.27) with
     many isomeric forms which catalyzes the oxidation of lactate to
     pyruvate via transfer of H to NAD.  Isomeric forms of LDH in the
     blood are indicators of heart damage.

Lamellar bodies:  Arranged in plates or scales.  One of the characteristics
     of Type II alveolar cells.

Lavage fluid:  Any fluid used to wash out hollow organs, such as the lung.

Lecithin:  Any of several waxy hygroscopic phosphatides that are widely
     distributed in animals and plants; they form colloidal solutions  in
     water and have emulsifying, wetting and hygroscopic properties.

Legume:  A plant with root nodules containing  nitrogen fixing bacteria.

Lesion:  A wound, injury or other more or less circumscribed pathologic
     change in the tissues.

Leukocyte:  Any of the white blood cells.

Lewis base:  A base,  defined in the Lewis acid-base concept,  is  a sub-
     stance that can  donate an electron pair.

Lichens:  Perennial plants which are a combination of two plants, an alga
     and a fungus, growing together in an association so intimate that they
     appear as one.

Ligand:  Those molecules or anions attached  to the central atom  in  a
     complex.

Light-fastness:  The  ability of a dye  to maintain its original color under
     natural or indoor light.

Linolenic acid:  An unsaturated fatty  acid essential  in  nutrition.

Lipase:  An enzyme that accelerates the hydrolysis or  synthesis  of  fats
     or  the breakdown of lipoproteins.
                                    G-28

-------
Lipids:   A heterogeneous group of substances which occur widely in bio-
     logical materials.   They are characterized as a group by their
     extractability in nonpolar organic solvents.

Lipofuscin:   Brown pigment granules representing 1ipid-containing residues
     of lysosomal digestion.   Proposed to be an end product of lipid
     oxidation which accumulates in tissue.

Lipoprotein:  Complex or protein containing lipid and protein.

Loading rate:   The amount of a nutrient available to a unit area of body
     of water over a given period of time.

Locomotor activity.  Movement of an organism from one place to another
     of its own volition.

Long-pathlength infrared absorption:  A measurement technique in which a
     system of mirrors in a chamber is used to direct an infrared beam
     through a sample of air for a long distance (up to 2 km); the amount
     of Infrared absorbed is measured to obtain the concentrations of
     pollutants present.

Lung compliance (C,):  The volume change produced by an increase in a
     unit change in pressure across the lung, i.e., between the pleural
     surface and the mouth.

Lycra:  A spandex textile fiber created by E. I. du Pont de Nemours & Co.,
     Inc., with excellent tensile strength, a long flex life and high
     resistance to abrasion and heat degradation.   Used in brassieres,
     foundation garments, surgical hosiery, swim suits and military and
     industrial uses.

Lymphocytes:  White blood cells formed in lymphoid tissue throughout the
     body, they comprise about 22 to 28 percent of the total number of
     leukocytes in the circulating blood and function in immunity.

Lymphocytogram:  The ratio, in the blood, of lymphocyte with narrow
     cytoplasm to  those with broad cytoplasm.

Lysosomes:  Organelles found in cells of higher organisms that contain
     high concentrations of degradative enzymes and are known to destroy
     foreign substances that cells engulf by pinocytosis and phyocytosis.
     Believed to be a major site where proteins are broken down.

Lysozymes:  Lytic  enzymes destructive to cell walls of certain bacteria.
     Present in some body fluids, including tears and serum.

Macaca speciosa:   A species of monkeys used in  research.

Macrophage:  Any large, ameboid, phagocytic cell  having a nucleus  without
     many lobes, regardless of origin.
                                    G-29

-------
Malaise:  A feeling of general discomfort or uneasiness, often the first
     indication of an infection or disease.

Malate dehydrogenase:  An enzyme (EC 1.1.1.37) with at least six Isomeric
     forms that catalyze the dehydrogenation of malate to oxaloacetate
     or its decarboxylation (removal of a CO- group) to pyruvate.  Malate,
     oxaloacetate, and pyruvate are intermediate components of biochemical
     pathways.

Mannitol:  An alcohol derived from reduction of the sugar, fructose.
     Used in renal' function testing to measure glomerular (capillary)
     filtration.

Manometer:  An  instrument for the measurement of pressure of gases or
     vapors.

Mass median diameter (MMD):  Geometric median size of a distribution of
     particles  based on weight.

Mass spectrometry (MS):  A procedure for identifying the various kinds of
     particles  present in a given substance, by ionizing the particles
     and subjecting a beam of the ionized particles to an electric or
     magnetic field such that the field deflects the particles in angles
     directly proportional to the masses of the particles.

Maximum flow  (V  ):  Maximum rate or expiration, usually expressed at
     50 or 25 percent of vital capacity.

Maximum mid-expiratory flow rate (MMFR):  The mean rate of expiratory gas
     flow between 25 and 75 percent of the forced expiratory vital capacity.

Mean (arithmetic):  The sum of observations divided by sample size.

Median:  A value in a collection of data values which is exceeded  in
     magnitude  by one-half the entries in the collection.

