SEPA
             United States
             Environmental Protection
             Agency
            Office of Health and
            Environmental Assessment
            Washington DC 20460
EPA/600/8-86/O2OA
July 1986
Review Draft
             Research and Development
Second
Addendum to
Air Quality
Criteria for
Particulate
Matter and Sulfur
Oxides (1982):

Assessment of
Newly Available
Health  Effects
Information
Review
Draft
(Do Not
Cite or Quote)
                         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.

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(Do Not
Cite or Quote)
EPA/600/8-86/020A
        July 1986
      Review Draft
       Second Addendum to
      Air Quality Criteria for
      Participate Matter and
       Sulfur Oxides (1982):

 Assessment of Newly Available
    Health Effects Information
                    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 Developent
            U.S. Environmental Protection Agency
            Research Triangle Park, NC 27711

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                                 DISCLAIMER
    This document is an external draft for review purposes only and does not
constitute Agency  policy.   Mention of trade names  or commercial  products
does not constitute endorsement or recommendation for use.

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                                   CONTENTS
LIST OF FIGURES ....	       v
LIST OF TABLES	      vi
AUTHORS AND CONTRIBUTORS	     vii
REVIEWERS	    yiii
OBSERVER	    '  xi

1.  INTRODUCTION	     l-i
    1.1   PHYSICAL AND CHEMICAL PROPERTIES OF AIRBORNE PARTICULATE
          MATTER AND AMBIENT AIR MEASUREMENT METHODS 	     1-2
    1.2   PHYSICAL/CHEMICAL PROPERTIES OF SULFUR OXIDES AND THEIR
          TRANSFORMATION PRODUCTS AND AMBIENT MEASUREMENTS METHODS ...     1-9
    1.3   KEY AREAS ADDRESSED IN EMERGING NEW HEALTH EFFECTS DATA ....     1-14

2.  RESPIRATORY TRACT DEPOSITION AND FATE	!	     2-1
    2.1   RESPIRATORY TRACT DEPOSITION AND FATE OF INHALED AEROSOLS ..     2-1
    2.2   SULFUR OXIDES DEPOSITION AND CLEARANCE	     2-14
    2.3   POTENTIAL MECHANISMS OF TOXICITY ASSOCIATED WITH INHALED
          PARTICLES AND S02 	     2-15
    2.4   SUMMARY	     2-18

3.  EPIDEMIOLOGICAL STUDIES OF HEALTH EFFECTS ASSOCIATED WITH
    EXPOSURE TO AIRBORNE PARTICLES AND SULFUR OXIDES	    ,3-1
    3.1   HUMAN HEALTH EFFECTS DUE TO SHORT-TERM EXPOSURES TO
          PARTICLES AND SULFUR OXIDES 	     3-1
          3.1.1   Mortality Effects of Short-Term Exposures 	     3-2
          3.1.2   Morbidity Effects of Short-Term Exposures 	 	     3-12
    3.2   EFFECTS OF ASSOCIATED WITH LONG-TERM EXPOSURES TO AIRBORNE
          PARTICLES AND SULFUR OXIDES 	     3-18
          3.2.1   Mortality Effects of Chronic Exposures 	     3-18
          3.2.2   Morbidity Effects of Long-Term Exposures 	     3-26

4.  CONTROLLED HUMAN EXPOSURE STUDIES OF SULFUR DIOXIDE HEALTH
    EFFECTS	     4-1
    4.1   NORMAL SUBJECTS EXPOSED TO SULFUR DIOXIDE	     4-2
    4.2   CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS EXPOSED
          TO S02 	     4-9
    4.3   FACTORS AFFECTING THE PULMONARY RESPONSE TO S02 EXPOSURE
          IN ASTHMATICS	     4-9
          4.3.1   Dose-Response Relationship 	:	     4-9
          4.3.2   S02-Induced Versus Nonspecific Airway Reactivity ..       4-21
          4.3.3   Oral, Nasal, and Oronasal  Ventilation	     4-23
          4.3i4   Time Course of Response to S02 in Asthmatics 	     4-26
          4.3.5   Exacerbation of the Responses of Asthmatics to
                  S02 by Cold/Dry Air	     4-29

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r
                                            CONTENTS (continued)
                   4.4   MECHANISM(S) 	
                         4.4.1   Mode of Action	•	
                         4.4.2   Breathing Mode and Interaction with Dry Air 	
                         4.4.3   Tolerance (Attenuation of Response) to S02  with
                                 Repeated Exposure 	
                   4.5   CONCLUSIONS	•	
               5.  EXECUTIVE SUMMARY
                   5.1   RESPIRATORY TRACT DEPOSITION AND FATE SUMMARY 	
                   5.2   SUMMARY OF HEALTH EFFECTS ASSOCIATED WITH EXPOSURE TO
                         AIRBORNE PARTICLES 	
                   5.3   SUMMARY OF CONTROLLED HUMAN EXPOSURE STUDIES OF SULFUR
                         DIOXIDE HEALTH EFFECTS 	
               6.  REFERENCES
4-34
4-34
4-36

4-37
4-39

5-1
5-1

5-2

5-7

6-1
                                                      iv

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                              LIST OF FIGURES
2


3



4


5
Idealized representation of typical fine and coarse
particle mass and chemical composition distribution in an
urban aerosol	

Regional deposition of monodisperse aerosols by indicated
particle diameter for mouth breathing (alveolar) ...-..:..,
Estimates of thoracic deposition of particles between 1
and 15 urn by Miller et al. (1986) for normal augmenters
(solid lines) and mouth breathers ,	
Predicted initial dose to the TB region as a function of
body mass by Phalen et al.  (1985)		
Adjusted frequency of cough for the 27 region-cohorts
from the Six-Cities Study at the second examination
plotted against mean TSP concentration during the
previous year	
       Adjusted mean percent of predicted FEVi at the first
       examination for the 27 region-cohorts from the'Six Cities
       Study plotted against mean TSP concentration during the
       previous year	
Page



1-3


2-3



2-9


2-11




3-34




3-35

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                                LIST OF TABLES
Table


 1
 3B
Summary of quantitative conclusions from epidemiological
studies relating health effects to acute exposure to
ambient air levels of S02 and PM 	
         Summary of quantitative conclusions from epidemiological
         studies relating health effects to chronic exposure to
         ambient air levels of S02 and PM	
         Summary of asthmatic subject characteristics from newly
         available controlled human exposure studies of effects of
         sulfur dioxide on pulmonary function	
Summary of normal subject characteristics from newly
available controlled human exposure studies of effects of
sulfur dioxide on pulmonary function 	
         Summary of results from controlled human exposure studies
         of pulmonary function effects associated with exposure of
         asthmatics to S02 	
                                                                 Page
                                                                          3-4
                                                                 3-28
                                                                  4-3
                                                                           4-6
                                                                  4-11
                                      vi

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AUTHORS AND CONTRIBUTORS


         The following people served as authors or otherwise contributed to pre-
paration of the present addendum.  Names are listed in alphabetical order.


Dr. Lawrence J. Folinsbee
Environmental Monitoring and Services, Inc.
Chapel Hill, NC  27514

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

Dr. Timothy R. Gerrity
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Chapel Hill, NC  27514

Dr. Donald H. Horstman
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Chapel Hill, NC  27514

Dr. Howard Kehrl
Health Effects Research Lab
U.S. Environmental Protection Agency
Chapel Hill, NC  27514

Dr. Dennis Kotchmar
Environmental  Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

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

Dr. L. Jack  Roger
Environmental  Monitoring  and Services,  Inc. -
Chapel Hill,  NC   27514                             ;^
                                       vii

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 REVIEWERS
 review.
         A preliminary draft version of the present addendum was circulated for
         Written or oral review comments were received from the following
individuals, most of whom participated (along with the above authors  and  con-
tributors) in a peer-review workshop held at EPA's Environmental Research
Center in Research Triangle Park, NC on May 22-23, 1986.
Dr. Karim Ahmed
Natural Resources Defense Council
122 E. 42nd Street
New York,.NY  10168

Mr. John Bachmann
Ambient Standards Branch (MD-12)
Office of Air Quality Planning and Standards
Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. David Bates
Department of Medicine
St. Paul's Hospital
University of British Columbia
Vancouver, British Columbia
Canada  V6Z 1Y6

*Dr. Robert Bechtel
National Jewish Center for Immunology
  & Respiratory Disease
1400 Jackson Street
Denver, CO  80206

Dr. Per Camner
The Karolinska Institute
P.O. Box 60400
S-104 01 Stockholm
Sweden

Mr. Jeff Cohen
Ambient Standards Branch (MD-12)
Office of Air Quality Planning and Standards
Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Jack Hackney  213/922-7561
•Room 51
Environmental Health Service
Rancho Los Amigos Hospital
7601 Imperial Highway
Downey, CA  90242
                                     vm

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 REVIEWERS (continued)
 Dr. Carl Hayes
 HERL (MD-55)
 Environmental Protection Agency
 Research Triangle Park, NC  27711

 Dr. Ian Higgins
 American Health Foundation
 320 E.  43rd Street
 New York, New York  10017

 Dr. Steve Horvath
 Prof.  Inst.  of Eny.  Stress
 University of California
 Santa Barbara, CA  93106

 *Dr.  Jane Koenig
 Dept.  of Environmental Health, SC-34
 University of Washington
 Seattle, WA  98195

 Dr. Emmanuel Landau
 American Public Health Assoc.
 1015  15th Street,  N.W.
 Washington,  DC  20005

 Dr. Alan Marcus
 Department of Mathematics
 Washington State University
 Pullman, WA  99164-2930

 Dr. Bart Ostro
 California Air Resources Board (IPA)
 Research Division
 1800  15th Street
 Sacramento,  CA  95812

 Dr. Haluk Ozkaynak
 KSG-EEPC
 Harvard  University
 79 JFK Street
 Cambridge, MA  02138

 *Dr. William Pierson
 Northwest Asthma & Allergy Center
•4540 Sand Point Way, N.E.
 Seattle,  WA   98105
                                       IX

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REVIEWERS (continued)
Mr. Larry J. Purdue
EMSL (MD-77)
Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Neil Roth
6115 Executive Blvd.
Rockville, MD  20852

Dr. Neil Schacter
Mt. Sinai Medical Center
24-30 Annenberg
1 Gustave L. Levy Place
New York, NY  10029

*Dr. Dean Sheppard
Cardiovascular Research Institute
University of California
San Francisco, CA  94143

Dr. Frank Speizer
Channing Laboratory
180 Longwood Avenue
Boston, MA  02115

Dr. John Spengler
Harvard School of Public Health
Department of Environmental Science
665 Huntington Avenue
Boston, MA  02115

Dr. David L. Swift
Johns Hopkin University
   School of Hygiene
615 N. Wolfe Street
Baltimore,  MD  21205
                                      Physiology
 ^Written reviews only.

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OBSERVER
         The following member of the Clean Air Scientific Advisory Committee
(CASAC) of EPA's Science Advisory Board attended the May 22-23, 1986 work-
shop as an observer on behalf of CASAC.

Dr. Timothy Larson
Environmental Engineering and Science Program
Dept. of Civil Engineering EX-100
University of Washington
Seattle, WA  98195
                                      XI
                                                                .s

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                           CHAPTER 1.   INTRODUCTION
     The United States  Clean  Air Act and its 1977 Amendments mandate that the
U.S.  Environmental Protection Agency  (U.S.  EPA) periodically review  criteria
for National Ambient Air Quality Standards (NAAQS) and revise such standards  as
appropriate.  The most  recent periodic review of the  scientific  bases under-
lying the NAAQS for  particulate  matter (PM)  and sulfur oxides (SOX)  culminated
in the 1982 publication of the EPA document Air Quality Criteria for Particulate
Matter and  Sulfur Oxides  (U.S.  EPA, 1982a),  an  associated  PM staff paper  (U.S.
EPA,  1982b) which examined  the  implications of  the  revised  criteria for the
review of the PM NAAQS, an addendum to the criteria document addressing further
information on health  effects (U.S.  EPA, 1982c), and  another staff  paper re-
lating the revised scientific criteria to the review of the SOV  NAAQS (U.S. EPA
                                                              /\
1982d).   Based on the  criteria  document, addendum and staff papers, revised
24-hr and annual-average standards for PM have been proposed (Federal Register,
1984a) and public comments on the proposed revisions have been received both in
written form and  orally at  public hearings  (Federal  Register, 1984b).  Consid-
eration of possible revision of  the sulfur oxides NAAQS is still under way.
     Since  preparation  of the  above  criteria document,  addendum, and staff
papers (U.S. EPA, 1982a,  b,  c,  d),  numerous  new scientific studies  or analyses
have become available  that  may  have bearing  on  the  development  of criteria for
PM or SO  and thus may notably impact proposed revisions of those standards now
        /\
under consideration by EPA.   In  December 1985 the Clean Air Scientific Advisory
Committee (CASAC) of EPA's Science Advisory Board met to discuss the PM proposals
and  possible  implications of the newly  available information.   CASAC recom-
mended that a  second addendum to the 1982 Criteria Document (U.S. EPA, 1982a)
be prepared to  evaluate new studies and  their  implications  for derivation of
health-related criteria for the  PM NAAQS.   In  the process  of  responding to
CASAC's recommendations,  the  Agency also determined that it would be useful  to
examine studies that have emerged since  1982 on the health effects of sulfur
oxides.
                                      1-1

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     Accordingly, the present  addendum  (1)  summarizes key findings from the
1982 EPA  criteria document and  first  addendum (U.S.  EPA, 1982a,c) as they
pertain to derivation of  health-related criteria,  and (2) provides an  updated
assessment of newly  available  information of potential  importance for  deriva-
tion of health  criteria for both the PM and  SOX  standards, with major emphasis
on evaluation of human-health studies published since 1981.  Certain background
information of crucial importance for understanding the assessed health effects
findings  is  also summarized.   This  includes  information on physical  and  chemi-
cal  properties  of PM, sulfur oxides, and associated  aerosols (including acid
aerosols)  and  ambient monitoring techniques.  However,  new studies on  associa-
tions between acid aerosols and  health  effects are being  evaluated in a separate
issue paper.


1 1  PHYSICAL  AND  CHEMICAL PROPERTIES  OF  AIRBORNE  PARTICIPATE  MATTER  AND
  '    AMBIENT AIR MEASUREMENT  METHODS
      As noted in the 1982 EPA criteria  document (U.S.  EPA,  1982a), airborne
 particles exist in  many  sizes and  compositions  that vary widely  with  changing
 source contributions and meteorological conditions.   However, airborne particle
 mass tends to cluster in two principal size groups:   coarse  particles, general-
 ly  larger than  2 to 3  micrometers  (um) in diameter;  and fine particles,  gener-
 ally smaller than  2 to 3 um  in diameter. The dividing line between the  coarse
 and the fine sizes  is frequently given as 2.5 um, but the distinction according
 to  chemical composition  is neither sharp nor fixed; it  can depend on the con-
 tributing sources,  on meteorology, and on the age of the aerosol.
      Fine  particle volume (or mass)   distributions  often exhibit two modes.
  Particles in the nuclei  mode  (which includes  particles  from 0.005 to 0.05 um  in
  diameter) form  near sources  by condensation of  vapors  produced by high tempera-
  ture  processes  such  as  fossil-fuel  combustion.  Accumulation-mode particles
  (i e   those  0.05-2.0  um in  diameter)  form  principally by coagulation or growth
  through  vapor condensation of  short-lived  particles in  the  nuclei mode.  Typi-
  cally  80 percent  or  more of the  atmospheric sulfate mass  occurs in  the accu-
' mulation-mode'.   Particles in  the  accumulation  mode normally do  not grow into
  the coarse mode.   Coarse  particles  include  re-entrained surface dust,  salt
  spray,  and  particles  formed  by mechanical  processes  such  as  crushing  and
  grinding.
                                        1-2

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      Primary particles are  directly discharged  from manmade or natural  sources.
Secondary particles  form by  atmospheric chemical  and physical  reactions, and
most  of the  reactants involved are emitted as  gaseous pollutants.  In the air,
particle growth  and  chemical  transformation occur through gas-particle and
particle-particle interactions.  Gas-particle interactions include  condensation
of  low-vapor-pressure molecules,  such  as  sulfuric  acid (H2$04)  and organic
compounds,  principally  on fine particles.   The only particle-particle interac-
tion  important in atmospheric processes is coagulation among fine particles.
      As  shown in  Figure 1,  fine atmospheric particles mainly  include sulfates,
carbonaceous material,  ammonium, lead,  and nitrate.   Coarse particles  consist
mainly  of oxides  of  silicon,  aluminum, calcium,  and  iron,  as well  as calcium
carbonate,  sea salt,  and material  such as tire particles and vegetation-related
particles  (e.g.,  pollen,  spores).  The  distributions of fine and  coarse parti-
cles  overlap; some chemical species found  mainly in one mode may  also be found
in the other.
                                             CRUSTAL MATERIAL
                                             (SILICON COMPOUNDS
                                             IRON. ALUMINUM). SEA
                                             SALT, PLANT PARTICLES
SULFATES. ORGANICS.
AMMONIUM. NITRATES.
CARBON. LEAD. AND
SOME TRACE CONSTITUENTS
  1       3
Particle Diameter -
                                                              100
                                                300
    Figure 1. Representative example of typical bimodal mass distribution (measured
    by impactors) and chemical composition in an urban aerosol.  Although some
    overlap exists, note substantial differences in chemical composition of fine versus
    coarse modes. Chemical species of each mode are listed in approximate order of
    relative mass contribution. Note that the ordinate is linear and not logarithmic.
    Source: Modified from Whitby (1975) and NAS (1977).
                                       1-3

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     The carbonaceous  component of  fine  particles contains  both  elemental
carbon  (graphite  and soot)  and nonvolatile  organic carbon (hydrocarbons in
combustion exhaust and  secondary organics formed by photochemistry).   In many
urban and nonurban areas,  these species are  the most abundant fine particles,
after sulfates.   Secondary organic  particles  form by oxidation of primary
organics by  a cycle that  involves ozone and  nitrogen oxides.   Atmospheric
reactions of nitrogen oxides yield nitric acid vapor (HMO,) that may accumulate
as nitrate particles in the fine or coarse  modes.  Most atmospheric sulfates
and nitrates are water-soluble and tend to absorb moisture.  Hygroscopic growth
of sulfate-containing particles  markedly  affects their size, reactivity, and
other physical  properties  which influence  their biological and  physical
effects.
     The relative proportions  of particles  of different chemical  composition
and size  ranges can vary  greatly in  ambient air, depending upon  emission
sources from which they originate and interactions with  meteorological condi-
tions, e.g., relative humidity (RH) and temperature.  Particles  from combustion
of fossil fuels  or  high-temperature  processes, e.g., metal  smelting,  tend to
fall in the  fine (<2.5  urn) or small  coarse mode  (<10  um'MMD)  range;  those from
crushing or  grinding processes,  e.g.,  mining operations,  tend to be mainly  in
the coarse mode (>2.5 urn),  with a substantial fraction in excess of 10 urn.
     Another important  distinction concerning airborne particles is the broad
characterization that can  result from  different  methods commonly used  for rou-
tine monitoring  purposes.   The most  commonly  used  methods  for  collection and
measurement of airborne particles were described in U.S.  EPA (1982a).  As noted
there,  differences  in  measurements  obtained  from  various instruments  and
methods used to measure PM levels have important implications for derivation of
quantitative dose-response relationships from epidemiologic  studies and for
establishing air  quality criteria and  standards.   It is generally  not  practic-
able to discriminate on the basis of either  particle size  or chemical  composi-
tion when assessing  particulate matter data from routine monitoring networks.
Characteristics  of the  collected samples  are dependent on  the types of sources
in the vicinity, weather conditions and sampling procedures.  Difficulties that
result  and  limitations  of  measurements were  also  discussed in  detail  in the
1982 EPA criteria document (U.S. EPA, 1982a).
     When considering  measurements of airborne  particles  it is essential to
specify the  method  used and to recognize that results obtained  with one method
                                      1-4

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 and under a given  set  of conditions are not  necessarily  applicable  to  other
 situations.   For example, attempts  have  been  made  to  relate  findings based  on
 smoke measurements  (that relate mainly  to  dark-colored  characteristics  of
 particles from incomplete combustion of  coal  or other hydrocarbon fuels) to
 situations  involving total suspended particulate matter (TSP) or size-specific
 fractions thereof (measured directly in  terms of weight).  Because the  former
 (smoke)  methods were used in many early epidemiological studies and the Tatter
 are now more often  used  for monitoring purposes in many countries, conversion
 from one type of measurement to the other would be desirable, but for reasons
 noted below,  there can be no generally applicable conversion factor.   Compara-
 tive evaluation of the two methods has been undertaken at numerous sites (Ball
 and Hume, 1977; Commins  and Waller, 1967:  Lee et al., 1972), but the results
 emphasize that they measure different qualities of the particulate matter and
 cannot be directly  compared with one another (U.S.  EPA, 1982a).
      Sampling  airborne  particles is  a complex  task  because of the wide spectrum
 of  particle  sizes and  shapes.    Separating particles by aerodynamic  size pro-
 vides a  simplification  by disregarding variations in particle shape and  relying
 on  particle settling velocity.    The  aerodynamic diameter of a particle is not a
 direct measurement  of  its size  but  is the  equivalent  diameter of a  spherical
 particle  of  specific gravity which would settle at the same  rate as  the mea-
 sured particles.   Samplers  can  be  designed  to  collect  particles  within sharply
 defined  ranges  of aerodynamic  diameters  or to simulate the deposition pattern
 of  particles  in the human respiratory system,  which exhibits a more gradual
 transition from acceptance to exclusion  of  particles.   High-volume   (hi-vol)
 samplers, dichotomous samplers,   cascade impactors,  and cyclone samplers are the
 most  common  devices with specifically  designed collection characteristics.
 These samplers  rely on  inertia!  impaction techniques for separating particles
 by  aerodynamic size, filtration techniques  for collecting the  particles and
 gravimetric measurements  for determining mass concentrations.   Mass  concen-
 trations  can also  be estimated  using methods that measure  an  integral property
 of  particles such  as optical  reflectance, and empirical relationships between
mass concentrations  and the  integral measurement can be used to predict mass
concentration, if a  valid physical  model  relating  to  the  measurements exists
and empirical  data verify the model  predictions.
     The  hi-vol sampler collects particles  on a glass-fiber  filter by drawing
air through the  filter  at a flow rate of -1.5 m3/min,  and is used to measure
                                      1-5

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total  suspended  participate  matter (TSP).   The hi-vol  sampler has  outpoints  of
«25 urn at a wind speed of 24 kph and 45 |jm at 2 kph.   Although sampling  effec-
tiveness  is wind-speed sensitive, no more than a 10 percent day-to-day variabi-
lity occurs  for  the same ambient concentration  for  typical  conditions.   The
hi-vol is one of the most reproducible particle samplers in use, with a typical
coefficient  of  variation of 3 to  5.   One  major problem associated with  the
glass-fiber  filter  used  on the hi-vol is formation of artifact mass caused by
the presence  of  acid gases in the air (e.g.,  artifactual  formation of sulfates
                                      o
from SOg), which can add 6 to 7  ug/m  to  a 24-h sample.   The hi-vol  has  been
the sampler most widely used in the U.S. for routine monitoring and has yielded
TSP mass estimates used in many American epidemiological studies.
     Hi-vol samplers with size-selective inlets (SSI) Jiave recently been devel-
oped which collect  and measure particles <10  urn or  <15 urn.   Except  for  the
inlet, these  samplers  are identical  in design and operation  to the TSP hi-vol.
Versions  are now being  used in  epidemiologic health effects  studies,  and
several models are being evaluated for possible routine monitoring use.
     The  dichotomous  sampler is a low-volume  gravimetric  measurement device
which  collects fine  (<2.5 urn) and coarse  (>2.5  urn to <10 or  15 urn)  ambient
particle  fractions.  The  sampler uses Teflon® filters which minimize artifact
mass formation.   The earlier inlets used with this sampler were very wind-speed
dependent, but newer  versions are much improved.   Because  of low sampling flow
rate,  the  sampler  collects submilligram quantities of particles and  requires
microbalance  analyses,  but is capable of  reproducibility of +10  percent or
better.   The  method,  however,  has only begun  to be employed  on any major scale
to  generate  size-selective data  on  PM mass assessed  in  relation  to  health
effects evaluated in epidemiological  studies.
     Cyclone  inlets with  cutpoints around  2 urn have  long  been used to separate
the fine particle fraction, can be used with samplers designed to cover a range
of  sampling  flow rates  and  are  available  in a variety of  physical  sizes.
Applications  of  cyclone  inlets  are found in 10- and 15-um cutpoint inlets for
both dichotomous and  hi-vol  samplers.   Samplers with  cyclone  inlets  could be
expected to have coefficients of variations similar to those of the dichotomous
or SSI hi-vol samplers,  and  until  recently have also found only limited  use  in
epidemiological  studies of PM health effects.
     Cascade  impactors have  been used to obtain mass distribution by particle
size.   Because care  must be exercised to prevent  errors  (e.g., those due to
                                      1-6

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particle bounce  between stages),  these  samplers are  normally not used as
routine monitors.   A study by Miller  and DeKoning (1974) comparing cascade
impactors with hi-vol  samplers  showed  inconsistencies in mass collections by
the impactors.
     Samplers that  derive  mass  concentrations by analytical techniques other
than direct weight  have been  used extensively.  One  of  the earliest was  the
British smokeshade  (BS)  sampler,  which measures the  reflectance  of particles
collected on a filter and uses empirical  relationships to estimate mass concen-
trations.   These relationships are more sensitive to carbon concentrations than
mass (Bailey  and  Clayton,  1980)  and hence are  very difficult  to  interpret as
either  total  or size-selective  PM mass  present in the  atmosphere.   The  BS
method  and  its  standard variations typically collect  PM with  an  =4.5 urn DJ-Q
cutpoint under field conditions,  with  some particles  ranging from 7 to 9  urn  at
times being collected (McFarland et al.,  1982).  Thus, even if larger particles
are present in the  atmosphere, the  BS method collects mainly fine-mode  and
small coarse-mode particles.  The BS method  neither directly measures  mass nor
determines  chemical  composition  of collected PM.   Rather,  it  measures light
absorption  of particles  indicated by reflectance from a  stain  formed  by parti-
cles collected on  filter paper.   Reflectance of  light from the stain  depends
both on density of the stain,  or amount of PM collected,  and optical  properties
of collected  PM.   Smoke particles composed of  elemental  carbon in incomplete
fossil-fuel combustion  products typically make  the greatest contribution to
darkness of the  stain,  especially in urban areas.   Thus, the amount of elemen-
tal carbon,  but not organic  carbon,  in  the  stain tends to be most  highly
correlated  with  BS  reflectance  readings.   Other nonblack, noncarbon particles
also have  optical  properties  which can affect  the  reflectance readings,  but
usually with negligible contribution to optical absorption.
     Because  the  relative  proportions  of atmospheric  carbon and  noncarbon PM
can vary greatly from site to site  or from  one time  to  another  at  the same
site,  the  same absolute BS reflectance  reading can be  associated with very
different  amounts  (or mass) of  collected particles or even with very  different
amounts of carbon.   Site-specific calibrations of reflectance  readings against
actual  mass measurements  from collocated gravimetric monitoring  devices are
therefore  mandatory in  order  to obtain  credible estimates of atmospheric
concentrations of particulate matter based on the BS method,  A single  calibra-
tion curve  relating  mass or atmospheric concentration  (in pg/m )  of particulate
                                      1-7

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matter to BS reflectance readings obtained at a given site may serve as a basis
for crude  estimates  of the levels  of PM  (mainly  particles  <10 urn) at that site
over  time,  so long as  the chemical  composition  and relative proportions of
elemental carbon  and  noncarbon PM do not change.  However, the  actual  mass or
smoke concentration at a given site  may  differ markedly  from  values calculated
from a given reflectance reading on either of the two most widely used  standard
curves (the  British  and OECD standard smoke curves).  Thus,  much care  must  be
taken in  interpreting the meaning of any BS value reported in terms of ug/m ,
and such  "nominal" expressions  of airborne particle concentrations are  not
meaningful  unless related to  direct determinations of  mass  by gravimetric
measurements carried out at the same geographical location and close in time to
the BS readings.
     The  AISI  light  transmittance  method is similar in approach to the BS
technique, collects particles with a D5Q cutpoint =5.0 urn aerodynamic diameter,
uses  an air intake similar to that  of  the  BS method, and has  been used for
routine monitoring in  some  American cities.  Particles are  collected on a
filter-paper tape periodically advanced to allow accumulation of another stain,
opacity of the stain is  determined  by  transmittance of light  through  the
deposited  material  and tape,  and  results  are expressed in terms of optical
density or  coefficient of haze (CoH) units  per 1000 linear feet of  air sampled
(rather than  mass units).   Readings of  COH  units  are more responsive  to non-
carbon particles  than are BS measurements,  but again,  the AISI  method  does  not
directly measure  mass  or determine chemical composition of collected particles.
                               o
Attempts  to  relate COH to ug/m  also require site-specific calibration of COH
readings  against  mass  measurements  determined  by  a collocated gravimetric
device, but the accuracy of such mass estimates  are  subject to question.
      Since  the  hi-vol method collects particles  much larger  than those collec-
ted by  BS or AISI methods,  intercomparisons  of  PM measurements by the BS or
AISI  methods  to equivalent TSP units, or  vice versa, are very  limited.  For
example,  as shown by  several studies, no consistent  relationship exists between
BS  and TSP measurements  taken at various sites or  at  the same site  during
various seasons.   One exception is the relationship  observed between BS and TSP
'during  severe London  air pollution episodes when  low  wind-speed conditions
caused settling out of larger  coarse-mode particles.  Because fine-mode particles
predominated, TSP and BS  levels  (in  excess of ~500  ug/m3) tended to converge,
as expected  if mainly fine-mode particles were present.
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      Many  analytical  techniques are available to determine chemical properties
 of  particles collected on a  suitable substrate.  Most of the techniques, such
 as  those for elemental sulfur,  have been  shown to be more precise than the
 analyses  for  gravimetric mass  concentration.   Methods  are available  that
 provide  reliable  analyses  for  sulfates,  nitrates,  organic fractions,  and
 elemental  composition (e.g.,  sulfur,  lead, silicon), but not all analyses can
 be  used for  all  particle samples  because of  factors such as  incompatible
 substrates  or inadequate sample size.   Results  can be  misinterpreted when
 samples  have not  been appropriately segregated  by  particle size  and  when
 artifact mass is formed on the  substrate  rather than collected in  particulate
 form, e.g., positive  artifacts likely in nitrate and sulfate determinations (as
 noted below).
1.2  PHYSICAL/CHEMICAL  PROPERTIES OF SULFUR  OXIDES  AND THEIR TRANSFORMATION
     PRODUCTS AND AMBIENT MEASUREMENT METHODS
     The only  sulfur oxide that occurs at  significant  concentrations in the
atmosphere  is  sulfur dioxide,  one of the four  known gasrphase sulfur oxides
(sulfur monoxide,  sulfur dioxide, sulfur  tn'oxide,  and  disulfur  monoxide).   As
discussed in U.S.  EPA (1982a),  sulfur dioxide is a  colorless  gas detectable  by
taste at levels of 1000 to 3000 yg/m3 (0.35-1.05 ppm).  Above 10,000 ug/m3 (3.5
ppm), it has a pungent irritating odor.
     As also discussed in U.S.  EPA  (1982a),  S02 is mainly removed  from  the
atmosphere  by  gaseous,  aqueous,  and surface oxidation to  form acidic sulfates.
Gas-phase oxidation of S02 by the hydroxyl (OH) radical  is well understood; not
so well  understood,  however, is  oxidation  of S02 by hydroperoxyl (H02)  and
methyl peroxyl  (CH302)  radicals.   The ready solubility of S02 in water is due
mainly to formation  of bisulfite (HS03~)  and sulfite (SOj2-) ions,  which are
easily oxidized to form acidic  sulfates by reacting with catalytic metal ions
and dissolved  oxidants.   Sulfur  dioxide reacts on the surface of a variety of
airborne solid  particles,  such  as ferric  oxide, lead dioxide, aluminum oxide,
salt, and charcoal.          '
     Sulfur trioxide  (S03),  which  can  be emitted into the air  directly or
result from reactions mentioned earlier,  is  a  highly reactive gas.   In  the
presence of moisture  in the  air,  it is  rapidly  hydrated to form  sulfuric  acid.
In the air, then,  it is sulfuric acid in  the form of an aerosol  that is found
                                      1-9

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rather  than  S03, and  it is generally  associated with other pollutants in
droplets  or  solid particles of widely  varying  sizes.   The acid is strongly
hygroscopic, and  droplets  containing it readily take up further moisture from
the air until  they are in  equilibrium with  their  surroundings.   If any ammonia
is present,  it reacts  with sulfuric acid to  form various ammonium sulfates,
which continue to exist as an  aerosol  (in droplet or crystalline form, depend-
ing on the relative humidity).
     The  sulfuric acid may also react further with other compounds in the air
to produce other sulfates.   Some sulfates reach the air directly from combus-
tion or industrial  sources, and near oceans, sulfates exist in aerosols gene-
rated from ocean spray.   As discussed in U.S.  EPA (1982a),  sulfate particles
fall mainly  in the fine-mode (<2.5  urn)  size  range.   These particles, in the
presence  of  moisture  in air, combine with  water  to form coarse-mode  aerosols
(i.e., >2.5 urn).
     Many sulfur compounds are present  in  the  complex mixture  of urban air
pollutants.   Some are  naturally occurring and some are manmade.  Total biogenic
sulfur emissions  in the United States have been estimated to be  in the range of
5 to 6 million metric  tons  annually.  Additional contributions from coastal and
oceanic  sources  may also be significant.  Anthropogenic (manmade) sources are
estimated to  emit  about  26 to 27  million  metric tons of SOX  (mostly  S02)
annually  in  the United States.  Most manmade sulfur oxide emissions  are from
stationary point sources;  over 90 percent  of these are S02 and the rest are
sulfates.
     Once S02  is emitted into  the lower atmosphere, maintenance of a  tolerable
environment  depends on the ability of wind  and  turbulence  to disperse the
pollutants.  Factors  affecting the  dispersion of  S02  from combustion sources
include  (1)  temperature and efflux velocity of the gases,  (2) stack height, (3)
topography and the proximity of other buildings,  and (4) meteorology.   Some of
the  S02 emitted  into  the  air  is removed  unchanged onto  various  surfaces,
including soil,  water, grass and vegetation.   The remaining S02 is transformed
into  sulfuric  acid or other sulfates by various  processes in the presence of
moisture, and.these transformation products are then removed by dry deposition
'processes or by precipitation.  The relative proportion of  S02  and its  trans-
formation products resulting from atmospheric processes varies with increasing
distance from emission  sources and residence time  (age)  in the atmosphere.
With  long-range  transport  (over hundreds or thousands  of  kilometers), extensive
                                      1-10

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 transformation of S02 to sulfates  occurs, with  dry  deposition of acidic sulfates
 or their wet  depositon  in  rain  or snow contributing to  acidic precipitation
 processes.
      The most  commonly  used collection and  measurement methods for  sulfur
 oxides were described in the  1982 EPA criteria document  (U.S. EPA,.  1982a).  A
 clear understanding  of  the underlying  bases  and limitations of particular
 methods is  essential  for adequate interpretation of epidemiological  studies
 discussed later.  If  S02 were the only contaminant in air, all measurement
 methods for that gas  would  give  comparable  results,  indicating the true concen-
 tration of S02.   In  typical  urban environments,  however,  other pollutants are
 always present and although sampling  procedures  can be arranged to minimize
 interference from particulate matter  by first  filtering  the air, errors  still
 arise due  to  other gases  and vapors.   Thus,  variations in specificity  and
 accuracy of methods  must be  taken into account in comparing  results from
 various studies.
      Methods for measurement of SOp  include  (1)  manual methods, which involve
 collection of the sample over a specified  time period  and  subsequent  analysis
 by a  variety  of analytical techniques, and (2)  automated  methods,  in which
 sample collection and analysis  are performed  continuously and  automatically.
 In the most commonly  used manual methods, the analyses  of the collected samples
 are based on colorimetric,  titrimetric,  turbidimetric,  gravimetric,  x-ray fluo-
 rescent, chemiluminescent,  and ion exchange chromatographic measurement  prin-
 ciples.      :              "/
      The most  widely  used manual method for determination of atmospheric  SO,, is
 the West-Gaeke pararosaniline  method.   An improved  version  of this colorimetric
 method,  adopted in 1971  as  the  U.S.  EPA reference  method,  can measure ambient
                               o
 S02 at levels  as low  as  25  ug/m  (0.01 ppm) with  30 min to  24 hr sampling time.
 The method has acceptable  specificity  for  S02, if properly implemented; how-
 ever,  samples collected  in  tetrachloromercurate(II) can  undergo temperature-
 dependent decay leading to the  underestimation of  ambient  S02 concentrations.
 A variation of  the method  uses  a  buffered formaldehyde  solution  for sample
 collection,  reducing  the temperature-dependent  decay problem.  Certain American
'epidemiological  studies  employed  the West-Gaeke or other  variations  of the
 pararosaniline method.
      A titrimetric (acidometric)  method, whereby S02 is collected  in dilute
 hydrogen peroxide and the resultant H2SO,  is titrated with standard alkali, is
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the standard method  mainly  used in Great Britain and by the Organization for
Economic Cooperation and Development (OECD).   The method requires long  sampling
times (24 h),  is  subject to interference from atmospheric acids  and bases, and
can be  affected by  errors  due to  evaporation  of reagent during sampling,
titration errors, and alkaline contamination of glassware.   It has been used  to
provide aerometric S0« estimates reported in many British and European  epidemi-
ological studies.
     Some other  methods  use alkali-impregnated  filter papers  for collection  of
S02 and subsequent analysis as sulfite or sulfate. Most involve extraction
prior to analysis;  but nondispersive  x-ray  fluorescence allows direct  measure-
ment of S0« collected on sodium carbonate-impregnated membrane filters.  These
methods have not been widely used for routine air monitoring or epidemiological
studies.
     Two of the most sensitive methods for measuring SQ2 are based on chemilu-
minescence and ion exchange chromatography.   With the former, SO,, is absorbed
in a tetrachloromercurate solution and then oxidized with potassium permanga-
nate; oxidation  of  the absorbed S0«  is accompanied  by  chemiluminescence de-
tected by a photomultiplier tube.  With the latter, ion exchange chromatography
can be  used  to determine ambient  levels of  S02 absorbed into dilute hydrogen
peroxide and oxidized  to sulfate,  or  S02  absorbed into  a buffered formaldehyde
reagent.  These  methods  have not yet  been widely employed for routine  monitor-
                                        •^
ing uses.
     Sulfation  methods,  based on reaction of airborne  sulfur compounds with
lead dioxide paste  to form lead sulfate, have  been used both in the  United
States  and Europe to estimate ambient S02  concentrations  over extended time
periods.  However,  data  obtained  by  sulfation methods are affected by many
physical and chemical  variables and  other  interferences  (such as wind speed,
temperature, and humidity); and they are not specific for S02, since sulfation
rates are also affected  by  other airborne sulfur  compounds (e.g., as sulfates).
Thus,  although sulfation  rates  (mg  S03/100 cm2/day) have been  converted to
rough  estimates  of S02  levels  (in  ppm),  these  cannot be accepted as accurate
measurements of atmospheric  S02 levels.   This is notable here  because lead
dioxide  gauges provided estimates of S02 data  used in some pre-1960s  British
epidemiological  studies  and also in some American epidemiologic  studies.
     Automated methods for measuring ambient S02 levels have  been widely  used
for  air monitoring. Some early continuous S0*2 analyzers, based on conductivity
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and coulometry, were  subject  to interference by many ambient air substances.
More recent commercially available analyzers using these measurement principles
exhibit improved  specificity  for SO^ through incorporation  of  sophisticated
chemical and physical  scrubbers.
     Continuous SO^ analyzers that  use  flame photometric detection (FPD),
fluorescence, or seconds-derivative spectrometry  are now commercially available.
The FPD  method involves measurement of the  band emission  of  excited S02
molecules formed  from  sulfur  species in a hydrogen-rich flame and can exhibit
high sensitivity  and  fast  response,  but must be used with selective scrubbers
or coupled with gas chromatographs to achieve high specificity.  Fluorescence
analyzers detect  characteristic fluorescence of the SQy  molecule  when irra-
diated by UV  light, have acceptable sensitivity and  response  times, are in-
sensitive to sample flow rate, and require no support gases.   However, they can
be affected by  interference due to water vapor  (quenching effects)  and certain
aromatic hydrocarbons  and  must employ ways to minimize such  effects.  Second-
derivative spectrometry  can provide  highly specific measurement of SO* in the
air, with continuous  analyzers based on this principle  being  insensitive to
sample flow rate  and  requiring no support gases.   U.S.  EPA has  designated con-
tinuous analyzers  based on many of the above principles (conductivity, coulome-
try, flame  photometry,  fluorescence, and  second-derivative  spectrometry) as
equivalent methods for measurement of atmospheric SC^.
     Two main methods  have been used to measure  total  water-soluble, sulfates
collected on  filters  along with other suspended particulate  matter.  With the
turbidimetric method,  samples are collected on sulfate-free glass  fiber or
other efficient filters, the  sulfate is  extracted and precipitated with barium
chloride, and the  turbidity of the suspension is measured spectrophotometrically.
Samples are normally  collected over 24-h periods by hi-vol sampler.  However,
no distinction can be made between  sulfates  and  sulfuric acid  present in the
air and collected on  the filters; and some material  present  as  acid in the air
may be  converted  to neutral  sulfate on  the filter during sampling.   With the
methyl thymol  blue method,  samples are collected as in the turbidimetric method
and the extract is  reacted with  barium  chloride,  but the barium remaining in
solution  is  then  reacted  with methylthymol blue and the sulfate  determined
colorimetrically by measurement of uncomplexed methylthymol blue.  This modifi-
cation allows the procedure to be automated, but the same limitations -as noted
                                     1-13