Mesoscale:  Of  or relating to meteorological phenomena from 1 to 100
     kilometers in horizontal extent.

Messenger RNA:  A type of RNA which conveys genetic information  encoded
     in the DMA to direct protein synthesis.

Metaplasia:  The abnormal transformation of an adult, fully differentiated
     tissue of  one kind into a differentiated tissue of another  kind.

Metaproterenol:  A bronchodilator used for the treatment  of bronchial
     asthma.

Metastases:   The shifting of a disease from one part of the body to another;
     the appearance of neoplasms in parts of  the  body remote  from  the seat
     of the primary tumor.
                                    G-30

-------
Meteorology:  The science that deals with the atmosphere and its phenomena.

Methemoglobin:  £+form of hemoglobin in which the normal reduced state
     of iron (Fe  ) has been oxidized to Fe  .   It contains oxygen in
     firm union with ferric (Fe  ) iron and is not capable of exchanging
     oxygen in normal respiratory processes.

Methimazole:  An anti-thyroid drug similar in action to propylthiouracil.

Methyltransferase:  Any enzyme transferring methyl groups from one compound
     to another.

Microcoulometric:  Capable of measuring millionths of coulombs used in
     electrolysis of a substance, to determine the amount of a substance
     in a sample.

Microflora:  A small or strictly localized plant.

Micron:  One-millionth of a meter.

Microphage:  A small phagocyte; a polymorphonuclear leukocyte that is
     phagocytic.

Millimolar:  One-thousandth of a molar solution.  A solution of one-
     thousandth of a mole (in grams) per liter.

Minute volume:  The minute volume of breathing; a product of tidal volume
     times  the respiratory frequency in one minute.

Mitochondria:  Organelles of the cell cytoplasm which contain enzymes
     active in the conservation of energy obtained in the aerobic part
     of the breakdown of carbohydrates and fats,  in a process called
     respiration.

Mobile sources:  Automobiles, trucks and other pollution sources which  are
     not fixed in one location.

Modacrylic  fiber:  A manufactured fiber in which  the fiber-forming sub-
     stance is any long chain synthetic polymer composed of  less than 85
     percent but at  least 35 percent by weight of acrylonitrite units.

Moeity:  One of two  or more parts into which something  is divided.

Mole:  The  mass,  in  grams, numerically equal to the molecular weight  of
     a substance.

Molecular correlation spectrometry:  A spectrophotometric technique which
     is used to  identify unknown absorbing materials and measure  their
     concentrations  by using preset wavelengths.

Molecular weight:  The weight of one molecule  of  a substance obtained
     by adding the gram-atomic weights of each  of the  individual  atoms
     in the substance.
                                    G-31

-------
Monocyte:   A relatively large mononuclear leukocyte, normally constituting
     3 to 7 percent of the leukocytes of the circulating blood.

Mordant:   A substance which acts to bind dyes to a textile fiber of fabric.

Morphological:   Relating to the form and structure of an organism or any
     of its parts.

Moving average:  A procedure involving taking averages over a specific
     period prior to and including a year in question, so that successive
     averaging periods overlap; e.g. a three-year moving average would
     include data from 1967 through 1969 for the 1969 average and from
     1968 through 1970 for 1970.

Mucociliary clearance:  Removal of materials from the upper respiratory
     tract via ciliary action.

Mucociliary transport:  The process by which mucus is transported, by
     ciliary action, from the lungs.

Mucosa:  The mucous membrane; it consists of epithelium, lamina propria
     and, in the digestive tract, a layer of smooth muscle.

Mucous membrane:  A membrane secreting mucus which lines passages and
     cavities communicating with the exterior of the body.

Murine:  Relating to mice.

Mutagen:  A substance capable of causing, within an organism, biological
     changes that affect potential offspring through genetic mutation.

Mutagenic:  Having the power to cause mutations.  A mutation is a change
     in the character of a gene (a sequence of base pairs  in DNA) that
     is perpetuated in subsequent divisions of the cell  in which  it occurs.

Myocardial infarction:  Infarction of any area of the heart muscle usually
     as a result of occlusion of a coronary artery.

Nares:  The nostrils.

Nasopharyngeal:  Relating to the nasal cavity and the pharynx (throat).

National Air Surveillance Network (NASN):  Network  of monitoring  stations
     for sampling air to determine extent of air pollution;  established
     jointly by federal and  state governments.

Near ultraviolet:  Radiation of the wavelengths 2000-4000  Angstroms.

Necrosis:  Death of cells that  can  discolor  areas of  a  plant or kill
     the entire plant.

Necrotic:  Pertaining to the pathologic  death of  one  or more cells,  or
     of a portion of  tissue  or  organ, resulting  from  irreversible damage.
                                   G-32

-------
Neonate:  A newborn.

Neoplasm:  An abnormal tissue that grows more rapidly than normal; synonymous
     with tumor.

Neoplasia:  The pathologic process that results in the formation and
     growth of a tumor.

Neutrophil:  A mature white blood cell formed in bone marrow and released
     Into the circulating blood, where it normally accounts for 54 to 65
     percent of the total number of leukocytes.