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for  the  turbidimetric method  apply,  including lack of distinction  between
sulfates and sulfuric acid.
     As for sulfuric acid, no fully satisfactory method exists  for its measure-
ment in the  presence of  other  pollutants  in the air, but some procedures exist
for  examining  acidic properties of suspended  particles  or acid aerosols in
general.   Almost all of the strong acid content of ambient  aerosols consists  of
sulfuric acid  (HpSO.) and  its partial atmospheric  neutralization product,
ammonium bisulfate  (NH^HSO^);  however,  ammonium sulfate [(NH.^SO^], the final
neutralization product,  is  only v/eakly acidic.  Nitric acid (HN03) and  hydro-
chloric acid (HC1)  are  other strong acids found in the ambient air (mainly  as
vapors or,  when incorporated  into fog droplets,  as constituents of  acid
aerosols).   Ambient air acidic aerosol concentrations can be expressed  in terms
          +  3                               3
of umols H /m  or as H2S04 equivalent in ug/m  (at 98 ug/umol).   Unfortunately,
no systematic  surveys of average acid aerosol  concentrations in United  States
airsheds were  available  at the time the 1982 EPA  criteria  document (1982a) was
prepared, nor  is  such systematic survey information  available  for more  current
acidic aerosol  levels.   However, Lioy and Lippmann  (1985)  have  recently  sum-
marized some of the highest levels reported  for  recent years in  North America,
including levels  in the  range  of 20 to 30 ug/m  H2S04  (1 hr mean).   This  is  in
contrast to  the highest  level  (680 ug/m   H2S04   1 hr mean) recorded in  the
United Kingdom in  London  in 1962 and  even  higher  levels  almost  certainly
present during earlier London air pollution episodes.
1.3  KEY AREAS ADDRESSED IN EMERGING NEW HEALTH EFFECTS DATA
     Important new  health  effects information has emerged in three main areas
since preparation of the 1982 EPA criteria document and addendum:  (1) new data
which permit  more  definitive characterization of respiratory tract deposition
patterns for  inhaled  particles  of various size  ranges,  e.g.,  fine-mode (<2.5
urn) vs.  larger coarse mode particles (>2.5 urn, <10 pm, <15 urn, etc.); (2) new
reanalyses of certain key British epidemiology studies, which used BS methods
for measuring PM levels,  and additional new  epidemiologic  studies,  employing
other non-gravimetric or gravimetric PM measurement methods, that assess health
effects  associated  with exposures to PM and  SO  in contemporary urban airsheds
                                               J\
of the  1970s  and 1980s; and  (3)  new controlled human exposure studies which
                                     1-14

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more precisely  define  exposure-response relationships for pulmonary  function
decrements and respiratory symptoms due to acute SC  exposure.
                                      1-15

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               CHAPTER 2.  RESPIRATORY TRACT DEPOSITION AND FATE
2.1  RESPIRATORY TRACT DEPOSITION AND FATE OF INHALED AEROSOLS
     As  discussed  in U.S. EPA  (1982a),  the respiratory system is the  major
route of  human  exposure  to airborne suspensions of  particles  (aerosols) and
gases such as S02-   In inhalation toxicology, deposition refers to removal from
inspired  air of inhaled  particles or gases  by  the  respiratory tract and the
initial  regional pattern of these deposited materials.   Clearance  refers to
subsequent translocation (movement of material  within the lung or to  other
organs),  transformation,  and  removal of  deposited substances from the  respira-
tory tract.  It  can also  refer to removal of reaction products  formed from SOp
or particles.   Retention refers to the temporal  pattern of uncleared deposited
particulate  materials  or gases  and  reaction products.  These phenomena  are
complicated by  interactions that occur  among particles, gases such as  S0? or
endogenous ammonia, and water vapor in the airways.
     Deposition patterns of inhaled aerosols and gases are affected by physical
and chemical properties,  e.g.,  aerosol particulate size distribution,  density,
shape,  surface  area,  electrostatic charge,  hygroscopicity or  deliquescence,
chemical  composition, gas  diffusivity and solubility, and  related reactions.
The geometry  of the  respiratory airways from  nose  and mouth to  the  lung
parenchyma also  influences  aerosol deposition;  important morphological  parame-
ters include diameters, lengths, inclinations to vertical, and branching angles
of airway segments.   Physiological  factors that affect  deposition  include
breathing  patterns,  respiratory tract airflow  dynamics,  and  variations of
relative  humidity  and  temperature in the airways.  Clearance from the  respira-
tory tract depends on many factors,  including  site of  deposition, chemical
composition  and properties of deposited  particles,  reaction products,  muco-
ciliary transport  in  the tracheobronchial tree, macrophage phagocytosis, and
pulmonary  lymph  and  blood flow.   An  understanding of respiratory tract  anatomy
and regional  deposition and clearance of particles is essential for interpreta-
tion of the results of health effects studies discussed later.
                                      2-1

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     The respiratory tract includes the passages of the nose,  mouth,  nasopharynx,
oropharynx, epiglottis, larynx,  trachea, bronchi,  bronchioles, and small ducts
and alveoli of  the  pulmonary  acini.   In regard  to  respiratory -tract deposition
and clearance of  inhaled  aerosols, three main regions can be  considered:   (1)
the extrathoracic (ET)  region,  which includes 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) the tracheo-
bronchial (TB)  region,  which  includes the primary conducting  airways  of  the
lung from the trachea to  the terminal bronchioles  (i.e.,  that portion of the
lower respiratory tract having  a ciliated epithelium);  and (3) the pulmonary
(P) region, which consists of the  parenchyma! airspaces  of the lung, including
the respiratory bronchioles,  alveolar ducts, alveolar sacs, atria, and alveoli
(i.e., the gas-exchange region).   The extrathoracic region,  as defined above,
corresponds  exactly  to the  nasopharynx,  as defined by  the  International
Commission on  Radiological  Protection  (ICRP)  Task  Group  on  Lung Dynamics
(Morrow et a!.,  1966).  The thoracic region  corresponds  to that portion of the
respiratory tract distal to, and including, the trachea (i.e., TB + P).
     As  discussed in U.S.  EPA  (1982a), evaluation  of 'mechanisms by  which
inhaled particles ultimately  affect human health  requires recognition of the
importance of  deposition  and clearance phenomena in the  respiratory  tract.
Major regions  of the respiratory  tract differ markedly in structure, size,
function, and sensitivity or reactivity to deposited particles.  They  also have
different mechanisms-for particle  elimination or clearance.
     The 1982 EPA criteria document depicted available experimental  deposition
data for total  and regional  deposition in a series of figures (i.e.,  Figures
11-3 to 11-9 of U.S.  EPA, 1982a).  Curves  for alveolar deposition and  estimates
of  tracheobronchial  deposition, along with an extrapolation of the upper  bound
of  the  TB  curve to the point predicted by Miller et al.  (1979),  are reproduced
here in  Figure  2.  Added  to the figure are the more recent data of Svartengren
(1986), Heyder  (1986),  and Emmett  et  al. (1982) for  deposition of particles >10
urn  in aerodynamic diameter (DQe) in healthy adult subjects breathing through a
mouthpiece..
     In  the  studies reported by Heyder (1986),  mean inspiratory flow rates   of
250 and  750  cm3s"1 were used with a  four-second breathing cycle, resulting  in
minute  ventilations of 7.5 and 22.5 L min"1, respectively.  At the higher flow
rate, TB deposition of  10 urn  Dae particles was  0.14;  fractional deposition for
                                       2-2

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    1.0
cc
LL

o
o_
111
O
    0.8
    0.7
z
o
ir   0.6
  	ESTIMATE OF ALVEOLAR DEPOSITION, NOSE BREATHING


       | RANGE OF TRACHEOBRONCHIAL DEPOSITION,
       I MOUTH BREATHING


"	EXTRAPOLATION OF ABOVE TO POINT ( gS ) PREDICTED

        BY MILLER et al., (1979)

-Q9 EMMETT et al. (1982); 337 cm3 s'1, 6s BREATHING CYCLE  /g
 n« ucvncR (19RB): 750 cm3 s'1. 4s BREATHING CYCLE     jK-V.
       —I	1—I    I   I  I  I    I
        RANGE OF ALVEOLAR DEPOSITION,
        MOUTH BREATHING
         i_iviivib.i • **fc "•• \ i w*. — it — T< —*•• — '	
     QB HEYDER (1986); 750 cmi? s], 4s BREATHING CYCLE
     A A HEYDER (1986); 250 cm3 s'1, 4s BREATHING CYCLE
0.5 —O^ SVARTENGREN (1986)
     OPEN SYMBOLS: TRACHEOBRONCHIAL DEPOSITION
     SOLID SYMBOLS: ALVEOLAR DEPOSITION

                         0.3  0.4 0.5
                                                      2.0   3.0  4.0 5.0
         PHYSICAL DIAMETER,
                                              AERODYNAMIC DIAMETER, p.m
                                                                        10 121416 20
Figure 2  Regional deposition of monodisperse aerosols by indicated particle diameter for mouth
breathing (alveolar, tracheobronchial) and nose breathing (alveolar). The alveolar band  indicates
the range of results found by different investigators using different subjects and flow parameters
for alveolar deposition following mouth breathing. Variability is also expected following nasal
inhalation  The tracheobronchial band indicates intersubject variability in deposition over the
range of sizes as measured by  Chan and Lippmann (1980). Deposition is expressed as fraction
of particles entering the mouth (or nose). Also shown is an extrapolation of the upper bound of
the TB curve to the point predicted by Miller et at. (1979). The extrapolation illustrates the hkely
shape of the curve in this size range but is uncertain.  However, the data  of Emmett et al. (1982),
Heyder (1986), and Svartengren (1986) tend to substantiate this extrapolation. In the Svartengren
(1986) studies, subjects took  maximally deep inhalations at a flow of 500  cnr* s''.
                                              2-3

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12 pm D   particles was 0.09.  In contrast, the lower flow rate yielded deposi-
tion  fractions of  0.17  and 0.12,  respectively,  for 10  pm and 12 pm  Dae
particles.   Emmett  et al. (1982) observed an average TB deposition of 0.36 in
three  subjects who  inhaled 10 |jm Dao particles at a mean inspiratory  flow rate
          O  1                     ClG                                     _ "I
of  337  cm s   with 10 breaths/min  (i.e., minute ventilation of 10.1 L min  ).
Under these breathing conditions the alveolar region deposition fraction for 10
pm particles averaged 0.06.
     The deposition of 11.5, 13.7, and  16.4  pm DQe particles was studied by
Svartengren (1986)  using a different exposure  regime.   Subjects took four
maximally deep inhalations at a flow of 500 cms   from a glass bulb apparatus
each  time particles were sprayed up into the bulb.  Exposure times varied from
2 to  5 min.   Six subjects  were  studied at the 11.5 and  13.7 pm sizes, while
five  subjects were studied at 16.4 urn Dae.   The  average alveolar deposition
fraction was 0.01 at  the  largest particulate  size  and 0.04  at the 11.5  and 13.7
pm  sizes.   By subtracting alveolar deposition from the  measured  total lung
deposition, the average  TB deposition fractions of the 11.5, 13.7, and 16.4 pm
D  particles were  0.27,  0.17, and  0.12,  respectively.   The data of Svartengren
  36
 (1986),  along with the data of Heyder (1986) and  Emmett et al.  (1982), tend to
 substantiate the extrapolation of  the  upper  bound of the TB curve in  Figure  2
 to the  point predicted  by Miller et al.  (1979).
      Numerous subject-related and  environmental factors  can influence  deposi-
tion  and clearance  of aerosols,  including inhalation patterns (rate and route),
 airway  dimensions  in relation to  pulmonary  function measurements,  disease
 state,  particle composition,  and  the  presence of pollutant gases.   Detailed
 discussion  of  effects  of such factors on deposition patterns  is beyond the
 scope of this  addendum  (for more  details, see U.S. EPA, 1982a,b; Lippmann et
 al.,  1980;  Garrard et al.,  1981;  Svartengren et al.,   1986;  Lippmann and
 Schlesinger,  1984).   However,  the results  of Heyder et al.  (1982) on  the
 biological  variability of  particulate deposition  in controlled and spontaneous
 mouth breathing are of interest since this was an important issue raised in the
 1982 EPA criteria  document.  Using  both breathing patterns and particulate
 sizes ranging, from 1 to 7pm D  ,  they studied total deposition and deposition
'rate in 20  subjects.  The variability of deposition rate between  subjects
 spontaneously  breathing  the  same  aerosol is associated with morphological and
 physiological  factors but  is  mainly governed by  physiological factors (i.e.,
 primarily  individual flow  rate).   Heyder et al.   (1982) contend that this type
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of variability is the most  important when considering health-related issues of
inhaled particulate matter.
     Data on respiratory  tract  deposition can be used to provide an evaluation
of deposition  of typically observed ambient particulate distributions.   The
similarity  of  experimental deposition  data from  human subjects breathing
monodisperse aerosols in a laboratory setting to the general  population breath-
ing multimodal urban aerosols was  examined  in studies published after  prepara-
tion of the 1982 EPA criteria document (U.S. EPA, 1982a).   Miller et al.  (1982)
studied total  respiratory tract deposition  in five subjects  using a mixture of
monodisperse polystyrene  latex spheres 0.6,  1, and 2 tim in size.   Their experi-
mental results suggest  that the deposition of mixed monodisperse and monodis-
perse  single aerosols  is  similar for fine particles.  However, the theoretical
modeling of Diu and Yu (1983) indicate that the regional deposition patterns of
polydisperse aerosols can be  quite complex.  They assumed  a log. normal size
distribution and  studied  total  and regional deposition with nasal  and mouth
breathing for  geometric standard deviations (a )  of 1.0  (monodisperse),  1.5,
2.5,  and  3.5.   The results of  Diu and  Yu  (1983)  support the observation  of
Morrow (1981)  that the  mass  deposition of mono-  and  polydisperse aerosols
differs  little if a  <2.  .Typically, a  values  reported for distribution of
urban  and  rural  aerosols is usually around  2 (see Chapter 5, U.S.  EPA, 1982a).
In the theoretical  studies of  Diu and Yu (1983),  larger values of ag  are pre-
dicted to  impart significant complexities  in regional  deposition patterns due
to competing mechanisms interacting with the sequential filtering effect of the
respiratory tract.
      Over  half of the total mass  of a typical ambient  mass  distribution would
be deposited in the extrathoracic  region,  most of this being coarse particles,
during normal  nasal breathing  (see Chapter 11 of  U.S.  EPA,  1982a).  Clearance
of most  of this material  to  the esophagus  would  occur within minutes.  Some
fraction  of the  hygroscopic fine mass (e.g.,  sulfates and nitrates that grow  to
2-4  urn in  the respiratory  tract)  might also be deposited and dissolve in the
extrathoracic  region.   Smaller fractions  of both the hygroscopic and non-
hygroscopic fine particles (mostly <1 urn)  would be deposited in the  tracheo-
bronchial   and  alveolar  regions,   respectively.    Clearance  of  hygroscopic
material  by dissolution and reaction would  be relatively rapid  in  both regions.
Clearance of insoluble coarse-mode substances would increase from less than  an
                                       2-5

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hour for  the  larger particles deposited in the  upper portion of the tracheo-
bronchial  region  to as  much as a  day for that deposited more distally.
Insoluble  fine  and coarse  particles  deposited  in the alveolar  region  have
clearance  half-times varying from  weeks to years for the  fast phase and  slow
phase, respectively.
     With  mouth-only breathing,  the regional  deposition pattern changes  mark-
edly, with extrathoracic deposition reduced and  both tracheobronchial and pul-
monary deposition  enhanced.   Extrathoracic deposition, although  reduced,  still
would be dominated by coarse mode aerosols and contain little fine-mode  contri-
bution.   Endogenous ammonia in human airways may, however, reduce the deposi-
tion of  acid aerosols  (U.S. EPA,   1982b).   Remaining non-hygroscopic fine
particle  deposition efficiency would change  little over nasal breathing  (<20
percent).
     In essence,  regional  deposition of ambient particles in the  respiratory
tract does not  occur at divisions  clearly corresponding  to atmospheric aerosol
distributions.  Coarse-mode  and hygroscopic  fine-mode particles are deposited
in all three  regions.   A fraction  (5 to 25 percent) of the. remaining  fine-mode
particles  (e.g.,  organics  and carbon not associated with hygroscopic  material)
is deposited in the tracheobronchial/alveolar regions.   With mouth-only breath-
ing, as  illustrated in Figure 2, little particulate mass in  excess of 15  pro is
deposited  in  the  thoracic  region,  and  little  mass  greater than  10  urn  is
deposited  in the alveolar region.
     Oronasal breathing (partly via the mouth and partly  nasally) typically
occurs for healthy adults while undergoing moderate to heavy exercise.   Swift
and Proctor  (1982) computed deposition for oronasal breathing as a function of
particulate  size,  correcting  for  deposition  in  the  parallel nasal and  oral
airways,  and  compared these results  to those for mouth breathing via  tube.
Using minute  ventilations  of 24.5  and 15 Lmin  , their  analyses  predicted that
total thoracic  deposition at all sizes is more or less  essentially the  same as
for pulmonary deposition noted above for mouth only breathing,  i.e.,  with very
few particles over 10  pm D    in size being  likely to reach tracheobronchial
regions.   Trac'heobronchial   deposition  with  oronasal  breathing  at a higher
minute ventilation  (45  Lmin"1)  has  been examined by Miller et al.  (1984).   Data
for extrathoracic  and  tracheobronchial deposition were  fit to  logistic  regres-
sion models  yielding  significantly improved fits of  the deposition data.  As
done by  Swift and Proctor  (1982),  a  50/50 split in  airflow between the  nasal
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 and oral  pathways  was assumed.   Simulated oronasal breathing  at a minute
 ventilation of 45 Lmin    resulted in tracheobronchial  deposition  fractions  of
 0.21,  0.17, 0.14 and  0.09 for particles  of 8,  9,  10, and 12 urn  in aerodynamic
 diameter,   respectively.   When the  experimental  deposition  data  of Heyder
 (1986),  separately  for  nasal and  oral  breathing, are combined to  simulate
 oronasal  breathing,  the  results  are in agreement with the analyses of Miller et
 al.  (1984).
     More   recently, thoracic deposition and  its  component parts have been
 examined  by Miller  et al.  (1986),  as a function  of particulate  size,  for
 ventilation rates  ranging from normal  respiration  to heavy exercise  in individ-
 uals who,  as per Niinimaa et al.  (1981), habitually breathe oronasally (mouth
 breathers) and  in  those who normally employ  oronasal  breathing when minute
 ventilations exceed about 35  Lmin"   (normal augmenters),,   Published data  from
 various  laboratories for  ET  and TB deposition, along with  previously unpub-
 lished  data of  Lippmann  and co-workers  at New York University, were  fit to
 logistic  regression models prior to examining the influences of breathing mode
 and activity level  on TB, P, and thoracic  (TB + P) deposition.   For  the ET
 region,  an  impaction  parameter  was used that was  a function of aerodynamic
 diameter  and inspiratory  flow rate,  and  the logistic models provided signifi-
 cantly  improved fits of  the  nasal  and oral inspiration data compared to  the
 linear  models  of Yu et  al.  (1981) that also used  an impaction parameter  and
 that formed the basis of the Swift  and  Proctor  (1982) analyses.   Since  TB
 deposition is  due  primarily  to  inertia!  impaction  in the  upper airways and  to
 sedimentation  in the lower airways,  the logistic analysis  for the  TB region  was
 based upon aerodynamic diameter rather than on an impaction parameter.    The
 proportionality  of airflow between the nose and mouth as  a function  of activity
 level was  determined from Figure 2 of Niinimaa  et al. (1981).
     Thoracic  deposition results given by  Miller  et al.  (1986)  are shown in
 Figure  3,   along with  the thoracic  deposition  results  of Swift and Proctor
 (1982).  With  minute ventilations (V£) of  40 or 60  Lmin"1 (panel  A), there  is
 not  much  difference between  normal  augmenters  and mouth  breathers in thoracic
 deposition for Dge beyond the peak  of the  deposition curve.  For  vV less  than
'35  Lmin"  , the  Miller et al. (1986) analyses-result in  substantially  lower
 deposition in  normal augmenters compared to mouth breathers.  As vV increases,
 thoracic deposition  for  normal augmenters initially decreases for a given D  ,
                                                                            06
 increases  through  the  oronasal switching point, and then decreases.   For mouth
                                      2-7

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breathers, however, there  are minimal  changes in thoracic deposition at lower
ventilation rates with  monotonic declines  in  deposition  as  vV  increases beyond
30 train"1.
     Swift and  Proctor  (1982) computed  bands  of  total  thoracic deposition as  a
fraction  of  particles entering the mouth  and nose during oronasal and oral
breathing, using vV of  approximately 24.5 Lmin   and 15 Lmin  ,  respectively.
The shaded area of  Panel  B (Figure 3)  represents  a composite of these data
based on  the  lower  band of the  low  vV  and the upper  band  of  the  higher vV.
While neither Swift and Proctor (1982)  nor the U.S.  EPA  (1982a,b)  extended the
bands for TB  deposition beyond 8 urn, some  thoracic deposition  could  be  projec-
ted for 10 to 15 ug particles with  oronasal  breathing.   More recent experi-
mental data utilized  in Miller et al.  (1986) indicate that there is a gradual
decline in thoracic deposition for large particulate sizes and that there can
be significant  deposition  of  particles  greater than 10  urn,  particularly  for
mouth breathers.
     It should  be noted that  the deposition studies cited previously all  used
adult subjects,  yet many  of  the  epidemiology studies cited in the  PM/SO
                                                          •                /\
criteria  document  (U.S. EPA,  1982a)  and  in  this  addendum  report  effects
observed in children.   Anatomical and functional  differences between adults  and
children are  likely to  yield  complex interactions with  the major  mechanisms
affecting respiratory  tract  deposition.   In  a study  of  over  1800 Mexican-
American, white, and  black children 7 to  20  years of age, Hsu et al. (1979)
found significant  differences of  lung  volume and  flow rate among the  three
races, and between male and female subjects.  Further analyses of these data  by
Hsi et al. (1983) demonstrated that using sitting height as a predictor greatly
reduced the racial  differences of ventilatory function and allowed the applica-
tion of a single set  of prediction equations  for children of all three  groups.
Other studies are available on normal pulmonary  function values  (Swiniarski et
al., 1982), intrasubject variability (Hutchinson et al., 1981), influence of
physical performance capacity on the growth of lung volumes (Anderson et al.,
1984), and postnatal  growth and size of the pulmonary acinus (Osborne et al.,
1983).
     To date, experimental  deposition  data in children's lungs are not avail-
able.  Analogous to the development of mathematical models  for  deposition in
adults, the thrust for age-dependent dosimetry modeling has been from
                                      2-8

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   0.5
   0.4
 O
 80.3
 o.
 LU
 Q
 O

 §0.2
 ec
 O
 X

   0.1
'A
    obi.
 I   I  I  I Mill	1    I  I  IlltU
      	MOUTH BREATHERS
      ——	 NORMAL AUGMENTERS
J	I   I  I
                  JtU
                                                       i  mm
                                                          \\
                                                                      i  i  i-ni-ri
      1.0
10.0                1001.0
        AERODYNAMIC DIAMETER,
                                                                   10.0
                                                                          100
Figure 3. Estimates of thoracic deposition of particles between 1 and 15 jum by Miller et al. (1986)
for normal augmenters (solid lines) and mouth breathers (broken lines) are shown for minute venti-
lation (VE) exceeding the switch point of 35 L min'1 (A) and for lower ^g (B). Normal augmenters
are individuals who normally use oronasal breathing to augment respiratory airflow when ^E exceeds
about 35 L min'T, while mouth breather refers to those individuals who habitually breathe oronasally
(Niinimaa et al., 1981). The shaded area (B) is a composite of the .computed bands of thoracic depo-
sition of particles less than 8 /urn by Swift and Proctor (1982) for Vg of approximately 24.6 and 15
L min"'.
                                           2-9

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scientists dealing primarily with  radiological  protection issues (Hofmann et
al., 1979; Hofmann,  1982a,b;  Crawford,  1982).   More recently, Phalen et  al.
(1985) have studied the postnatal  enlargement of human  tracheobronchial  airways
and its implication  for the deposition  of particles ranging from 0.05 to 10 urn
in size.  They  made  some morphometric measurements in replica lung  casts of
people aged 11  days  to 21 years.   The model  predictions  for deposition  during
inspiration only were  computed  for three states of physical  exertion —  low
activity,  light exertion, and heavy exertion.  Scaling  techniques were employed
to make age-dependent adjustments from adult flow rates.
     While the  predictions of  Phalen et al.  (1985) indicate that,  in general,
increasing age is associated with decreasing particulate  deposition efficiency,
high flow  rates and large particulate  sizes do not exhibit consistent age-
dependent differences.   Since ^E  at a given  state  of activity is approximately
linearly related to  body mass,  children will  inhale more air per unit body
mass, resulting in  higher TB  doses.   For resting ventilation, this age-related
dose effect,  as a  function of particulate size, is  illustrated  in Figure 4.
While children  may  be  at greater  risk than adults  from exposure  to particulate
matter on the basis  of deposition during inspiration,  information  is needed on
possible age-dependent differences in ET deposition, deposition over the entire
breathing cycle, mucociliary  clearance, and tissue sensitivity, to  put this
risk into perspective relative to health effects evaluations.
     Other deposition  characteristics of individuals and atmospheric distribu-
tions (as well  as  other factors) can cause variations  in regional  deposition.
The following examples illustrate potentially important variations in exposure/
deposition patterns:
     (1) The  peak  in alveolar deposition efficiency for nasal and mouth-only
breathing (Figure 2) tends to  occur at  or  near the normal minimum in  the  ,
bimodal distribution (2 to 4 pm MMAD).   However,  near emission  sources or in
other polluted  conditions,  substantial increases can  occur  in the coarse- or
fine-mode contribution to this most efficiently  deposited range.
     (2) The  deposition of both coarse and  fine particles in the tracheobron-
chial region  can  be increased over normal ranges by increased breathing rates
during  exercise and by cigarette smoking,  in both bronchitic and asthmatic
subjects, generally  reducing alveolar deposition.  Since  retention of particles
at 24 hr was  significantly lower when bronchoconstriction was induced before
                                     2-10

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                4
                T
      AGE - YEARS

    8    10     12
14
 r
16
T
                                                       18
0.00
            10
20     30      40

   BODY MASS -KG
                                                 60
      Figure 4. Predicted initial dose to the TB region as a
      function of body mass. Assumptions include equivalent
      upper airway deposition for all ages, inhalation of
      particles at 1 mg/m3 concentration in air, and resting
      minute ventilation.

      Source: From Phalen et al. (1985).
                           2-11

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inhalation of particles than when bronchoconstriction was induced after inhala-
tion, Svartengren et  al.  (1984) postulated that bronchoconstriction may serve
as a defense  mechanism for the alveolar region.  However,  enhanced tracheo-
bronchial deposition  may not  be  protective, especially  for  disease states
(e.g.,  bronchitis) or other conditions that constrict, inflame, or cause mucous
build-up in airways.   Further  complicating our  understanding  of  lung clearance
mechanisms in obstructive  airways  disease  is the variety  of mucociliary trans-
port patterns that  can be observed,  including  regurgitation,  stasis,  spiral
motion, and movement toward the opposite bronchus (Isawa et al.,  1984).
     (3) Regional mass deposition data do not provide insights regarding local-
ized "hot  spot" deposition.   Significantly higher  particulate mass to  lung
surface ratios  can  occur in the extrathoracic and tracheobronchial regions as
compared to the alveolar region.   Gerrity et al. (1979)  computed  the  average
particle surface concentration of an inhaled 8 urn MMAD aerosols in each genera-
tion of  the Weibel  lung model  (Weibel,  1963) and predicted as  much as  two
orders of magnitude difference between particulate surface concentration in the
segmental bronchi compared  to  terminal  bronchioles.   Local surface concentra-
tions of deposited  particles within large  airways are probably higher  than the
average.   Also,  respiratory disease states  that result  in altered breathing
patterns (e.g.,  increased  oral  breathing)  may lead to increased deposition of
particles in particular respiratory tract regions.
     (4) Although the  probability  of deposition of particles  larger than  10 urn
in the alveolar region is  low,  small  numbers of such particles have been  found
in human lungs  (U.S.  EPA,  1982a,b).  Some  evidence  suggests  that  those  large
insoluble coarse substances that  do penetrate may be cleared at a much slower
rate.  Animal  tests indicate that  15 pm particles  instilled  in this  region
clear much more slowly than smaller particles  of the same composition (U.S.
EPA, 1982a,b).
     Besides  variations  in regional  deposition patterns  found  for inhaled
particles and factors  affecting typical  deposition patterns, regional differ-
ences  exist  for clearance mechanisms by which  inhaled particles penetrating
various levels  of the respiratory tract are removed.   The effects of  inhaled
particulate matter  and other  noxious agents, e.g.,  irritative gases, on  clear-
ance mechanisms  represent  one  of  the major categories of toxic actions exerted
by such  air  pollutants.   Detailed reviews of clearance mechanisms and effects
on them  due  to  inhaled particles and sulfur dioxide  (S02) are presented else-
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where  (U.S.  EPA, 1982a,b; Lippmann  et  al.,  1981; Lippmann and  Schlesinger,
1984).
     Mucocillary  clearance  and  alveolar  clearance mechanisms  are of most
concern here.   Lung  mucociliary  clearance is the major  defense  mechanism by
which  inhaled particles  deposited  in the tracheobronchial airways are removed
from the respiratory tract.   Particle-laden mucus is transported by the tips  of
cilia which are immersed in an aqueous sol layer.  Airway mucus transport rates
decrease distally from  the  trachea (Asmundsson and Kilburn,  1970;  Foster et
al., 1980) with particle residence times  of  potentially  as much  as  300 minutes
in the  terminal  bronchioles  (Lee et al., 1979).  Mucociliary clearance  half-
times  of the  healthy lung can range typically  between 30 minutes  and several
hours,  depending  on  the initial  distribution of particles and mucus transport
rates  within  each airway.   Lung mucociliary clearance  can  be  impaired  by
disease states  of the  lungs  (Lippman et al.,  1980).   Svartengren et al.  (1986)
have observed marked dysfunction of  lung  mucociliary  clearance (Camner et al.,
1973;  Levandowski et al.,  1985;  Garrard et al.,  1985) and  a virtual halt in
tracheal mucus  transport (Levandoswki  et al.,  1985)  unless  supplemented  by
cough.  Retarded  mucus transport  within  the lungs can   lead  to increased
residence times of inhaled particles.
     Two general types  of  alveolar clearance mechanisms  are  generally recog-
nized:  absorptive and non-absorptive.   Absorptive mechanisms involve active
and  passive  transport  processes,  whereby deposited  particles  permeate  the
alveolar epithelium  and penetration  of endothelial barriers  occurs prior to
uptake  into the blood  or lymphatic transport.   These  processes are  most  effec-
tive in removing highly soluble particles.  Phagocytosis  of deposited particles
by alveolar  macrophages is  generally accepted  as  the chief non-absorptive
clearance process.   Some  low-solubility materials may escape phagocytosis and
accumulate as focal  deposits  within  parenchyma! tissues.  In  the  ICRP (1979)
lung model  it  has been suggested that as much as  40 percent of  particles
deposited in  alveoli migrate, either free or  phagocytized,  to the  distal
portions of the ciliated airways for subsequent removal  by mucociliary clear-
ance.   Alveolar  clearance  rates  depend  in large part on particle  solubility.
Several studies  of long-term  clearance  of highly insoluble particles  in  the  1-
to 4-ug range  (Bailey  et al., 1982;  Bohning  et al.,  1982;  Philipson et al.,
1985)  report  two phases with  half times  of approximately 20  and  300 days,
though  Philipson  et  al.  (1985)  observed  slow  half-times of  as much  as  2500
                                     2-13

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days.  Stahlhoffen et  al.  (1980) measured the long-term clearance  of  ferric
oxide particles (moderately insoluble) between 1 and 9 urn MMAD and found single
phase clearance half-times  of between 70 and 110 days that appeared to depend
on particle size.
     Continuous exposures  to  ambient aerosols result  in  the simultaneous
deposition and  redistribution of particles.   The regional  dose  of particles
inhaled continuously may thus differ significantly from the regional pattern of
acute aerosol  deposition.   Brain  and Valberg (1974)  developed  a  model of
retention  of  continuously inhaled  particles  based on the  ICRP  (1966) lung
model.  Gerrity et al. (1983) further defined  it to the Weibel   (1963)  lung
model, taking  into account  individual  airway mucus  transport rates.    The
Gerrity et al.  (1983)  model  predicts  maximum  doses  to the  trachea and  respira-
tory bronchioles for a moderately insoluble 10-um aerosol.
     Deposition of inhaled sulfate compounds in the respiratory  tract is
complex and  depends upon breathing patterns  and physical  properties  of the
inhaled particles.  Deposition patterns  and clearance mechanisms for sulfates
depend upon their  particular size ranges (mainly fine particles  <2.5  um)  as
discussed  above.   Of most importance  is the  fact  that deeper penetration  of
particles  into  the respiratory tract  occurs  during  breathing  through the mouth
or oronasally than during nasal breathing.
     Of particular concern  from  a health standpoint  is  the fact that acidic
aerosols exist in ambient air mainly in the size range of 0.3 to  0.6 um (MMAD),
well within the range of readily inhalable fine-mode particles capable of pene-
trating deeply  into  tracheobronchial  and alveolar  regions  of the respiratory
tract.  Under  fog  conditions, where acidic components are  often incorporated
into water droplets of larger sizes up to 10-15 pm, concern exists  in regard to
the potential for  health effects being associated with the increased deposition
of  acidic  fog  droplets  in  the  tracheobronchial  regions  of the  respiratory
tract.
2.2  SULFUR DIOXIDE DEPOSITION AND CLEARANCE
     As discussed in U.S. EPA (1982a,c), sulfur dioxide is soluble in water and
readily absorbed  upon  contact with the moist  surfaces  of the nose and upper
respiratory passages.  It is well established that the gas is almost completely
removed (95 to 99 percent) by nasal absorption under resting conditions in both
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man and  laboratory animals.   A recent  study  by Schachter and coworkers (in
press) also  indicates similar, almost  complete, removal  of  S02 in  nasal
passages during nasal breathing under increased exercise conditions.   Schachter
et al. (in press) exposed six subjects to 2.62 mg S02/m  (1 ppm) in  an environ-
mental chamber to  study  nasal  absorption of  inhaled  S02.   A  6 min rest was
followed by 4  to 6 min of exercise  at  450  kpm during which subjects  breathed
only  via the  nose.   A catheter was placed in the oral cavity and connected to
an  S02  analyzer.  No  detectable  quantities  of S02 could be measured when
sampling from  the mouth.   In  addition,  saliva samples were  analyzed  for
dissolved S02; no  dissolved S02 was detected.  These results confirm previous
observations that the nose is extremely efficient in removing S02-
      Other human studies indicate that S02 penetration to the lower respiratory
tract increases with activity and increased ventilation associated with a shift
from  nasal to  oronasal  breathing at a mean ^ of 30 L min   (Niinimaa et al.,
1980, 1981; D1Alfonso, 1980).  Most studies on deposition of SO, in animals and
humans have  been done at concentrations greater than 2.62 mg/m  (1 ppm).  The
95  to 99 percent removal of S02  by  the upper  respiratory tract has not been
confirmed at  levels  ordinarily found in  ambient  air  (generally less  than  0.1
mg/m3 [0.038  ppm]).   It is expected, however, that similar deposition patterns
would be observed at these lower concentrations of S02-  Once inhaled, S02 is
absorbed  quickly into the  mucus  layer lining  the  ET and TB  regions, where
reactions  can occur  which  might result  in alterations  in the viscosity of
mucus.   Absorbed S02  can also be transferred  rapidly  into the systemic circula-
tion.   Less  than 15 percent of the  total inhaled S02 is likely to  be exhaled
immediately,  with  only small amounts (about  3 percent) being desorbed during
the first 15 minutes  after the end of exposure (U.S.  EPA, 1982a,b).
 2.3   POTENTIAL MECHANISMS  OF  TOXICITY  ASSOCIATED WITH  INHALED PARTICLES AND S02
      U.S.  EPA (1982a) noted  that  numerous  possibilities exist by which a wide
 variety of toxic effects may be exerted by inhaled particles once deposited in
 the  respiratory tract.  Certain general types of mechanisms of toxicity can be
 identified to  apply  across  a wide  range  of mixtures of inhaled particles,
 either acting alone or in  combination  with  other common gaseous  air  pollutants,
 such as  S00,  NO ,  or ozone.   These include,  for  example,  possible irritant
                                      2-15