Ninhydrin:  An organic reagent used to identify amino acids.

Nitramine:  A compound consisting of a nitrogen attached to the nitrogen
     of amine.

Nitrate:  A salt or ester of nitric acid (N03~).

Nitrification:  The principal natural source of nitrate in which ammonium
     (NH.+) ions are oxidized to nitrites by specialized microorganisms.
     Othlr organisms oxidize nitrites to nitrates.

Nitrite:  A salt or ester of nitrous acid (NCL~).

Nitrocellulose:  Any of several esters of nitric acid formed by its action
     on cellulose, used in explosives, plastics, varnishes and rayon;
     also called cellulose nitrate.

Nitrogen cycle:  Refers to the complex pathways by which nitrogen-containing
     compounds are moved from the atmosphere into organic life, into the
     soil, and back to the atmosphere.

Nitrogen fixation:  The metabolic assimilation of atmospheric nitrogen by
     soil microorganisms, which becomes available for plant use when the
     microorganisms die; also, industrial conversion of free nitrogen into
     combined forms used in production of fertilizers and other products.

Nitrogen oxide:  A compound composed of only nitrogen and oxygen.  Components
     of photochemical  smog.

Nitrosamine:  A compound consisting of a nitrosyl group connected to the
     nitrogen of an amine.

Nitrosation:  Addition of a nitrosyl group.

N-Nitroso compounds:   Compounds carrying the functional nitrosyl  group.

Nitrosyl:  A group composed of one oxygen and  one nitrogen  atom  (-N=0).

Nitrosylhemoglobin (NOHb):  The red, respiratory  protein  of erythrocytes
     to which a nitrosyl group is attached.
                                    G-33

-------
N/P Ratio:   Ratio of nitrogen to phosphorous dissolved in lake water,
     Important due to its effect on plant growth.

Nucleolus:   A small spherical mass of material within the substance of the
     nucleus of a cell.

Nucleophilic:  Having an affinity for atomic nuclei; electron-donating.

Nucleoside:  A compound that consists of a purine or pyrimidine base com-
     bined with deoxyribose or ribose and found in RNA and DNA.

S'-Nucleotidase:  An enzyme (EC 3.1.3.5) which hydrolyzes nucleoside 5'-
     phosphates into phosphoric acid (H^PO.) and nucleosides.

Nucleotide:  A compound consisting of a sugar (ribose or deoxyribose),
     a base  (a purine or a pyrimidine), and a phosphate; a basic structural
     unit of RNA and DNA.

Nylon:  A generic name chosen by E. I. du Pont de Nemours & Co., Inc.
     for a group of protein-like chemical products classed as synthetic
     linear polymers; two main types are Nylon 6 and Nylon 66.

Occlusion:  A point which an opening is closed or obstructed.

Olefin:  An open-chain hydrocarbon having at least one double bond.

Olfactory:   Relating to the sense of smell.

Olfactory epithelium:  The inner lining of the nose and mouth which contains
     neural  tissue sensitive to smell.

Oligotrophic:  A body of water deficient in plant nutrients; also  generally
     having  abundant dissolved oxygen and no marked stratification.

Oribitals:  Areas of high electron density in an atom or molecule.

Orion:  An acrylic fiber produced by E. I. du Pont de Nemours  and  Co.,  Inc.,
     based on a polymer of acrylonitrite; used extensively for outdoor
     uses, it is resistant to chemicals and withstands  high  temperatures.

Osteogenic osteosarcoma:  The most common and malignant of bone  sarcomas
     (tumors).  It arises from bone-forming cells and affects  chiefly
     the ends of long bones.

Ovarian primordial follicle:  A spheroidal cell aggregation  in the ovary
     in which the primordial oocyte  (immature female  sex cell)  is  surrounded
     by a  single layer of flattened  follicular cells.

Oxidant:  A  chemical compound which  has the ability  to  remove electrons
     from  another chemical species,  thereby oxidizing it;  also,  a  substance
     containing oxygen which reacts  in air  to produce a new  substance,  or
     one formed by the action of sunlight  on  oxides  of  nitrogen and hydro-
     carbons.
                                    G-34

-------
Oxidation:   An ion or molecule undergoes oxidation by donating electrons.

Oxidative deamination:  Removal of the NHL group from an ami no compound
     by reaction with oxygen.            *•

Oxidative phosphorylation:  The mitochondria! process by which "high-
     energy" phosphate bonds form from the energy released as a result of
     the oxidation of various substrates.  Principally occurs in the tri-
     carboxylic acid pathway.

Oxyhemoglobin:  Hemoglobin in combination with oxygen.  It is the form
     of hemoglobin present in arterial blood.

Ozone layer:  A layer of the stratosphere from 20 to 50 km above the
     earth's surface characterized by high ozone content produced by ultra-
     violet radiation.

Ozone scavenging:   Removal of 0, from ambient air or plumes by reaction with
     NO, producing NO- and 0-.

Paired electrons:   Electrons having opposite intrinsic spins about their
     own axes.