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effects that  result in decreased air flow due to airway constriction, altered
mucociliary transport and effects on alveolar macrophage activity.   Other toxic
effects and underlying mechanisms of action are much  more chemical-specific,
and  depending on the  particular materials  involved,  may  include forms  of
systemic toxicity involving  non-respiratory system organs and functions.   The
main focus of discussion here is on general  mechanisms of toxicity rather than
more chemical-specific ones.
     The tracheobronchial portion of the respiratory system is  the site of de-
position of a mixture  of fine (especially hygroscopically fine) and  relatively
small  (<10-15 urn) coarse-mode particles.   Bronchoconstriction  is  one common
response to deposition of particles in  this region  and has been reported in
response to short-term exposure  to high  levels of various "inert" dusts, as
well as acid and alkaline aerosols of varying particle sizes.  Bronchoconstric-
tion produced  by  acute exposures is likely because of neurologically-mediated
reflexive actions arising from chemical  and/or mechanical  stimulation of  irri-
tant neural receptors in the bronchi.  Since particle deposition and epithelial
nerve endings  tend  to  concentrate near airway  bifurcations, deposition at such
points may exert  an influence on pulmonary mechanical changes due to chemical
or mechanical  stimulation of receptors.   Reflex coughing and bronchoconstric-
tion due to irritant effects of  particles  or  SO,,  on tracheobronchial region
receptors  may be related to  effects  observed in various epidemiological
studies, e.g.,  aggravation of chronic  respiratory  disease states such  as
asthma, bronchitis,  and  emphysema.   Also, as noted earlier, some persons with
asthma or  other respiratory  diseases  may have elevated particle  deposition
rates in the tracheobronchial region which may contribute to a cascading effect
of  further bronchoconstriction  and increased  particle  deposition in that
region.
     Referring to  the earlier discussion of particle  clearance mechanisms,
several more  potential mechanisms of toxicity  associated  with  inhalation of
airborne particles can be readily discerned. This includes a plausible sequence
of  events  by which  inhaled  particles  can contribute to chronic obstructive
pulmonary disease (Albert et al., 1973;  Lippmann et al., 1980).  That is, in-
haled particles and noxious gases can stimulate changes in the distribution and
activities of  various  cell  types lining  the tracheobronchia'l airways.  Acute
exposures to  high levels of airborne particles initially  stimulate  increased
mucus  secretion  and mucociliary  flow useful in clearing  inhaled  particles.
                                     2-16

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However, with continuous  or  repeated  exposures, more marked changes can occur,
e.g., marked  and persistent  depression  in bronchial  clearance, increase in
secretory cell number,  increase  in the thickness  of the mucous layer  (Lippman
and Schlesinger,  1984).   Also, certain particles and gases affect the  number of
ciliated cells or their  functioning  so as to  alter  (i.e.,  speed or slow)
mucociliary clearance  rates.   Mucociliary clearance  is affected by  fine
sulfuric acid aerosols,  high levels of carbon  dust, and cigarette smoke.
     Because of  the  above mucociliary clearance phenomena, airborne particles
may be  importantly  involved  as etiological factors that contribute to various
types of chronic  lung diseases, as discussed by U.S.  EPA (1982a,b) and Lippmann
et al.  (1980).   This includes:   likely involvement in  the pathogenesis  of
chronic bronchitis;  increasing susceptibility  to  acute bacterial and viral
infections, especially in  populations or groups (e.g.,  children,  the elderly
and cigarette smokers)  already predisposed to  such infections  by other factors;
and likely aggravation of preexisting disease states,  e.g., chronic bronchitis
or emphysema, or other  respiratory conditions such as  bronchial asthma.  Also,
some  individuals (e.g.,  those with  Kartagener's  syndrome) have genetically
inherited defects  in ciliated cell function  or other  disease  states, which
result  in much reduced  mucociliary clearance  of inhaled  particles and poten-
tially greater vulnerability to toxic  effects  of such particles.
     Particle deposition  within the  alveolar region of the lungs is mainly
limited to fine and coarse particles of less than  10 urn D_ .   Several  important
                                                         we
characteristics  in the alveolar  region affect responses to inhaled particles.
Clearance from the  alveolar  region is much slower than from the tracheobron-
chial region.   The  alveolar  region is the  site  of  oxygen uptake and of various
non-respiratory  functions  of  the  lungs that may be affected by pollutant  expo-
sures.  Many victims of  London air pollution  episodes  were patients  suffering
from cardiopulmonary diseases  (e.g,,  emphysema  and bronchitis), which normally
reduce  the  lungs'  ability to transfer oxygen  to  blood.  Individuals with
chronic lung disease and  nonuniform ventilation distribution will  be  sensitive
to pollution if  only because the delivered dose to the region that  is being
ventilated will be higher than it would be if  ventilation were normally distri-
buted.  Although this  added  load (due to  pollution  exposure)  is  usually
tolerable in normal  individuals,  the  added stress  and  chain of events may lead
to fatal or irreversible damage in individuals already  compromised with cardio-
pulmonary disease.
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 2.4  SUMMARY
      Studies published since preparation of the earlier criteria document  (U.S.
 EPA, 1982a) and the previous addendum (U.S.  EPA, 1982c) support the conclusions
 reached at that  time  and  provide clarification  of several issues.   In light of
 previously available data, new literature was reviewed with  a focus towards  (1)
 the thoracic deposition and clearance of large particles,  (2)  assessment of
 deposition during oronasal  breathing,  (3)  deposition in possibly  susceptible
 subpopulations, such  as children,  and (4)  information that would  relate  the
 data to refinement  or interpretation of ancillary issues,  such as  inter- and
 intrasubject variability  in deposition, deposition  of monodisperse  versus
 polydisperse aerosols, etc.  Major results for  the first three  areas are given
 below.
      The thoracic deposition of particles >10 urn D3Q and their  distribution in
                                           "~       etc
 the TB and P regions  was  studied by  a  number  of investigators (Svartengren,
 1986;  Heyder, 1986;  Emmett et al.,  1982).   Depending  upon  the breathing  regimen
 used,  TB deposition ranged from 0.14  to 0.36  for 10-pm Dae particles,  while  the
 range for 12-um  Dge particles  was  0.09 to  0.27.  For particles 16.4 urn  Da , a
 maximally deep  inhalation  pattern  resulted  in TB deposition  of 0.12.
      The experimental  data cited above  were obtained  from human  exposure
 studies in which the subjects inhaled through a mouthpiece.   Some  of the minute
 ventilations employed would more normally occur with  oronasal  breathing  (partly
 via the mouth  and partly  nasally).   Various  studies  (Swift  and Proctor, 1982;
 Miller et al.,  1984,  1986)  have simulated deposition during oronasal breathing
 by adjusting for parallel  nasal  and  oral  deposition  as a  function of  air  flow
 through the respective compartments.  While the  magnitude  of deposition in
 various regions depends heavily upon  minute ventilation, there  is,  in general,
 a gradual decline in  thoracic  deposition for large particle  sizes, and there
 can be significant deposition of particles  greater than 10 urn D  ,  particularly
                                                                36
 for individuals who habitually breathe through  their mouth.    Thus,  the  deposi-
 tion experiments wherein  subjects  inhale  through a mouthpiece are relevant  to
 examining the  potential  of particles to penetrate to the lower respiratory
.tract and pose a potentially increased risk.   Increased risk may be  due to
 increased localized dose or to the  exceedingly long half-times for clearance of
 larger particles (Gerrity  et al.,  1983).
      Although  experimental data are  not  currently available for deposition  of
 particles in the lungs  of children,  some trends are  evident from  the  modeling
                                      2-18

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results of  Phalen et  al.  (1985).   Phalen and  co-workers  made morphometric
measurements  in  replica lung casts of  people  aged 11 days to  21 years  and
modeled deposition during  inspiration  as a function of  activity level.  They
found that, in general,  increasing age is associated with decreasing particu-
late deposition efficiency.   However,  very high flow rates and large particu-
late sizes  do not exhibit consistent age-dependent differences.  Since minute
ventilation at a  given state of activity is approximately linearly related to
body mass,  children  receive  a higher TB  dose  of  particles than do  adults  and
would appear  to  be at a greater risk,  other factors (i.e., mucociliary clear-
ance, particulate losses in the head, tissue sensitivity, etc.) being equal.
                                     2-19

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     CHAPTER 3.   EPIDEMIOLOGICAL STUDIES OF  HEALTH  EFFECTS  ASSOCIATED WITH
               EXPOSURE TO AIRBORNE PARTICLES AND SULFUR OXIDES
     Extensive published information exists  concerning  health effects associ-
ated with exposure  to  airborne particulate matter and sulfur  oxides.   Detailed
evaluations of this  extensive  literature (including discussions of potential
mechanisms of  toxicity and findings emerging from  animal  toxicology  experi-
ments, controlled  human exposure  studies,  and epidemiological studies)  are
provided  in  the 1982  EPA  criteria document  (U.S.  EPA, 1982a), as well  as
several other critical reviews of the subject (WHO,  1979; Holland et al., 1979;
Lippmann et  al.,  1980; Lippmann and Schlesinger, 1984).   Key health  effects
findings emerging  from the earlier criteria review (U.S. EPA, 1982a)  are sum-
marized below, providing  a perspective against which more  recently published
studies are then highlighted and evaluated.
3.1.  HUMAN HEALTH EFFECTS DUE TO SHORT-TERM EXPOSURES TO PARTICLES AND
      SULFUR OXIDES
     As  reviewed  by  U.S.  EPA (1982a), much  information  has been generated by
experimental animal  studies  and controlled human exposure studies in regard to
health  effects associated with  short-term  (<24  hr.) exposures to airborne
particles  and  sulfur oxides.  However, the  most  crucial  information  gained in
regard  to  effects on human  health  of exposure to realistic concentrations of
airborne particles  has come from epidemiological  studies.   Complicating such
studies  is the frequent co-occurrence of  elevated levels  of sulfur  oxides  along
with  airborne  particles.   Attention  is directed here mainly to epidemiological
studies  concerning  the health effects of exposure to particulate  matter  and
sulfur  oxides  that yield information relevant to the development of  exposure-
effect  and exposure-response relationships.
                                       3-1

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3.1.1.  Mortality Effects of Short-Term Exposures
     As discussed  in U.S. EPA  (1982a),  the  most clearly defined effects on
mortality arising from  exposure to sulfur oxides and  particulate matter have
been sudden increases in the number of deaths occurring, on a day-to-day basis,
during episodes  of  high pollution.  The most notable of these occurred in  the
Heuse Valley  in  1930,  in Donora in 1948  and in London in 1952.  Additional
episodes with  notable  increases in mortality occurred  in  London  during  various
winters from  1948 to 1962.   Besides evaluating  mortality  associated with major
episodes, epidemiology  studies  also focused  on  more  moderate  day-to-day varia-
tions in mortality within large cities in relation to PM and SO  pollution.
                                                               f\
     The large body of literature concerning such studies carried out  in the
United Kingdom, elsewhere in Europe, the United States and Japan was  critically
reviewed in detail  by U.S.  EPA (1982a).  As discussed there,  various  method-
ological problems with  most  of the studies  precluded  drawing of quantitative
conclusions regarding  exposure-effect or exposure-response  relationships  of
importance for deriving air  quality standards.  Among  the  main problems were
inadequate measurement  or control  for potentially confounding variables  and
inadequate quantisation of exposure to airborne particles, $62 or other associ-
ated pollutants (e.g., sulfates).  <•
     Despite  such problems,  U.S.  EPA  (1982a) concluded that the  then available
studies collectively indicated that mortality  was clearly and substantially
                                                                         o
increased when airborne particle 24-hr concentrations exceeded 1000 ug/m  (as
measured by the  BS  method) in  conjunction with elevations of SO, levels  in
                     o                                            £-
excess  of  1000 pg/m  (with  the elderly or others with  severe  preexisting
cardiovascular or respiratory  disease mainly being affected).  As for evalua-
tion of risks of mortality at lower exposure levels,  U.S.  EPA (1982a) concluded
that studies conducted in London by Martin and Bradley (1960) and Martin (1964)
yielded useful,  credible bases  by which to derive  conclusions  concerning
quantitative exposure-effect relationships.   Table 1 summarizes key conclusions
drawn from these and other critical studies  of  mortality  and  morbidity effects
associated with  short-term  (24-hr) exposures to particulate  matter and S02, as
stated earlier in the 1982 EPA criteria document (U.S. EPA 1982a).
     The studies by Martin and Bradley  (1960)  and Martin (1964) dealt with a
relatively small  body  of data on  relationships  between  daily mortality in
Greater, London and  daily variations in  pollution  (smoke  and sulfur dioxide)
during  the winter of 1958-59.   Aerometric data from multiple sampling sites
                                      3-2

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used in their  analysis  can be considered reasonably representative of outdoor
concentrations in  the areas  where  people lived, although the  inclusion  of
outer, less-densely populated  areas  meant that average exposure may have  been
underestimated.  During  the winter  of  1958-59', Martin  and  Bradley  (1960)
reported that  mortality increased on  some days when smoke concentrations
increased by more  than  100 ug/m  over the previous day or when S02 concentra-
tions increased by 70 ug/m3 (0.025 ppm).   Increases in daily mortality were up
to about 1.2 times expected values assessed from 15-day moving averages.   Thick
fog  (visibility less  than  200 meters) was also  associated with increases in
mortality.   The  relative  importance of  the  three  factors (smoke,  S02, fog)
could not be  clearly  determined, but on  the  basis  of other work,  the authors
considered  that  smoke was  probably  most important.  When results  were con-
sidered on  an  absolute  basis (Lawther, 1963), it was concluded that increases
in mortality became evident when the 24-hr mean concentrations of smoke and
                                  3              3
sulfur dioxide exceeded 750  ug/m  and 710 ug/m  (^0.25  ppm),  respectively.
Studies on  day-to-day variations  in mortality in  London were  continued  if»
successive  winters and  coupled with the  records of emergency  hospital admis-
sions.  Martin (1964) showed correlations between  both the daily mortality  and
hospital admission data and  concentrations  of smoke  or  S02-   There was  no
clearly defined  level (threshold) above which effects  were seen,  but fairly
consistent  increases  in  both mortality and hospital  admissions occurred  when
concentrations of  smoke  and sulfur dioxide each exceeded a 24-hr mean of  about
500  ug/m .  Based  on  the  above  analyses  and  a reanalysis of the  Martin  and
Bradley data  set  by Ware  et al.  (1981), U.S. EPA (1982a) concluded that small
increases  in  mortality among  the elderly and chronically ill  may have  been
associated  with BS and S02 levels in the range of 500  to  1000 ug/m  .  Much less
certainty was  attached to  suggestions of possible slight  increases  in mortality
at  still  lower BS or S02 concentrations,  based on the  Ware et al.  (1981)
reanalyses.
      In subsequent years,  because of reductions in London  BS  levels brought
about  by  implementation of the British Clean Air  Act and  more gradual  S02
reductions, only  few  occasions occurred when smoke or S09  levels exceeded 500
     3
ug/m .   Analyses   of  daily mortality in London in  relation to  variations in
smoke  and  S02 levels  during  winters  from 1958-59  to 1971-72  were reported by
Mazumdar et al.  (1981).    These  analyses  are  of  special value in attempting to
define  lowest  levels  of exposure to  particulate matter and/or S02 associated
                                       3-3

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 with increased mortality, because they  include  winters when levels of  those
 pollutants never exceeded 500 ug/m .  The results obtained for airborne parti-
 cles (measured in terms of BS) were analyzed in relation to linear and quadra-
 tic models,  which Mazumdar et al.  (1981)  found to provide good  fits to the  data
 examined after relevant potentially confounding variables,  e.g., temperature
 and humidity,  were taken  into account  statistically.   U.S.  EPA  (1982a) con-
 cluded  that both of the models  suggest small increases in mortality at smoke
 levels  below 500  ug/m3  and, possibly, to  as  low  as 150-250 ug/m3.
      In a publication newly  available  since completion of U.S.  EPA (1982a),
 Mazumdar et al.   (1982) reported further  on  three types of analyses of London
 mortality during the 1958-59  to 1971-72  winters:   (1) year-by-year multiple
 regressions, (2)  stratification  using nested quartiles of one pollutant within
 another,  and (3)  multiple  regression of a subset of high-pollution days.  Steps
 were taken in  each analysis  to  control  for  potentially confounding factors.
 Mortality and  pollution variables were first divided  by their winter  means
 (indexed  or percent) to adjust  for  year-to-year variation.   Seasonal  trends
 were adjusted  for by treating each  variable as a deviation  (residual)  from
 15-day  moving  averages; these  residuals were then corrected for weather factors
 by  regressing  separately indexed mortality,  S02  and smoke residuals in tempera-
 ture and  humidity residuals of the same day, previous  day and lag days  up  to 1
 wk;  and dummy  variables were  used to remove day-of-week effects.  The corrected
 indexed pollution variables were then reconverted to absolute units by multiply-
 ing  each  value by the corresponding  winter mean, but the mortality values  were
 left in indexed form.
     Mazumdar  et  al.  (1982) reported that the year-by-year multiple regressions
yielded generally much smaller coefficients for S00 (14 winter x = 1.17 percent
                       3                          -
 mortality  increase/mg/m  S02;  p  >0.10)  versus those for  smoke  (14 winter  x =
 25.09 percent/mg/m3  smoke;  p  <0.01).  Also,  the  nested quartile analyses using
 16 cells  (i.e., 4 quartiles of smoke within 4 quartiles of S02 and vice versa),
were  reported  as  only partially successful,  in  that  substantial covariation
 remained  between  the two  pollutants  in  the  highest  and lowest  quartiles.
Visual  inspection  of  other cells,  the authors noted,  nevertheless suggested a
much  larger  smoke than  S02 effect.   Last, multiple regression analyses,  using
the  100 days  during  the  14 winters when the two pollutants were in their
highest deciles (excluding  5  days  during the 1962 episode), were reported  as
showing that mortality  increases monotonically with smoke for fixed S02  levels
                                      3-5

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 but mortality only increased with  S02 levels above 0.7 mg/m3 for fixed smoke
 levels.   The  authors  concluded that  their analyses of  London  data for 14
 winters  support  the  conclusion that  mortality was significantly positively
 associated with  air  pollution, but  the  mortality/pollution association was
 almost entirely due to smoke.   They also  noted  possible contributions of S0? at
 sufficiently high  pollutant  levels (i.e.,  both S02 and smoke >0.7 mg/m3).  *
 Results  from linear and quadratic models of mortality regressed on smoke alone
 led the  authors to state a preference  for the quadratic model supplemented by a
 hypothesis  that at low smoke levels  (<0.3  mg/m ),  smoke  serves as a surrogate
 for an  unidentified  variable  (e.g., a highly  toxic fraction  of particulate
 emissions).
      More  recently, Ostro  (1984) reported that  new  analyses  of the same 1958-59
 to  1971-72 London winter  data  indicate some risk of mortality even at smoke
 levels below 150 ug/m .   Specifically, Ostro (1984) employed a variation of a
 standard multiple regression model  to test whether the  data supported the
 existence of a  "threshold" at BS =  150 ug/m3.   Observations  across the range of
 pollutant  levels were divided into two segments,  those  falling  below versus
 those above 150  ug/m  .  Regression analyses for data below 150  ug/m3,  con-
 trolling for important potentially confounding factors  (e.g.,  temperature,
 humidity,  etc.), indicated a  statistically significant  pollutant effect  on
 mortality below the BS =  150 ug/m3 level.   For 11 of 14  winters, the  coeffi-
 cients for  mortality  associations  with BS values below 150 were statistically
 different from  zero at p  <0.10.  Additional analyses focused on  the  last seven
winters, starting in  1965-66,  during which there were  no BS values  above  500
    o
ug/m  .   The  mortality coefficients  were  significant at p <0.05  for  six  years
and at the  0.01 level  in  four of the years.   Ostro (1984) concluded  that these
results  are  suggestive of  a strong association of  BS with mortality,  holding
temperature and humidity constant,  at levels below 150 ug/m3.
     The Mazumdar et  al.  (1982) and Ostro  (1984)  analyses produced  generally
analogous results  in  relation  to reported findings  on  PM effects:   (1) each
found  significant positive associations  between- increased mortality and  BS
levels for most of the 14  London winters from 1958-59 to 1970-71, when the data
were  analyzed  on a year-by-year basis;  (2)  the coefficients obtained  for
mortality associations with lower  BS values were generally larger than values
obtained with higher  BS levels,  a counterintuitive result; and (3) no clearly
defined  threshold  for  BS-mortality  associations could be  identified based on
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 either  set  of  analyses, both of which showed small but significant, associations
                        O
 at levels below  500 ug/m  BS.*
      No readily  obvious reasons stand out as explaining the reported stronger
 correlations  between  lower BS values and mortality  than associations seen at
 higher  BS  levels,  although both  Mazumdar  et al.  (1982)  and Ostro  (1984)
 tendered some possibilities  (for  example,  the low  levels of  smoke  in later
 years may  have contained  higher  proportions of respirable particles or  specific
 toxic materials).  Still  other questions can be raised in regard to  these
 analyses;  for example:   (1) whether or not the effects of smoke and S02 can be
 credibly separated out,  given the very  high correlation (generally  >0.80  or
 0.90) between BS and S02 levels  in the  subject data  set;  (2) whether  unmeasured
 variables,  such  as indoor  air  pollution levels,  might have  also covaried with
 outdoor BS and  S02  concentrations and  contributed to observed  mortality
 effects; or  (3)  whether  other  uhevaluated longer-term changes  in demographic
 characteristics  of  the London population (age,  socioeconomic levels,  ethnic
 mix, etc.) over the  14 winters might not be such as to contribute to spurious
 apparent associations between mortality increases and BS or S02.  Also, Roth et
; al.  (1986) present findings suggesting that use of deviations of mortality from
 15-day  moving averages  may hide the true relationship  between pollution and
 mortality.   None of  these issues can be definitively  resolved at this time,
 although it seems unlikely that long-term demographic shifts during the 14 year
 study  period could account for significant year-by-year associations; nor is
 it likely that  indoor air exposures would  be consistent from  year  to year,
 given  variations in yearly climatic conditions  coupled with gradual  changes in
 heating practices (shifts away from open hearth burning of coal in residences)
 that occurred during the 14 year  study period.
  *Note:   An  unpublished  analysis of  the 1958-71  London  winter data, set by
   Shumway et al.  (1983)  also  produced results indicative  of risk below the  500
   ug/m3  level of smoke.   These analyses used a general  multiple regression model
   and detrending  of  data to  correct for  temperature and autocorrelation
   effects.   The best model for predicting cardiovascular,  respiratory or overall
   mortality used lagged temperature and logs of same day levels of S02 or smoKe.
   Results  were reported  to  indicate  that  pollution  acts, positively  and
   instantaneously,  whereas  temperature  acts  negatively,  with  the  strongest
   component a lag of two days.   Also, the strongest associations, as measured by
   multiple coherence, occur at periods of 7-21 days, implying that pollution and
   temperature episodes must persist in order to influence mortality.
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     Regardless of the  above  considerations,  the following conclusions  appear
warranted based on the  earlier criteria review  (U.S. EPA, 1982a) and present
evaluation of newly available analyses of the London mortality experience:   (1)
markedly increased mortality occurred, mainly among the  elderly and chronically
ill, in association with BS and S02 concentrations above 1000 ug/m , especially
during episodes when such pollutant elevations occurred  for several  consecutive
days; (2) the  relative  contributions of BS and  S02 cannot be clearly distin-
guished  from those of  each other,  nor can the  effects of other  factors  be
clearly delineated,  although  it appears likely  that coincident high humidity
(fog) was also important (possibly in providing conditions leading to formation
of  HoSO/,  or other acidic aerosols);  (3) increased risk  of mortality is  associ-
    £  T"                                                                   ^
ated with exposure  to BS and  S09  levels  in the range of  500 to  1000 ug/m ,
                                                        O
clearly at  concentrations  in excess of ^700 to 750 ug/m ;  and (4)  less  certain
evidence  suggests possible slight increases  in  the risk of  mortality  at  BS
levels below 500 ug/m3,  with no specific  threshold levels  having  yet  been
demonstrated or  ruled out at  lower  concentrations  of BS  (e.g., at  150  ug/m )
nor potential  contribution of other plausibly confounding variables having yet
been fully  evaluated.
     In  another  study of air  pollution relationships with mortality reported
since  the earlier criteria  review  (U.S.  EPA,  1982a),  Mazumdar and Sussman
(1983) evaluated  associations between mortality events and  daily particulate
matter and  S02 levels  in  Pittsburgh,  PA.   The analysis, limited to investiga-
tion of same-day  events, reported a  possible  relationship between heart disease
mortality/morbidity  and same  day particulate  levels  (measured in terms  of  COH),
but not same-day  S02 levels.   The analyses  specifically evaluated daily mortal-
ity rates during  1972-1977 for all of Allegheny  County, PA in relation  to  daily
average  COH and  S02 measurements obtained at each of  three  air monitoring
stations:   one at the  center of the County within a high  pollution section of
Pittsburgh; another  situated relatively near  the first  in  a somewhat less
polluted area; and  a third  in a distinctly cleaner area  on  the northeast  edge
of the County.   Corrections  for trend and  seasonal factors were made by use of
daily  deviations  from 15-day moving averages  for air pollution, temperature and
mortality variables.   Multiple regression  analyses revealed no statistically
 significant associations  between  mortality  for all  ages or heart disease
mortality  in  relation  to  either  S02 or COH  when  regressed  on each variable
 alone.   When S02 and COH were considered jointly,  only  the associations between
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 total  or heart disease mortality  and  COH measurements at the Hazelwood (high
 pollution area) station were significant  at  p <0.05.  These  results,  however,
 cannot be accepted as providing meaningful information on mortality-air pollu-
 tion associations in the Pittsburgh area  in view of: (1) inadequate character-
 ization of county-wide air pollution levels against which to compare mortality
 rates  for the  entirety of  Allegheny County,  the  S02 and  COH  levels  at each  of
 the three monitoring stations used  not being highly correlated (mostly r < 0.4
 to 0.5) with values  at  the  other stations; (2)  internal  inconsistencies whereby
 larger coefficients  were  obtained for  associations  of mortality to COH readings
 at the cleaner air  station on  the edge of the County than the intermediate
 pollution station near the  center of  the County; and (3)  the  use of a large
 number of separate mortality regression  analyses,  from among which  only  two
 were significant at  p <0.05.
      In addition to  the  above  reanalyses of  London mortality data,  reanalyses
 of mortality data from New York City in  relation  to air pollution  have  been
 recently reported by Ozkaynak and Spengler (1985).   These investigators carried
 out time-series analyses on a subset of  New  York City data included  in a prior
 analysis by Schimmel (1978) which was critiqued during  the  earlier criteria
 review  (U.S.  EPA,  1982a).   The  present  reanalyses  by Ozkaynak and  Spengler
 (1985) evaluated 14 years (1963-76) of daily  measurements of  mortality (the  sum
 of heart, other  circulatory, respiratory, and cancer mortality), COH,  S02,  and
 temperature.  Prior to regression analysis, efforts were made to  remove assumed
 low-frequency  confounding  by  "filtering"  each variable  to remove  its slow-
 moving components.   This included not only use of  residuals  from 15-day moving
 averages, but  also   evaluation  of sensitivity of results  to other  filters.
 Initial  exploratory  analyses estimated regression  coefficients for  COH and  S02
 after all variables were preprocessed with one of several filters (e.g.,  taking
 residuals from 7-,   15-, or 21-day moving averages and other filters that
 removed  all  cycles  in  the  data that fell beyond indicated periods measured in
 days).   Overall,  the regression coefficients for COH ranged from  1.2 to 5.4
 daily  deaths  per unit of COH, most being statistically significant (p <0.05).
.Also,  a reasonable  range of variation in temperature specifications produced
 coefficients  ranging from  1.3  to 1.8 deaths per COH unit.  The risk  coeffi-
 cients  of Schimmel  (1978)  were  near the  lower  end of the range of  coefficients
 found  by Ozkynak and Spengler (1985).  The latter investigators noted  then that
 they were able to generate a fairly consistent set  of estimates by performing a
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number of sensitivity  analyses.   They also correctly note that these initial
estimates were subject to several technical limitations:   (1) misc]assification
of population  exposure can  occur in using  aerometric  data from one fixed
monitoring site;  (2)  the  exposure index,  COH,  is  imperfectly related to respi-
rable particle mass  levels;  and (3) the range of exploratory models initially
fit may  not  have been diverse enough.  Consequently, an additional  reanalysis
was undertaken.
     Specifically, more recent reanalysis of the New York City data reported by
Ozkaynak and Spengler (1985) used standard time-series methods to control for
covariates such  as  temperature and to handle  the problem of autocorrelation.
Their previous analysis  was  also extended by adding records of visibility and
weather  from three  New York City airports, in order to  examine spatial  homoge-
neity  of daily  air  pollution in New York City and to use  visibility  as f
surrogate for  aerosol  extinction (bext) or  for fine particle (FP)  pollution
as  discussed by  Ozkaynak et  al.  (1985).   The most salient  feature of the
mortality data found by this  reanalysis was a  strong seasonal component which
confounds  direct regressions  involving mortality,  air  pollution and weather
variables.  A  simple trigonometric expression was used that  removed the tempera-
ture  cyclic component  and rendered  nonseasonal  temperature nonsignificant.
Another  stationary autoregressive term was  also used to exhaust the time-series
structure of the mortality  records.  Consideration of  lagged regressions and
interactions  did not  improve the model's  predictive ability.  Time-series
analyses were  then performed  with a  linear model and in  a rnultivariate manner
in  which corrections for  seasonality and autocorrelation were introduced into
the  linear model.  Preliminary estimates of excess  deaths (e.) or elasticities
for  the  pollutant variables  were thereby  calculated, resulting in the following
findings:   (1) the time-series  analysis  showed S02 levels  to be significantly
correlated  with  mortality (e$02 =  2.3  percent);  (2)  COH also contributed
significantly  to excess  deaths  (eCQH =2.4 percent); (3) Bfixt, a variable used
as  a surrogate  for  FP pollution was also  a significant  contributor to excess
daily deaths  (~1.2 percent);  and (4) the total estimated excess deaths attri-
butable to air pollution was -6.0 percent.  The authors concluded that  although
these are interim results (they are  also  analyzing the data one year at  a time
 and by each quarter), these findings: (1) indicate that during the  study period
 ambient air pollution  of a  large urban area was  contributing to mortality,  (2)
 appear to corroborate  results from cross-sectional mortality studies,  and (3)
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Indicate that particulate air  pollution,  even at current levels, could be of
concern for public health.   However, the  authors again correctly noted limita-
tions  of  their analyses which preclude full reliance on these  preliminary
results for  risk assessment purposes:   (1) the  results  reflect aggregate
analyses of 14 years of data and more thorough analyses need to be done to take
into account  changing  S02 and  aerosol  composition  over the  period  (preliminary
analyses indicate no differences in pollutant coefficients for 1963 to 1970 and
1971 to 1976); (2) the results are based on aerometric data from one monitoring
station and visibility data from one airport (JFK); and (3) the effects of heat
waves  and  influenza  epidemics  during the study period have  not been considered
in any detail  in these preliminary analyses.
     Hatzakis  et al. (1986)  recently published a study of short-term effects of
air pollution  on mortality in  Athens, Greece, during 1975-82.  Daily concentra-
tions  of  S02 (acidimetric method) and smoke (standard British Method) measured
by  a five-station network in  Athens were evaluated in relation to mortality
data  abstracted from the Joint  Registries  of Athens and 18  other  contiguous
towns  in  the Greater Athens area.   The authors reported that adjusted daily
mortality (estimated by  subtracting the observed mortality value  from  an
 "expected"  value,  calculated  after fitting a sinusoidal  curve to the empirical
mortality data) was significantly and  positively  related to S02 levels .(b =
 +0.0058,  p = 0.05), but not  to  smoke  levels.   Separate multiple regression
 analyses  were done for S02  and smoke,  controlling  in each case for temperature,
 relative  humidity, secular,  seasonal,  monthly and weekly variations in mortality
 as well as  interactions of  the above variables with season.  Evaluation  of a
 possible threshold for the  S02-mortality effect was carried out by successively
 deleting from the regression  model  days with the  highest  S02 values.  These
 analyses resulted in the authors suggesting that, if there is an S02 threshold,
 it must lie slightly below 150 ug/m3 (mean daily value).
       The  latter result, as  stated  by  the authors, is not  consistent with
 results of  other  studies  in which S02  mortality  thresholds have been placed
 around the value of 300 ug/m3 (or, more credibly, around 500 M9/m  , as per U.S.
 EPA,  1982a):   Nor  is  the   failure to  find significant  associations between
 mortality  and  smoke  consistent with  other more  usual  published findings
 (although  differences in chemical  composition of  PM in  Athens and lack  of
 calibration  of smoke readings against  gravimetric  measurements make  it diffi-
 cult  to  compare smoke levels  from  Athens  versus  elsewhere).  Other questions
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 also arise which make it difficult to  fully  accept  the  reported  findings, e.g.:
 (1) how representative are the aerometric  data for  the  entire Athens metropoli-
 tan area from which the mortality data were  abstracted,  although the typography
 of the  area,  with Athens and  adjoining towns situated in a coastal  "bowl"
 surrounded by mountains,  and  high correlations (mostly r >0.50-0.60) between
 pollutant readings from  the  five network  stations  suggest thait  the aerometric
 data may  well  be  quite  representative;  (2)  whether  use of deviations  of
 observed mortality data  for  1975-82  from  expected  values derived from 1956-58
 mortality data as  a  pre-high  pollution baseline period  is statistically  sound;
 and  (3)  whether separate  regression  analyses for  S02 and smoke alone  are
 sufficient versus analyses with both these pollutants  included.
      In summary, the  above newly available reanalyses of New York  City data
 raise possibilities  that, with additional work, further  insights may emerge
 regarding mortality-air  pollution relationships in a  large U.S.  urban area.
 However, the  interim results  reported thus far do  not now permit'definitive
 determination of their usefulness for defining exposure-effect  relationships,
 given the  above-noted types  of caveats and  limitations.   Similarly,  it is
 presently difficult  to accept the findings of mortality associated  with rela-
 tively  low levels of  S02 pollution  in Athens, given questions  stated  above
 regarding representativeness  of the  monitoring data and the statistical  sound-
 ness of using deviations of mortality from  an  earlier baseline relatively
 distant  in  time.   Lastly, the newly reported analyses of mortality-air pollu-
 tion relationships in Pittsburgh  (Allegheny  County,  PA) utilized inadequate
 exposure characterization and the results contain  sufficient internal  incon-
 sistencies,  so  that  the analyses are not  useful  for delineating mortality
 relationships with either S02 or PM.

 3.1.2.  Morbidity  Effects of  Short-Term Exposures
      As  noted by WHO  (1979),  epidemiological  studies can be useful in assessing
 morbidity  effects  associated with air pollution in different communities or in
 areas where changes  in air pollution  occurred over  time.  In such studies, where
. respiratory diseases  are followed, it is  necessary  to  control for age distribu-
 tion,  socioeconomic  status,  and other possibly confounding  factors.   It  is also
 crucial  that  adequate characterization  of exposure  to  air pollutants of
 interest be carried out, if quantitative conclusions are to be  drawn regarding
 exposure-effect or  dose-response relationships.   However,  very few of the
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available epidemiological studies on  morbidity  effects associated with short-
term exposure to airborne particles  allow for such conclusions,  as evaluated by
U.S. EPA (1982a).
     Those reported  by Lawther  for  London populations  (see  Table 1) were
identified by U.S.  EPA (1982a)  as providing  credible bases for  drawing quanti-
tative-type  conclusions about  morbidity effects  associated  with airborne
particles (measured  as  smoke)  and  elevated S02 levels.  Lawther et al. (1970)
reported on  studies  carried out from 1954 to 1968 mainly in  London,  using a
diary technique for  sel^assessment  of day-to-day changes in  conditions among
bronchitic patients.   A daily  illness score  was calculated from the diary  data
and related  to  BS and $Q2  levels and weather  variables.   Pollution data for
most of the London studies were mean values from the group of  sites used in the
mortality/morbidity  studies of Martin  (1964);  those  aerometric measurements
likely provide  reasonable  estimates  of average exposure  in areas where  study
subjects lived or worked.   In early years of the studies, when pollution levels
were generally high, well defined peaks in illness score were  seen when concen-
trations of  either BS or S02 exceeded  1000  ug/m3.   With later reductions in
pollution, the  changes in condition became less frequent and  of smaller size.
From the  series  of studies as  a whole,  up to  1968,  it was concluded  that  the
minimum pollution  levels  associated  with significant changes  in the condition
of  the  patients  was a 24-hr mean BS  level  of -250 ug/m3  together with a 24-hr
mean S02  concentration of -500 ug/m3  (0.18  ppm).   A later study reported by
Waller (1971) showed that,  with much  reduced average levels of pollution, there
was an  almost complete disappearance of days with smoke levels exceeding 250
ug/m3 and  S02 levels over  500 ug/m3  (0.18 ppm).  As earlier,  some correlation
remained between changes in the conditions of the patients and daily concentra-
tions of  smoke  and S02, but the changes were small at these levels and it was
difficult  to discriminate  between  pollution effects  and those  of  adverse
weather.   Thus,  as concluded by U.S. EPA (1982a), the observed effects (wors-
ening of health status  among chronic  bronchitic patients) were  clearly associated
with BS  levels  of 250  to 500 ug/m3 and, possibly, somewhat lower  levels (<250
ug/m3) for highly  sensitive bronchitic patients.*
 *Note:   Roth et al. (1986)  have  recently raised questions regarding how well
  the  health indicator  values  used in the  Lawther  morbidity  studies reflect
  actual  health status and  suggest that  associations between temperature and
  health  may be understated  in  this data  set.