Parenchyma:  The essential and distinctive tissue of an organ or an ab-
     normal growth, as distinguished from its supportive framework.

Parenchymal:  Referring to the distinguishing or specific cells of a
     gland or organ.

Partial pressure:   The pressure exerted by a single component in a mixture
     of gases.

Particulates:  Fine liquid or solid particles such as dust, smoke, mist,
     fumes or smog, found in the air or  in emissions.

Pascal:  A unit of pressure  in the International System of Units.  One
     pascal is equal to 7.4  x 10   torr.  The pascal  is equivalent to one
     newton per square meter.

Pathogen:  Any virus, microorganism, or  other substance causing disease.

Pathophysiological:  Derangement of function seen in  disease; alteration
     in function as distinguished from structural defects.

Peptide bond:  The bond formed when two  amino acids react with each other.

Percent!les:  The percentage of all observations exceeding  or preceding
     some point; thus, 90th  percentile is a  level below which will  fall  90
     percent of the observations.

Perfusate:  A liquid, solution or colloidal  suspension that has  been  passed
     over a special surface  or through an appropriate structure.
                                    G-35

-------
Perfusion:   Artificial  passage of fluid through blood vessels.

Permanent-press fabrics:   Fabrics in which applied resins contribute to the
     easy care and appearance of the fabric and to the crease and seam
     flat-
     ness by reacting with the cellulose on pressing after garment
     manufacture.

Permeation tube:  A tube which is selectively porous to specific gases.

Peroxidation:  Refers to the process by which certain organic compounds
     are converted to peroxides.

Peroxyacetyl nitrate (PAN):  Pollutant created by action of sunlight on
     hydrocarbons and NO  in the air; an ingredient of photochemical smog.

pH:  A measure of the acidity or alkalinity of a material, liquid, or solid.
     pH is represented on a scale of 0 to 14 with 7 being a neutral state,
     0 most acid, and 14 most alkaline.

Phagocytosis:  Ingestion, by cells such as macrophages, of other cells,
     bacteria, foreign particles, etc.; the cell membrane engulfs solid or
     liquid particles which are drawn into the cytoplasm and digested.

Phenotype:   The observable characteristics of an organism, resulting from
     the interaction between an individual genetic structure and the
     environment in which development takes place.

Phenylthiourea:  A crystalline compound, CyHgN^S, that is bitter or tasteless
     depending on a single dominant gene in the tester.

Phlegm:  Viscid mucus secreted in abnormal quantity in the respiratory passages

Phosphatase:  Any of a group of enzymes that liberate inorganic phosphate
     from phosphoric esters (E.G. sub-subclass 3.1.3).

Phosphocreatine kinase:  An enzyme (EC 2.7.3.2) catalyzing the  formation of
     creatine and ATP, its breakdown is a  source of energy in the  contraction
     of muscle; also called creatine phosphate.

Phospholipid:  A molecule consisting of lipid and phosphoric acid  group(s).
     An example is lecithin.  Serves as an important  structural  factor
     in biological membranes.

Photochemical oxidants:  Primary ozone, NOp, PAN with  lesser amounts  of
     other compounds formed as products of atmospheric  reactions  involving
     organic pollutants, nitrogen oxides,  oxygen, and  sunlight.

Photochemical smog:  Air pollution caused  by chemical  reaction  of various
     airborne chemicals in sunlight.

Photodissociation:  The process by which  a chemical  compound breaks down into
     simpler components under the influence  of  sunlight or other radiant energy.
                                    G-36

-------
Photolysis:  Decomposition upon irradiation by sunlight.

Photomultiplier tube:  An electron multiplier in which electrons released
     by photoelectric emission are multiplied in successive stages by
     dynodes that produce secondary emissions.

Photon:  A quantum of electromagnetic energy.

Photostationary:  A substance or reaction which reaches and maintains a
     steady state in the presence of light.

Photosynthesis:  The process in which green parts of plants, when exposed to
     light under suitable conditions of temperature and water supply, produce
     carbohydrates using atmospheric carbon dioxide and releasing oxygen.

Phytotoxic:  Poisonous to plants.

Phytoplankton:   Minute aquatic plant life.

Pi n bonds:  Bonds in which electron density is not symmetrical about a
     line joining the bonded atoms.

Pinocytotic:  Refers to the cellular process (pinocytosis) in which the cyto-
     plasmic membrane forms invaginations in the form of narrow channels
     leading into the cell.  Liquids can flow into these channels and the
     membrane pinches off pockets that are incorporated into the cytoplasm
     and digested.

Pitting:  A form of extremely localized corrosion that results in holes in
     the metal.  One of the most destructive forms of corrosion.

Pituary:  A stalk-like gland near the base of the brain which is attached
     to the hypothalmus.  The anterior portion is a major repository for
     for hormones that control growth, stimulate other glands, and regulate
     the reproductive cycle.

Placenta:  The  organ in the uterus that provides metabolic interchange between
     the fetus  and mother.

Plasmid:  Replicating unit, other than a nucleus gene, that contains
     nucleoprotein and is involved in various aspects of metabolism in
     organisms; also called paragenes.