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     Since preparation of  U.S.  EPA (1982a) evaluations summarized in  Table  1,
additional studies have  appeared  concerning morbidity associated with short-
term exposure  to airborne  particles  and/or sulfur oxides.  Dockery  et  al.
(1982), fpr example,  reported on pulmonary function evaluations carried out  for
school children  in Steubenville,  OH as part of  the Harvard Six-Cities Study.
Pulmonary  function was evaluated immediately before  and  after air pollution
episodes  in 1978,  1979 and 1980, by relating spirometric measurements (appro-
priately  corrected  for height, etc.)  to  aerometric  data (e.g., TSP  and S02
levels) obtained from  state air pollution monitors.   Data for each individual
child were evaluated.   Linear decreases in forced vital  capacity (FVC)  with
increasing TSP concentrations were found, and slopes were determined for linear
relationships  fitting  the  data for four different observation periods (fall,
1978; fall, 1979;  spring,  1980; fall,  1980).  The  slope of FVC vs.  TSP was
calculated for 335  children with three or more observations during any of the
four study periods.   Of the 335 children examined,  194 were tested during more
than one  study period.  On average, estimated FVC was approximately 2 percent
lower  following each  alert,  whereas  forced  expiratory volume  in  0.75  sec
(FEVQ ?5) did  not change during the 1978  study but was decreased by 4 percent
during  the 1979 alert.  In the  spring of 1980,  similar declines were seen  in
FVC  and  FEVQ 75 values  as  were  found following the  previous  alerts,  but  no
significant  declines  were  seen  in  fall,  1980,  when  pollutant levels were
distinctly lower than for previous alerts (e.g., TSP  levels did not exceed 160
ug/m3  in  fall,  1980).  The largest declines in lung function were observed one
to two  weeks after the episodes.   Fifty-nine percent  of the children  had slopes
less  than zero  (i.e., decreasing  FVC  with increasing TSP).  The median slope
was  -0.081 mL/Mg/m3,  which is significantly less than  zero  (p <0.001)  by  a
Wilcoxan  Signed Rank  test.   The  median FVC vs.  S02  slope was  -0.057  mL/ug/m  ,
also  significantly (p <0.01)  less  than zero,  but the  relationship with mean
daily temperature was not significantly  less  than  zero.  Similar analyses
performed with  FEVQ ?5  also  showed the relationships (slopes) for S02 and  TSP
to be significantly  less than zero.
      Overall-,  these  repeated measurements of lung function showed statistically
 significant but physiologically small  and apparently reversible declines of FVC
 and FEV0 75 levels  to be  associated with  increases  of 24-hr  mean TSP levels.
 On days  of testing  for pulmonary function effects,  the TSP levels ranged from
 11.0 to  272  pg/m3  and  S02  levels  ranged from  0.0  to 281 ug/m  .  However,
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 maximum TSP levels of 312  or  422 ug/m3 occurring in  fall, 1978, 2 to 5 days
 prior to spirometric testing  may  have  contributed to  the  observed declines in
 lung function for  some  children included in data analyses for that period.
 Similarly,  the maximum  S02 value of 455 ug/m   recorded  on  days immediately
 preceding the spirometric  testing during the  Fall,  1979 period may have
 accounted for observed declines  in lung function.  The investigators  noted that
 it was not possible  to  separate the relative contributions of the two pollu-
 tants,  nor were any  thresholds  for the observed pulmonary function decrements
 discernable within the above  broad range of TSP and S02 levels.  Nevertheless,
 these results appear to  demonstrate that small,  reversible changes in pulmonary
 function can occur as the  consequence  of increased concentrations of TSP and
 SOp somewhere in the above ranges.   Whether such pulmonary function changes
 per se are adverse or can  lead  to other, irreversible changes or make the lung
 more susceptible to  later  insults remains to be resolved,  Evaluations of such
 issues may need to take into  account an apparent subset of "responders" within
 the population of  children  studied,  who showed  greater than average declines  in^
 lung function  in  relation to TSP or  S02 levels.   For example, the lowest
 quartile of  slopes  of FVC and FEVQ 75  versus  TSP were -0.386  and  -0.306
 mL/ug/m , respectively.                                                 4-••-.
      In another series of  studies conducted during the last few years, Ostro
 and  co-workers evaluated relationships between air pollution  indices for 84
 standard metropolitan statistical areas  (SMSA's)  mostly of 100,000  to  600,000
 people in size,  and indices of acute morbidity  effects, using  data derived from
 the National Center  for Health  Statistics (NCHS) Health Interview Survey (HIS)
 of 50,000  households comprising about  120,000  people  (Ostro,  1983;  Hausman  et
 al., 1984; Ostro,  in press).   In the most recent analyses reported,  Ostro (in
 press) used  HIS  results from 1976  to  1981 together with estimates  of  fine
 particle (FP) mass.  That  is,  for adults aged  18  to  65, days  of work  loss
 (WLDs),  restricted  activity  days  (RADs)  and respiratory-related restricted
 activity days  (RRADs) measured for a  two-week  period before  the day of the
 survey were used as measures of morbidity and analyzed in relation  to estimated
.concurrent two-week  averages  of FP or lagged in relation to  estimated 2-wk  FP
 averages from 2 to  4 weeks earlier.   The FP estimates were produced from the
 empirically derived regression equations of Trijonis.   These  equations,  as  used
 here,  incorporated  screened airport data and two-week average TSP  readings  at
 population-oriented monitors,  using these data taken from the metropolitan area
 of  residence.   Various  potentially  confounding factors (such as age, race,
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education, income, existence  of  a chronic health condition, and average two-
week minimum temperature) were controlled for in the analyses.   Various morbid-
ity measures  (WLDs,  RADs,  RRADs),  for workers  only or for all adults in
general, were  consistently  found to  be  statistically significantly  (p  <0.01 or
<0.05) related  to  lagged FP estimates (for air  quality  2  to 4  weeks prior to
the health interview data period),  when analyzed for each of  the  individual
years  from  1976 to  1981.   However,  less consistent associations were  found
between the health endpoints and more concurrent FP estimates.
     The approach  employed  by Ostro to estimate PM levels introduces into his
analyses a number  of uncertainties,  e.g.,  those  inherent in airport visibility
measurements, FP/visibility relationships, and TSP monitoring limitations (most
notably,  use  of the Trijonis equations characterizing  FP relationships to
visibility in  northeastern  U.S.  areas may not be appropriate for western U.S.
cities).  On the other hand, use of this spatially averaged indicator over time
within a  specific  area reduces some of these uncertainties.  Additional uncer-
tainties  derive from use of the HIS data base, with the vast majority of data
points  being  "0",  representing no  incidences  of  indicator effects being
recalled  in  the prior two weeks.   Questions  therefore  exist  regarding the
distributions  assumed  to underlie the health endpoint results and appropriate
modeling, then, of morbidity-air pollution relationships.  The overall  patterns
of  results obtained  from the reported analyses are  also  difficult to interpret.
They  may  suggest that acute morbidity  effects  are  associated  with fine-mode
particle  exposures occurring 2-4 weeks earlier,  but less  so with  immediately
prior FP exposures.   Variations  in  findings  reported by other investigators
regarding  lag  structures in data bases  relating mortality or  morbidity to PM
exposures  are  not such  as  to  rule out  such a possibility.  In  any  case, it is
not now clear as to how the  effects reported by Ostro (1986) might be used to
estimate  quantitative relationships between morbidity effects  and  more usual
24-hr or annual average  direct  gravimetric measures of  particulate matter air
pollution (e.g., TSP,  PM1Q, etc.).
      Mazumdar  and  Sussman (1983), discussed  earlier, not only studied  relation-
ships between' mortality  and measures of PM and  SOX  pollution in Pittsburgh, PA
during 1972-77, but  also included evaluations  of morbidity (indexed by emergency
hospital  admissions)  in relationship to  daily  COH  and S02  concentrations
corrected for  temperature  and seasonal  variations.  Significant associations
were reported between same-day  COH  values (which ranged  from  near 0.0 to 3.5
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units) and total  morbidity  and heart disease morbidity  for  all  ages  (1 to 59
yr) and > 60 yr age groups,  but no consistent statistically significant associ-
ations between morbidity  categories  and  same-day  SOp  levels  (ranging  from near
0 to  0.14  ppm)  monitored at the same stations.   However, these results cannot
be taken as indicative of associations between increased morbidity and elevated
PM or  S02  levels  in the Pittsburgh area, given limitations identified earlier
in relation to  the mortality analyses from the same  study,  i.e.:   (1) inade-
quate  characterization of air  pollution  concentrations representative of the
entirety of Allegheny  County from which  the morbidity data were  drawn, and (2)
internal inconsistencies  in the  results,  with various classes  of  morbidity
variously  being  more strongly associated with  S02  or COM measured at lower
pollution stations than higher pollution stations.
     Perry et al.  (1983),  followed 24 Denver asthmatic  subjects from January
through March,  1979, using  twice daily self-obtained measurements of each
subject's peak expiratory flow rates (from Mini-Wright  Peak  Flow Meters) and
recording use of  "as-needed" aerosolized bronchodilators and reports  of airway
obstruction symptoms  characteristic  of asthma.   These measures  of  morbidity'
were tested for  relationships  to air pollutants using a random effects model.
Dichotomous, virtual impactor  samplers  at  two fixed monitoring sites provided
                             2
daily  measurements  (in  ug/m ) of inhaled  PM  (total  mass,  sulfates, and
nitrates),  for coarse  (2.5  to  15 |jm) and  fine  fractions (<2.5 urn).   CO, S0«,
03, temperature and barometric pressure were also measured.  Of the environmen-
tal variables measured,  only fine nitrates were significantly associated with
increased  symptom reports and  increased bronchodilator  usage.   During  the
course of  this  study,  however,  TSP levels were  uncharacteristically low.  This
limits interpretation of  the study in relation to  PM effects.  Use of aero-
metric data from only two monitoring stations in Denver,  with unknown distances
in relation to  places  of residence for  subjects  matched to  the  proximal sta-
tion, also limits the usefulness of the reported findings.
     Bates and  Sizto (1983, 1985) have  also  reported results of an  ongoing
correlational  study relating hospital admissions in  southern  Ontario to  air
pollution  levels.   Data  for 1974, 1976,  1977,  and  1978  were discussed in the
1983  paper.   The more  recent  1985  analyses  evaluated data  up  to  1982 and
showed:  (1)  no  relationship between respiratory  admissions  and  S02 or COHs  in
the  winter;   (2)  a  complex relationship  between  asthma admissions  and
temperature  in the winter; and  (3)  a  consistent relationship between
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 respiratory  admissions  (both asthma and nonasthma) in summer and sulfates and
 ozone,  but not to summer COH  levels.   However,  Bates and Sizto note that the
 data analyses are now complicated  by  long-term  trends in respiratory disease
 admissions unlikely  related to air  pollution, but they nevertheless  hypothesize
 that observed effects may  be  due  to a mixture of oxidant and reducing pollu-
 tants which produce intensely  irritating  gases  or  aerosols in the summer but
 not in the winter.  More  definitive interpretation of these findings may be
 limited until  additional  results  findings  are  reported  from this  long-term
 continuing study.
      Of the  newly-reported analyses of short-term PM/SOX exposure-morbidity
 relationships discussed above,  the Dockery et al.  (1982) study provides the
.best-substantiated  and  most readily  interpretable  results.   Those results,
 specifically, point toward decrements in lung function occurring in associationj
 with  acute,  short-term increases  in  PM and S02 air pollution.   The  small,
 reversible decrements appear to persist for 1-2 wks after episodic exposures to|
 these pollutants  across a wide range, with  no  clear delineation  of threshold
 yet  being evident.   In some study periods effects  may haye been due to  TSP  and
 S0?  levels  ranging up  to 422  and  455  ug/m3,  respectively.   Notably larger
 decrements  in  lung function  were discernable  for  a subset  of  children
 (responders) than for others.   The  precise medical significance of the observedj
 decrements £er  se or any consequent long-term sequalae remain to be determined.
 The nature  and magnitude  of  lung  function decrements found  by Dockery et al.
 (1982),   it  should  be  noted,  are also consistent  with:  observations  of
 Stebbings and Fogelman (1979)  of gradual recovery in lung function of childrenj
 during seven days  following  a high PM  episode  in  Pittsburgh, PA  (max 1-hr  TSP
 estimated at 700 ug/m3);  and the  report of Saric et al.  (1981)  of 5 percent
 average declines  in PE^ Q being associated with high SO,, days  (89-235  ug/m ).
  3 2  EFFECTS ASSOCIATED  WITH LONG-TERM  EXPOSURES  TO AIRBORNE PARTICLES AND
       SULFUR OXIDES
  3.2.1.  Mortality Effects of Chronic Exposures
       WHO  (1979)  notes that,  in countries having  reliable systems for the
  collection and analysis  of data on deaths, based  on cause and area of resi-
  dence, .death  rates for  respiratory diseases  have  -commonly been found to  be
  higher  in towns  than in  rural  areas.   Many  factors, such as  differences  in
  smoking  habits,  occupation,  or social conditions may  be  involved in these

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contrasts; however,  in  a number of countries, a  general  association between
death rates  from  respiratory diseases and air pollution has been apparent for
many decades.  Analyses  of these data have been  of great value  as  a lead  for
epidemiologic studies, but the absence of information concerning other relevant
variables, such  as  smoking,  and the relatively crude  nature  of indices  of
pollution used in  many  of these studies  make  them unsuitable for the quantita-
tive assessment of exposure-effect relationships.
     The 1982 U.S. EPA criteria document (1982a) noted that certain large-scale
"macroepidemiological" (or "ecologic" studies as termed by some) have attracted
attention on the basis  of reported  demonstrations  of associations between
mortality and various indices of air pollution,  e.g.,  PM or SO   levels.   For
                                                               /\
example, Lave & Seskin (1970) reanalyzed mortality data from England and Wales,
and developed multiple  regression equations in terms  of  pollution  and  socio-
economic indices.  Their findings of positive correlations between  mortality
rates and  pollution are  of general  interest  but cannot contribute  to the
development  of  dose-response  relationships  because of  inadequate  exposure
indices  used in  the  analyses.  The authors  also  examined similar data for
standard metropolitan statistical areas (SMSAs)  in  the USA,  and in  a  later
paper (Lave  and  Seskin,  1972) attempted to assess  relative effects of air
pollution, climate,  and  home heating on mortality  rates.   Although  equations
were obtained relating  death rates to measurements  of suspended particulate
matter and total  sulfates (both by high-volume sampler), it is again doubtful
whether these can be regarded as valid in the absence of more adequate informa-
tion on  smoking  and  because of inadequate characterization of exposure para-
meters.
     Other studies  reported in further publications  (Lave  and Seskin,  1977;
Chappie and  Lave,  1981)  extended their earlier analyses.  Based on such later
work, analogous  positive associations between mortality and  air pollution
variables were reported  for  the  United  States.   Many criticisms similar  to
those indicated above for the earlier Lave  and Seskin (1970) study  apply here.
Of  crucial  importance are  basic difficulties associated with all  of their
analyses in  terms  of:   (1) use of  aerometric  data without regard to quality
assurance considerations,  notably including  use of sulfate measurements known
to  be of  questionable accuracy due to artifact formation during air sampling;
and (2)  questions  regarding how representative the air pollution data used in
the analyses are  as  estimates of actual exposures  of individuals included in
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their  study groups.   In some instances, for example, data from a single moni-
toring  station were apparently used to estimate pollution exposures for study
populations  from surrounding large metropolitan areas.
     The  1982 U.S.  EPA criteria document  (1982a) noted that further difficul-
ties in discerning consistent patterns of  association between mortality and air
pollution  variables are  encountered when  results of Lave and  coworkers  are
compared  with those obtained by  others  using analogous macroepidemiological
approaches.   For  example, Mendelsohn and  Orcutt (1979) carried out regression
analyses  of associations between 1970 mortality  rates  (for  404 county groups
throughout  the United  States)  and air  pollution exposures retrospectively
estimated  on the  basis of 1970 and 1974 annual average pollutant data from air.
monitoring  sites in the  same or nearby counties. Their results suggested fairly
consistent  (though variable) associations  between mortality for some age groups
(increasingly more  positive with age)  and sulfate levels but much less consis-
tent and  sometimes  negative associations  with TSP  or other pollutants.  The
combined  TSP-SO,  pollution-health elasticity obtained by Mendelsohn and Orcutt
(1979)  is similar to that obtained in the  earlier studies by Lave and coworkers,
all falling  in the  range  of 0.1 to 0.2.
     Other  results  obtained by Thibodeau  et  al.  (1980)  in carrying out large
scale  cross-sectional  analyses  of the above  type indicate that the regression
coefficients for  mortality relationships  with air  pollution  variables are
quite  unstable.   Also, Lipfert (1980)  reported results from an analysis taking
into account a smoking index based on state tax receipts, which he interpreted
as  showing sulfates to be  least harmful  of seven air pollutants (including S02
and TSP),  although  no adjustments for urban-rural differences in study popula-
tion residences were used. This is in contrast to unpublished analyses of 1970
United  States mortality data by Crocker et al. (1979), which found no signifi-
cant relationships  between air pollution  and total  mortality when  taking  into
account retrospectively estimated nutritional variables  and  a  smoking index.
Also,  results of Gerking  and Schultz  (1981), using the same data base, indi-
cated  a significant positive relationship between-TSP and total mortality when
_using  an  OLS model  similar to  that  of Lave and Seskin (1977) but found nega-
tive,  though  significant,  air  pollution  coefficients  after adding smoking,
nutrition,   exposure-to-cold, and  medical-care variables  to a two-equation
model.
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     U.S.  EPA (1982a)  also  noted that various criticisms of the above studies
have been advanced  by  authors of the other respective studies,  but it was  not
possible to  ascertain  which  findings  may be more valid  than others.  Thus,
although many  of the  studies qualitatively suggested positive  associations
between mortality and  chronic exposure to certain  air pollutants in the United
States, many key  issues  remained unresolved concerning reported associations
and whether they  are causal  or not.   Since preparation of the earlier Criteria
Document (U.S.  EPA, 1982a)  additional  ecological analyses  have  been  reported
regarding efforts  to   assess  relationships between mortality and long-term
exposure to particulate matter and other air pollutants.
     Lipfert (1984) conducted a series of cross-sectional multiple regression
analyses of 1969  and 1970 mortality rates for up to 112  U.S. SMSA's,  using the
same basic data set as Lave and Seskin (1978) for  1969 and taking into account
various demographic, environmental and lifestyle variables (e.g., socioeconomic
status and smoking).   Also  included in the Lipfert (1984) reanalysis were the
following additional  independent variables:  diet; drinking water  variables;
use of  residential  heating  fuels; migration; and  SMSA growth.   New dependent
variables included  age-specific mortality rates with  their  accompanying  sex-
specific age variables.   Both linear and several nonlinear (e.g., quadratic or
linear  splines testing  for  possible  threshold model specifications)  were
evaluated.  Efforts to replicate the  basic analyses  of Lave and  Seskin (1978)
and to  improve upon the fit of models using various  specifications led Lipfert
(1984)  to conclude  that:   (1)  differences  existed between high  and low pollu-
tion SMSAs unrelated to the magnitude  of  the  air pollution variables,  i.e. that
there  appear to  be important variables missing from the specification;  (2)
correction of  errors  in the  Lave-Seskin  data improved the regression fit and
significance  of some  of  the  coefficients;  but (3)   it was  not possible  to
conclude whether  S04  or TSP  has  a  statistically significant effect  on total
mortality or whether either  response is  linear.
     Lipfert  (1984) then introduced additional  variables of the type  listed
above  into  the  reanalysis  in  hopes  of  improving the specification  and  to
evaluate  possible collinearity with the  pollution variables.   The fact that
some observations were incomplete for some of the newly added variables neces-
sitated  the  analysis  of certain  subsets  of the original  Lave-Seskin  data  set.
Overall,  for these reanalyses,  in  which  regressions  were extended to include
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new variables in stepwise fashion (but retaining the 7 Lave-Seskin variables as
the first  step  in  each case), adding new variables significantly improved the
fit, but several of the original Lave-Seskin variables (including S04) became
non-significant as  the result of the additional variables.   Further analyses
included regressions  for mortality  restricted to  central city  areas  versus
SMSA-based regressions,  with  agreement  between coefficients  for  sulfates  being
quite poor (and negative for central city regressions broken down by age groups
<65  or  >65 yr).  Many  of the additional  explanatory variables  in the  above
reanalyses  (both  for  central  city and SMSA regressions) were  found  to  be
statistically  significant  and were then employed  in regressions using total
mortality  rates adjusted for age, nonwhite  population, poverty  and cigarette
smoking.   Results  obtained with use  of additional  explanatory variables and
varying model  specifications  were very mixed:   (1)  sulfate  coefficients were
quite unstable, ranging from near 0.0 to  0.049 (highly significant and corres-
ponding to an elasticity of  6  percent);  (2) TSP coefficients were similarly
variable,  with  similar maximum elasticity; (3) in  no case were TSP and sulfate
variables  significant in the same  regression; and (4) when the  full  set of
explanatory  variables  were  used with  the dummy pollution  variables, the coeffi-
cients  for the pollution variables  became  more significant.   Lipfert (1984),
based on  these total  mortality analyses,  concluded  that:  (1) the  Lave-Seskin
specification is  inadequate and provides  misleading results;  (2) using addi-
tional  explanatory variables improves the fit; (3) the existence of thresholds
for the air pollution  variables  can neither  be  proved  nor disproved; (4)
although  difficult to  separate S04  effects from TSP effects, the TSP coeffi-
cients  displayed  slightly more consistent  behavior across all the data  sets
considered;  and (5) effects for drinking water, ozone,  and (to a lesser extent)
coal  and wood heat warrant further investigation.
      Results obtained  by  Lipfert (1984)  with further age- and  sex-specific
 regression  analyses  for <65 yr old subjects, using all  other  variables  as
 defined in  the above  total  mortality regressions, produced similar results as
 for the total mortality analyses.   That is, as explanatory variables are added,
 the pollution variables tend to lose significance  and the  r  values  are con-
 siderably higher  than those of Lave and Seskin (1978), even when using the same
 specifications.  Based  on  the  age-  and sex-specific analyses:   (1)  sulfate was
 never significant  for males  (except for Lave-Seskin  specifications)  and only
 occasionally significant for females;  and (2) TSP  was more often  significant
                                      3-22