Plasmolysis:  The dissolution of cellular components, or the shrinking
     of plant cells by osmotic loss of cytoplasmic water.

Plastic:  A plastic is one of a large group  of organic compounds  synthesized
     from cellulose, hydrocarbons, proteins  or resins and capable of being
     cast, extruded, or molded into various  shapes.

Plasticizer:  A chemical added to plastics to soften, increase  malleability
     or to make more readily deformable.
                                    G-37

-------
Platelet (blood):   An irregularly-shaped disk with no definite nucleus;
     about one-third to one-half the size of an erythrocyte and containing
     no hemoglobin.   Platelets are more, numerous than leukocytes, numbering
     from 200,000 to 300,000 per cu. mm. of blood.

Plethysmograph:  A device for measuring and recording changes 1n volume of
     a part, organ or the whole body; a body plethysmograph 1s a chamber
     apparatus surrounding the entire body.

Pleura:  The serous membrane enveloping the lungs and lining the walls of
     the chest cavity.

Plume:  Emission from a flue or chimney, usually distributed stream-like
     downwind of the source, which can be distinguished from the surrounding
     air by appearance or chemical characteristics.

Pneumonia (interstitial):  A chronic inflammation of the interstitial tissue
     of the lung, resulting in compression of the air cells.  An acute, infec-
     tious disease.

Pneumonocytes:  A nonspecific term sometimes used in referring to types of
     cells characteristic of the respiratory part of the lung.

Podzol:  Any of a group of zonal soils that develop in a moist climate,
     especially under coniferous or mixed forest.

Point  source:  A single stationary location of pollutant discharge.

Polarography:  A method of quantitative or qualitative analysis based on
     current-voltage curves obtained by electrolysis of a solution with
     steadily  increasing voltage.

Pollution gradient:  A series of exposure situations in which pollutant con-
     centrations range from high to  low.

Polyacrylonitrile:  A polymer made by reacting ethylene oxide and  hydrocyanic
     acid.  Dyne! and Orion are examples.

Polyamides:  Polymerization products of chemical  compounds  which contain
     amino (-NH.) and carboxyl (-COOH)  groups.   Condensation  reactions
     between the groups.form amides  (-CONH-).  Nylon is an  example of
     a polyamide.

Polycarbonate:  Any of various tough transparent thermoplastics  characterized
     by high impact strength and high softening  temperature.

Polycythemia:  An increase above the normal  in the  number  of  red cells in the
     blood.

Polyester fiber:  A man-made or manufactured  fiber  in  which the  fiber-
     forming substance is any long-chain  synthetic  polymer composed  of
     at least 85 percent by weight  of an  ester of a dihydric  alcohol and
     terephthalic acid.  Dacron is  an example.
                                    G-38

-------
Polymer:   A large molecule produced by linking together many like molecules.

Polymerization: _  In fiber manufacture, converting a chemical monomer (simple
     molecule) into a fiber-forming material by joining many like molecules
     into a stable, long-chain structure.

Polymorphic monocyte:   Type of leukocyte with a multi-lobed nucleus.

Polymorphonuclear leukocytes:   Cells which represent a secondary non-
     specific cellular defense mechanism.  They are transported to the lungs
     from the bloodstream when the burden handled by the alveolar macrophages
     is too large.

Polysaccharides:   Polymers made up of sugars.  An example is glycogen which
     consists of repeating units of glucose.

Polystyrene:  A thermoplastic plastic which may be transparent, opaque,
     or translucent.  It is light in weight, tasteless and odorless, it
     also is resistant to ordinary chemicals.

Polyurethane:  Any of various polymers that contain NHCOO linkages and are
     used especially in flexible and rigid foams, elastomers and resins.

Pores of Kohn:  Also known as interalveolar pores; pores between air cells.
     Assumed to be pathways for collateral ventilation.

Precipitation:  Any of the various forms of water particles that fall from
     the atmosphere to the ground, rain, snow, etc.

Precursor:  A substance from which another substance is formed; specifically,
     one of the anthropogenic or natural emissions or atmospheric constituents
     which reacts under sunlight to form secondary pollutants comprising
     photochemical smog.

Probe:  In air pollution sampling, the tube or other conduit extending
     into the atmosphere to be sampled,  through which the sample passes
     to treatment, storage and/or analytical equipment.

Proline:  An amino acid, CgHgNO^, that can be synthesized from glutamate
     by animals.

Promonocyte:  An immature monocyte not normally seen in the circulating
     blood.

Proteinuria:  The presence of more than  0.3  gm of  urinary protein in a
     24-hour urine collection.

Pulmonary:  Relating to the lungs.

Pulmonary edema:  An accumulation of  excessive amounts  of fluid  in  the lungs.
                                    G-39

-------
Pulmonary lumen:   The spaces in the interior of the tubular elements of
     the lung (bronchioles and alveolar ducts).

Pulmonary resistance:  Sum of airway resistance and viscous tissue resistance.

Purine bases:  Organic bases which are constituents of DMA and RNA, Including
     adenine and guanine.

Purulent:  Containing or forming pus.

Pyrimidine bases:  Organic bases found in DNA and RNA.  Cytosine and
     thymine occur in DNA and cytosine and uracil are found in RNA.

QRS:  Graphical representation on the electrocardiogram of a complex of three
     distinct waves which represent the beginning of ventricular contraction.

Rainout:  Removal of particles and/or gases from the atmosphere by their
     involvement in cloud formation (particles act as condensation nuclei,
     gases are absorbed by cloud droplets), with subsequent precipitation.

Rayleigh scattering:   Coherent scattering in which the intensity of the
     light of wavelength g, scattered in any direction making an angle
     with the incident direction, is.directly proportional to 1 + cos r
     and inversely proportional to g .

Reactive dyes:  Dyes which react chemically with cellulose in fibers under
     alkaline conditions.   Also called fiber reactive or chemically
     reactive dyes.

Reduction:   Acceptance of electrons by an ion or molecule.

Reference method (RM):  For NO-, an EPA-approved gas-phase chemiluminescent
     analyzer and associated calibration techniques;  regulatory specifications
     are described in Title 40, Code of Federal Regulations, Part  50,
     Appendix F.  Formerly, Federal Reference Method.

Residual capacity:  The volume of air remaining in the lungs after  a maximum
     expiratory effort; same as residual volume.

Residual volume (RV):  The volume of air remaining in the  lungs after  a
     maximal expiration.  RV = TLC - VC

Resin:  Any  of various solid or semi-solid amorphous  natural organic sub-
     stances, usually derived from plant secretions,  which are  soluble  in
     organic solvents but not in water; also any of many  synthetic substances
     with similar properties used  in finishing  fabrics,  for  permanent  press
     shrinkage control or water repellency.

Ribosomal RNA:  The most abundant  RNA  in a cell  and  an  integral  constituent
     of  ribosomes.
                                    G-40

-------
Ribosomes:  Discrete units of RNA and protein which are instrumental  in the
     synthesis of proteins in a cell.  Aggregates are called polysomes.

Runoff:   Water from precipitation, irrigation or other sources that flows
     over the ground surface to streams.

Sclerosis:  Pathological hardening of tissue, especially from overgrowth
     of fibrous tissue or increase in interstitial tissue.

Selective leaching:  The removal of one element from a solid alloy by
     corrosion processes.

Septa:  A thin wall dividing two cavities or masses of softer tissue.

Seromucoid:  Pertaining to a mixture of watery and mucinous material  such
     as that of certain glands.

Serum antiprotease:  A substance, present in serum, that Inhibits the activity
     of proteinases (enzymes which destroy proteins).

Sigma (s) bonds:  Bonds in which electron density is symmetrical about a
     line joining the bonded atoms.

Silo-filler's disease:  Pulmonary lesion produced by oxides of nitrogen
     produced by fresh silage.

Single breath nitrogen elimination rate:  Percentage rise in nitrogen fraction
     per  unit of volume expired.

Single breath nitrogen technique:  A procedure in which a vital capacity
     inspiration of 100 percent oxygen is followed by examination of nitrogen
     in the vital capacity expirate.

Singlet state:  The highly-reactive  energy state of an atom in which certain
     electrons have unpaired spins.

Sink:  A  reactant with or absorber of a substance.

Sodium arsenite:  Na-AsO-, used with sodium  hydroxide  in the absorbing solu-
     tion of a 24-hour integrated manual method  for NO-.

Sodium dithionite:  A strong reducing agent  (a supplier of  electrons).

Sodium metabisulfite:  Na^Oj, used in absorbing  solutions of  N02 analysis
     methods.

Sorb:  To take up and hold by  absorption or  adsorption.
                                    G-41

-------
Sorbent:   A substance that takes up and holds another by absorption or
     adsorption.

Sorbitol  dehydrogenase:   An enzyme that interconverts the sugars, sorbitol
     and fructose.

Sorption:  The process of being sorbed.

Spandex:   A manufactured fiber in which the fiber forming substance is a
     long chain synthetic elastomer composed of at least 85 percent of a
     segmented polyurethane.

Spectrometer:  An instrument used to measure radiation spectra or to deter-
     mine wavelengths of the various radiations.

Spectrophotometry:   A technique in which visible, UV, or infrared radiation
     is passed through a substance or solution and the intensity of light
     transmitted at various wavelengths is measured to determine the spectrum
     of  light absorbed.

Spectroscopy:  Use of the spectrometer to determine concentrations of an
     air pollutant.

Spermatocytes:  A cell destined to give rise to spermatozoa (sperm).

Sphingomyelins:  A group of phospholipids found in brain, spinal cord, kidney
     and egg yolk.

Sphygomenometer:  An apparatus, consisting of a cuff and a pressure gauge,
     which is used to measure blood pressure.

Spirometry:  Also called pneometry.  Testing the air capacity of the lungs
     with a pneometer.

Spleen:  A large vascular organ located on the  upper left side of the abdominal
     cavity.  It is a blood-forming organ in early life.  It is a storage
     organ for red corpuscles and because of the large number of macrophages,
     acts as a blood filter.

Sputum:  Expectorated matter, especially mucus  or mucopurulent matter expec-
     torated in diseases of the air passages.

Squamous:  Scale-like, scaly.

Standard deviation:  Measure of the dispersion  of values about a mean
     value.  It is calculated as the positive square root of the average  of
     the squares of the  individual deviations from the mean.

Standard temperature and pressure:  0°C, 760 mm mercury.

Staphylococcus aureus:  A spherically-shaped, infectious species of bacteria
     found especially on nasal mucous  membrane  and skin.
                                    G-42

-------
Static lung compliance (c.stat):  Measure of lung's elastic recoil  (volume
     change resulting from cRange in pressure) with no or insignificant air-
     flow.

Steady state exposure:  Exposure to air pollutants whose concentration
     remains constant for a period of time.

Steroids:  A large family of chemical substances comprising many hormones and
     vitamins and having large ring structures.

Stilbene:  An aromatic hydrocarbon C...H.. used as a phosphor and in making
     dyes.                           ^ ^

Stoichiometric factor:  Used to express the conversion efficiency of a non-
     quantitative reaction, such as the reaction of NO- with azo dyes in air
     monitoring methods.

Stoma:  A minute opening or pore (plural is stomata).

Stratosphere:  That region of the atmosphere extending from 11 km above the
     surface of the earth to 50 km.  At 50 km above the earth temperature
     rises to a maximum of 0 C.

Streptococcus pyogenes:  A species of bacteria found in the human mouth,
     throat and respiratory tract and in inflammatory exudates, blood stream,
     and lesions in human diseases.  It causes formation of pus or even fatal
     septicemias.

Stress corrosion cracking:  Cracking caused by simultaneous presence of
     tensile stress and a specific corrosive medium.  The metal or alloy  is
     virtually unattached over most of its surface, while fine cracks progress
     through it.

Strong interactions:  Forces or bond energies  holding molecules together.
     Thermal energy will not disrupt the formed bonds.

Sublobular hepatic necrosis:  The pathologic death  of one or more cells,  or
     of  a portion of  the liver, beneath one or more lobes.

Succession:  The progressive natural development of vegetation towards
     a climax, during which one community is gradually  replaced by others.

Succinate:  A salt of succinic  acid  involved  in energy  production  in  the
     citric acid cycle.

Sulfadiazine:  One of a group  of sulfa drugs.  Highly effective against
     pneumococcal, staphlococcal,  and  streptococcal infections.

Sulfamethazine:  An antibacterial  agent of the sulfonamide  group,  active
     against homolytic  streptococci, staphytococci, pneumococci and  meningococci

Sulfam'limide:  A crystalline  sulfonamide  (CgHgN^S),  the  amide  of  sulfanilic
     acid and parent  compound  of most  sulfa arugs.
                                     G-43

-------
Sulfhydryl group:   A chemical radical consisting of sulfur and hydrogen
     which confers reducing potential to the chemical compound to which it is
     attached (-SH).

Sulfur dioxide (S0?):   Colorless gas with pungent odor released primarily from
     burning of fossil fuels, such as coal, containing sulfur.

Sulfur dyes:  Used only on vegetable fibers, such as cottons.  They are
     Insoluble in water and must be converted chemically in order to be
     soluble.  They are resistant (fast) to alkalies and washing and fairly
     fast to sunlight.

Supernatant:  The clear or partially clear liquid layer which separates
     from the homogenate upon centrifugation or standing.

Surfactant:  A substance capable of altering the physi ©chemical nature of
     surfaces, such as one used to reduce surface tension of a liquid.

Symbiotic:  A close association between two organisms of different species in
     which at least one of the two benefits.

Synergistic:  A relationship in which the combined action or effect of two
     or more components is greater than that of the components acting separately.

Systolic:  Relating to the rhythmical contraction of the heart.

Tachypnea:  Very rapid breathing.

Terragram  (Tg):  One million metric tons, 10   grams.

Teratogenesis:  The disturbed growth processes resulting in  a deformed
     fetus.

Teratogenic:  Causing or relating to abnormal development of the fetus.

Threshold:  The level at which a physiological or psychological effect begins
     to be produced.

Thylakoid:  A membranous lamella of protein and  lipid  in plant chloroplasts
     where the photochemical reactions of photosynthesis take place.
Thymidine:  A nucleoside  (<-in^l4N2^5^  t^iat  1S  comPose^  of  thymine  and
     deoxyribose; occurs  as a strQctural part  of  DMA.

Tidal volume (V,):  The volume of  air  that  is  inspired  or  expired  in a single
     breath during  regular breathing.

Titer:  The standard of strength of  a  volumetric  test solution.   For example,
     the  titration  of a volume of  antibody-containing serum with another
     volume containing virus.
                                    G-44

-------
Tocopherol:  a-d-tocopherol is one form of Vitamin E prepared synthetically.
     The a form exhibits the most biological activity.   It is an antioxidant
     and retards rancidity of fats.

Torr:  A unit of pressure sufficient to support a 1 mm column of mercury;
     760 torr = 1 atmosphere.

Total lung capacity (TLC):  The sum of all the compartments of the lung, or
     the volume of air in the lungs at maximum inspiration.

Total suspended particulates (TSP):  Solid and liquid particles present in
     the atmosphere.

Trachea:  Commonly known as the windpipe, a cartilaginous air tube extending
     from the larnyx (voice box) into the thorax (chest) where it divides,
     serving as the entrance to each of the lungs.

Transaminase:  Ami notransf erase; an enzyme transferring an ami no group from
     an a-amino acid to the carbonyl carbon atom of an a-keto acid.

Transmissivity (UV):  The percent of ultraviolet radiation passing through a
     a medium.

Transmittance:  The fraction of the radiant energy entering an absorbing
     layer which reaches the layer's further boundary.

Transpiration:  The process of the loss of water vapor from plants.
Triethanolamine:  An amine,  (HOChLCfrOgN, used  in the absorbing solution
     of one analytical method  for NO,.

Troposphere:  That portion of  the atmosphere  in which temperature decreases
     rapidly with altitude,  clouds  form, and  mixing of air masses by convection
     takes place.  Generally extends  to about 7 to 10 miles above the earth's
     surface.

Type 1 epithelial cells:  Squamous  cells which  provide a continuous lining
     to the alveolar surface.

Type I pneumonocytes:  Pulmonary surface epithelial cells.

Type II pneumonocytes:  Great  alveolar cells.

Ultraviolet:  Light invisible0to the  human  eye  of wavelengths  between 4x10
     and Sxio"9 m (4000 to BOA).

Urea- formaldehyde resin:  A  compound  composed of urea and  formaldehyde  in
     an arrangement that  conveys thermosetting  properties.
                                    G-45

-------
Urobilinogen:   One of the products of destruction of blood cells; found in
     the liver, intestines and urine.

Uterus:   The womb; the hollow muscular organ in which the impregnated ovum
     (egg) develops into the fetus.

Vacuole:  A minute space in any tissue.

Vagal:   Refers to the vagus nerve.  This mixed nerve arises near the medulla
     oblongata and passes down from the cranial cavity to supply the larynx,
     lungs, heart, esophagus, stomach, and most of the abdominal viscera.

Valence:  The number of electrons capable of being bonded or donated by
     an atom during bonding.

Van Slyke reactions:  Reaction of primary amines, including amino acids,
     with nitrous acid, yielding molecular nitrogen.

Variance:  A measure of dispersion or variation of a sample from its
     expected value; it is usually calculated as the square root a sum of
     squared deviations about a mean divided by the sample size.

Vat dyes:  Dyes which have a high degree of resistance to fading by light,
     NO  and washing.  Widely used on cotton and viscose rayon.  Colors are
     brilliant and of almost any shade.  The name was originally derived
     from their application in a vat.

Venezuelan equine encephalomyelitis:  A form of equine encephalomyelitis
     found in parts of South America, Panama, Trinidad, and the United States,
     and caused by a virus.  Fever, diarrhea, and depression are common.  In
     man, there is fever and severe headache after an incubation period of 2
     to 5 days.

Ventilatory volume (Vp):  The volume of gas exchanged between  the lungs and
     the atmosphere tnat occurs in breathing.

Villus:  A projection from the surface, especially of a mucous membrane.

Vinyl chloride:  A gaseous chemical suspected of causing at least one type
     of cancer.  It is used primarily  in the manufacture of polyvinyl
     chloride, a plastic.

Viscose rayon:  Filaments of regenerated cellulose coagulated  from  a solution
     of cellulose xanthate.  Raw materials can be cotton 1 inters or chips
     of spruce, pine, or hemlock.
                                                            o
Visible region:  Light between the wavelengths of 4000-8000 A.

Visual  range:  The distance at which an object can  be distinguished from
     background.

Vital capacity:  The greatest volume of air  that can be  exhaled from the
     lungs after a maximum  inspiration.
                                    G-46

-------
Vitamin E:  Any of several fat-soluble vitamins (tocopherols),  essential
     in nutrition of various vertibrates.

Washout:  The capture of gases and particles by falling raindrops.

Weak interactions:  Forces, electrostatic in nature, which bind atoms and/or
     molecules to each other.  Thermal energy will disrupt the Interaction.
     Also called van der Waal's forces.

Wet deposition:  The process by which  atmospheric substances are  returned
     to earth in the form of rain or other precipitation.

Wheat germ  lipase:  An enzyme, obtained  from wheat germ, which is capable
     of cleaving a fatty acid from a neutral fat; a lipolytic enzyme.

X-ray fluorescence spectrometry:  A nondestructive technique which utilizes
     the  principle that every element  emits characteristic x-ray  emissions
     when excited by high-energy radiation.

Zeolites:   Hydrous silicates analogous to feldspars, occurring in lavas
     and  various  soils.

Zooplankton:  Minute animal  life floating or swimming weakly in a body  of  water.
                                     G-47

-------