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for both males  and  females,  especially with threshold specifications.   Analo-
gous sex-specific analyses for persons > 65 yr old revealed further interesting
results: (1) the  migration variable was  the single  most  important  variable and
the age variable was  negative;  (2)  sulfate  was significant only with  the
Lave-Seskin  specification  (both sexes)  or with  other  variables suppressed
(females); and (3) TSP was never significant.
     In sum, it is  quite evident from the above results  that the air pollution
regression  results  for  the  U.S.  data  sets analyzed by Upfert (1984)  are
extremely  sensitive to  variations  in  the inclusion/exclusion of  specific
observations (for central city versus SMSA's or different subsets of locations)
or  additional  explanatory  variables  beyond those used in the earlier Lave and
Seskin  (1978)  analyses.   The results  are also highly dependent upon the parti-
cular  model  specifications  used,  i.e.  air  pollution coefficients  vary in
strength  of association with total or age-/sex-specific mortality  depending
upon  the  form  of the specification  and  the  range  of explanatory variables
included  in  the analyses.   Lipfert's overall  conclusion was that;  the  sulfate
regression  coefficients  are  not to be  taken  seriously  and,  since  sulfate and •
TSP interact with each other in these regressions,  caution is warranted  for T§P
as well.
     Ozkaynak  and Speingler  (1985)  have also  described recent  results from
ongoing attempts of a Harvard  University group to improve  upon some  of the
previous  analyses of mortality and morbidity  effects of air pollution in the
United States.  Ozkaynak and Speingler  (1985)  present principal  findings from a
cross-sectional  analysis of the 1980  U.S.  vital  statistics  and available air
pollution  data bases  for  sulfates,  and  fine,  inhalable and total  suspended
particles.   In these analyses, using multiple regression methods,  the associa-
tion  between various particle measures and 1980 total mortality were estimated
for 98 and  38  SMSA  subsets by  incorporating recent  information on  particle size
relationships  and a set of  socioeconomic variables to  control  for  potential
confounding.  Issues of model misspecification and spatial  autocorrelation  of
the residuals  were  also investigated.   Results  from the  various regression
analyses  indicated the  importance of considering particle size, composition,
and source  information  in modeling of PM-related health effects.    In  parti-
cular, particle  exposure  measures  related  to the  respirable  and/or toxic
 fraction  of the" aerosols, such  as  FP (fine particles)  and  sulfates were the
most  consistently  and significantly  associated  with the reported  (annual)
                                      3-23
                       1

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cross-sectional mortality  rates.   On the other hand, particle  mass  measures
that included  coarse particles  (e.g.,  TSP and IP)  were often found to be
non-significant predictors of total mortality.
     The Ozkaynak  and Spengler  (1985)  results noted above  for analysis  of
1980 U.S. mortality  provide  an  interesting overall contrast  to  the findings  of
Lipfert (1984) for 1969-70 U.S.  mortality data.  In particular, whereas Lipfert
found  TSP  coefficients  to be most  consistently  statistically  significant
(although varying  widely  depending  upon model specifications,  explanatory
variables included,  etc.), Ozkaynak  and Spengler found particle mass measures
including coarse particles (TSP,  IP) often to  be  non-significant predictors  of
total mortality.  Also,  whereas  Lipfert found the sulfate coefficients to  be
even more unstable than  the  TSP associations  with mortality (and questioned
the credibility of the sulfate  coefficients),  Ozkaynak  and Spengler  found that
particle exposure measures related to the respirable or toxic fraction of the
aerosols (e.g.,  FP  or sulfates)  to be  most consistently and significantly
associated with annual cross-sectional  mortality  rates.  It might be tempting
to hypothesize  that  changes  in air  quality or other factors from the earlier
data sets (for 1969-70) analyzed by  Lipfert (1984) to the later data (for 1980)
analyzed by  Ozkaynak and Spengler (1985,  1986)  may  at  least partly  explain
their contrasting results, but  there is at present no basis  by  which to deter-
mine if this is the  case or which set of findings may or may not most accurate-
ly characterize associations between mortality and chronic PM or SOX exposures
in the United States.
     Selvin et  al.  (1984) also used regression analyses applied to ecologic
data to  study the influence of  air  quality in the  U.S.  on  mortality.  The
analyses used  1968-72 mortality data aggregated by county (3082) or by groups
of counties comprising 410 1970 Census Public Use Sample (PUS) areas  (some of
which  may  be  a single heavily populated urban county,   e.g.   Los  Angeles,  or
several  sparsely populated rural  counties grouped together).  Total  mortality,
rather  than cause-specific,  rates  were calculated  for sex-,  race, and
age-specific categories and  were then evaluated by regression analyses in rela-
tion to air quality  values (for TSP, S02, and  N02) extracted from data collected
at 6625  monitoring  stations  during 1974-76.  County  level aerometric estimates
were interpolated  from average values  at  individual  monitoring stations,  and
air pollution estimates for  the 410  PUS  areas  were population-weighted averages
of the  county level  value.   Overall, various  regression analyses (taking into
                                     3-24

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account numerous  control  variables)  for county-wide  or PUS areas  in  all  of  the
U.S. or broken  down into regions (West,  South,  etc.)  yielded  extremely  mixed
results, with both positive and negative coefficients being obtained in various
analyses for mortality  in relation to TSP, SOp,  and N02-   The authors:   (1)
concluded that  their  results  provided no persuasive  evidence for  links between
air cjuality and general  mortality levels; (2) noted that  their results  were
inconsistent with previously published work; and (3) opined that linear regres-
sion analyses applied to nationally  collected  ecologic data cannot be  usefully
employed to  infer causal  relationships between  air quality and  mortality.
However, the  manner in  which  the Selvin et al.  (1984)  study  was conducted
provides little  basis for assigning  any credibility to  the results  obtained,
especially in view  of:   (1) use of 1974-76  air quality data to estimate  retro-
spectively exposures against  which to compare 1968-74 mortality data and; (2)
use of mortality data aggregated by county or by groups of counties with highly
variable relationships  between air  monitoring locations and  the  population
groups from which the mortality data were drawn.
     Turning  from ecological   or  macroepidemiological  studies   of  mortality
relationships to chronic air  pollution exposures in the  U.S., Imai  et  al.
(1986) have recently published analyses of  associations  between mortality from
asthma and chronic  bronchitis  and air pollution  variables  in Yokkaichi,  Japan.
An industrial  city on Ise Bay several hundred miles south of Tokyo, Yokkaichi's
industrial  base  and harbor  facilities were largely destroyed during World War
II.  They were  later  rebuilt  to include the establishment in 1957 of a petro-
leum complex that contained the largest oil-fired power plant  in  Japan,  which
burned high-sulfur oil  that resulted  in large SC^ emissions and consequent high
SO  concentrations in immediate residential/commercial areas around the harbor.
This continued until stringent emission controls were put in place and resulted
in dramatic decreases in SO   concentrations  in the highly  polluted area  around
                           *\
the harbor from 1972  to 1973  and thereafter.   Mortality rates  for the popula-
tion in that  high pollution  area were  compared  against  analogous rates  '(for
bronchial  asthma or chronic bronchitis  including  emphysema, determined  from
death certificates  issued during  1963-83) for people  living in less-polluted
areas of Yokkaichi.   Sulfur  oxides  levels (measured  by the  lead peroxide
method) averaged  across  several  monitoring  sites  in the polluted  harbor area
ranged .from around  1.0  to 2.0 mg/day (annual  average) during 1964-72 and then
steadily declined from  somewhat less than 1.0 mg/day in 1973 to less than 0.5
                                     3-25

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rag/day  in  1982.   This  is  in  contrast to SOX levels consistently  below  0.3
mg/day (annual average) at 3 monitoring sites in the low pollution areas  of the
city  throughout  1967 to  1982.   Annual average levels  for  other pollutants
(N02, TSP, Oxidants) monitored in the high pollution area were also consistent-
ly low, i.e. <0.02 ppm (N02),  <0.05 mg/m3 (TSP), and <0.05 ppm (oxidants, daily
max hourly  values)  from 1974  to 1982.  Results obtained indicated significant
differences between chronic bronchitis mortality for persons > 60 yr old  in the
high  pollution  area compared  against rates  for the same age group from  the
low-pollution control  area for 1967-70 and  extending  into  1971^74, somewhat
beyond  the  point where  marked declines became evident  in  SO  levels after
                                                              J\
control measures were  implemented.   Lagged correlations showed large signifi-
cant  associations between SO   levels and chronic bronchitis  mortality occur-
                            f\
ring  >1 yr later in the  high pollution area (the  largest  correlations  were
found for 4-5 yr lags).  In contrast, bronchial asthma mortality became  rela-
tively  higher in the polluted area  during  the 1967-70 period,  and began to
decrease  thereafter in more  immediate response  to the improvement  in  air
quality.
     These findings, overall, are quite interesting in that they relate mortal-
ity changes  in  populations in circumscribed urban  neighborhoods to air pollu-
tion  indices  obtained  from monitoring sites spatially located in close proxi-
mity  to the residences of the population groups for whom mortality rates were
determined.   Further,  consistently elevated mortality for  the elderly in the
high-pollution  area (relative to  the control  area) was evident  across  many
years while the SO  concentrations were high, but then declined following
                    A
reductions  in the  SO  levels, thus  enhancing the likelihood  of a causal   rela-
                     J\
tionship  between sulfur-containing  air  pollution  and  mortality  having  been
detected  in the study.   However,  it is not possible to quantitate with any
precision  the relative contributions to  the observed  mortality increases of
SOp  versus sulfates or other sulfur  agents (e.g., possibly H2S04 aerosols
likely  formed in the moist air of the coastal city).
      The  1982 EPA  document (U.S. EPA,  1982a)  also  noted that, other epidenrio-
logical  studies  have more specifically attempted to  relate lung cancer  mor-
tality  to chronic  exposures to  sulfur  oxides,  PM undifferentiated by chemi-
cal  composition,  or specific PM chemical species.  However,  the  1982 document
concluded  that  little or no  clear  epidemiological  evidence advanced to  date
substantiates hypothesized  links between  S02 or other  sulfur  oxides and  cancer;
                                      3-26

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nor does there  now  exist credible epidemiologies! evidence  linking increased
cancer rates  to elevations in  PM as a class, i.e.,  uncHfferentiated  as  to
chemical  content.

3.2.2.  Morbidity Effects of Long-Term Exposures
     Impairment of  pulmonary  function is likely to be  one  of the effects of
long-term exposures to  air pollution, since the  respiratory system  includes
tissues  that  receive the  initial impact when toxic  materials  are inhaled.
Acute and chronic changes  in pulmonary 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 European, Japanese, and American  communities.   However,  few
provide  more  than qualitative evidence relating pulmonary function changes to
airborne particles.   The few elevated earlier by  U.S.  EPA (1982a)  as providing
quantitative  evidence for  lung function effects due  to long-'teTm PM and/or SOX
exposure are.  summarized  in Table 2.
     One series of  studies,  reported on from the  early 1960s to the mid-1970s,
was  conducted by Ferris,  Anderson,  and others (Fern's and Andersen,  1962;
Kenline, 1962;  Andersen et al.,  1964;  Ferris  et  al., 1967, 1971, 1976).  The
initial  study involved  comparison of three  areas  within  a  pulp-mill town
(Berlin, New Hampshire).  Kenline  (1962)  reported  average 24-h SQ2 levels
(estimated  from sulfation rates) during a  limited  summer  sampling period
(August-September,  1960) to be  only  16  ppb and average 24-h TSP levels for the
two-month period  to be 183 jjg/m  .   In the  original   prevalence study  (Ferris
and  Anderson, 1962; Anderson et  al.,  1964),  no  association was found  between
questionnaire-determined symptoms and  lung  function tests  assessed  in the
winter and  spring of 1961 in the three  areas with differing pollution levels,
after standardizing for cigarette smoking.   The  authors  discuss why residence
is  a limited indicator  for exposure (Anderson  et al., 1964).  The study was
later extended to  compare Berlin,  New  Hampshire, with the cleaner city of
Chilliwack,  British Columbia in Canada (Anderson and Ferris, 1965).   Sulfation
rates (lead 'candle  method) and dustfall rates  were  higher in  Berlin than  in
Chilliwack.   The prevalence  of chronic respiratory  disease was greater  in
Berlin,  but the authors concluded that this difference was due to interactions
between  age and smoking habits  within the respective  populations.
                                      3-27

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3-28

-------
     The Berlin, New Hampshire, population was followed up in 1967 and again in
1973 (Ferris et a!., 1971, 1976).   During the period between 1961 and 1967,  all
                                                                         o
measured indicators of  air  pollution fell, e.g., TSP  from  about  180  ug/m   in
1961 to  131 ug/m3  in 1967.   In the 1973  follow-up, sulfation  rates  nearly
doubled  from  the 1967  level  (0.469  to 0.901 mg SOVlOO/cm2  day) while  TSP
                                3
values fell from  131  to 80 ug/m .   Only  limited S02 data were  available (the
mean of  a  series  of 8-h samples for selected weeks).   During the 1961 to 1967
period,  standardized respiratory symptom  rates decreased and, there was an  in-
dication that  lung function  also  improved.   Between  1967  to 1973,  age-sex
standardized respiratory symptom rates and age-sex-height standardized pulmonary
function levels were  unchanged.  Although some of the  testing was done during
the spring  versus  the summer  in the  different comparison  years,  Ferris and  co-
workers  attempted  to  rule out likely seasonal effects  by retesting  some sub-
jects  in both  seasons during  one year and found no significant differences in
test results.   Given that  the same set  of   investigators,  using the same
standardized procedures,  conducted  the symptom surveys and pulmonary function
tests over the entire course of these studies, it is unlikely that the observed
health endpoint  improvements  in the  Berlin study population were  due  to varia-
tions in measurement procedures, but rather appear to have been associated  with
                                              o
decreases  in TSP  levels from  180 to 131  ug/m .  The relatively small  changes
observed and  limited  aerometric data available, however, argue for caution in
placing  much weight on  these  findings as quantitative  indicators of effect or
no-effect levels for health changes in adults associated with chronic exposures
to PM measured as TSP.
     The earlier  criteria review  (U.S. EPA,   1982a) also  noted that  one  other
American study provided potentially useful qualitative  or quantitative informa-
tion regarding association of morbidity effects  in adults with ambient exposures
to S02 or particulate matter.   A cross-sectional study was conducted by Bouhuys
(1978) in  two  Connecticut communities in which  differences in respiratory and
pulmonary  function were  examined  in 3056 subjects  (adults  and  children).
Hosein  (1977a)  reported  on aerometric data  used  in the study,  which were
obtained at three sites in Ansonia  (urban)  and  four sites  in Lebanon (rural)
near the residences of  study subjects.  The TSP  levels  during the period of the
                                                     o
study  in Lebanon and Ansonia  were  39.5 and 63.1 ug/m  and S09 levels were  10.9
              o                                               *•
and 13.5 ug/m ,  respectively.   Site-to-site   variations on  the  same  day were
frequently  significant  in Ansonia  and also  occurred in Lebanon.   During the
                                     3-29

-------
years  1966-72,  annual average TSP  levels  in Ansonia ranged from 88  to  152
ug/m3.   No  historical data  for  SOp or TSP in Lebanon were  provided.   Size
fractionation (Hosein, 1977b)  of a limited number of TSP  samples  in Ansonia
showed  that 81  percent  of the TSP sample was 9.4  urn or less in diameter.
Binder et al. (1976) obtained for 20 subjects in Ansonia one 24-hour measure of
personal air  pollution exposure  for particles (<7 urn diameter),  St^, and N02-
Subjects with smokers in the home were exposed to significantly higher levels
than those without such exposure.  Personal exposure and outdoor exposures were
also  significantly  different.   The  mean personal respiratory level  was  114
    n                                                  2
ug/m  as compared to the outdoor TSP level of 58.4 ug/m .
     An  extended  version  of the MRC  Questionnaire  was  administered  via  a
computer data-acquisition  terminal  (Mitchell,  1976) between October  1972  and
January  1973 in  Lebanon and from mid-April  through July 1973  in Ansonia.   For
children 7  to 14 yrs) the response rate varied from 91 to 96 percent for boys
and girls.   For adults (25  to 64 years)  the response rate was 56 percent in
Ansonia  and 80 percent  in Lebanon.   After analysis of  non-responder versus
responder differences, the responders were considered to be representative of
the total population, although some significant  differences  were noted between
responders and  non-responders for some symptom reporting and current smoking in
some age groups.
     Bouhuys  (1978)  found no  differences between  Ansonia  and  Lebanon  for
chronic  bronchitis prevalence  rates but did note that  a history of bronchial
asthma  was  highly significant for male residents of Lebanon (the cleaner town)
as  compared to Ansonia  (the higher-pollution area).   No differences  were
observed between the  communities for pulmonary function tests adjusted for sex,
age,  height and smoking habits.   However, three  out of five symptoms (cough,
phlegm,  and plus  one dyspnea) prevalences were significantly higher  for adult
non-smokers  in  Ansonia  (p <0.001).  The mix  of  both positive and negative
health  effect results obtained in this cross-sectional  study make  it difficult
to  interpret.   Although  the study  generally found  few  air pollution effects,
the  statistically significantly  increased symptom rates raise questions as  to
whether some-impact  on health (due  to prior PM exposures, for example) might
have  occurred.   A follow-up longitudinal examination could have  determined
whether the effects  persisted.   Also, it may be that  the  reported  effects
related, more to historical  rather  than  current pollutant  levels or  to occupa-
tional  exposures  which were  not  examined.
                                      3-30

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      The  1982 Criteria  Document (U.S.  EPA,  1982a) further  indicated  that
 apparent  quantitative  relationships between air pollution and  lower respiratory
 tract illness in children were reported by Lunn et al. (1967),  These investi-
 gators  studied respiratory illness in 5- and 6-year old school children living
 in four areas of Sheffield,  England.   Air pollution concentrations showed a
 gradient  in 1964 across  four  study areas for  mean  24-hour smoke  (BS) concentra-
                    00
 tions from  97 ug/m  to  301  ug/m .   During  the following  year, the annual
 concentrations of smoke were about 20 percent lower and S02 about 10 percent
 higher,  but the gradient was preserved for each pollutant.   In  high-pollution
 areas,  individual 24-h mean  smoke concentrations  exceeded  500 ug/m  30 to 45
 times in 1964 and  0  to  15 times in 1965 for the  lowest and highest pollution
                                                       2
 areas,  respectively.   Sulfur dioxide exceeded 500 ug/nT 11 to 32 times in 1964
 and 0 to 23 times  in 1965 for  the lowest and highest  pollution  areas,  respec-
 tively.   Information  on  respiratory symptoms  and illness was  obtained by
 questionnaires completed by parents,  by physical  examination, and  by tests of
 pulmonary function (FEVQ 75 and  FVC).   Socioeconomic  factors (SES) were con-
 sidered in  the  analyses,  but parental  smoking and home-cheating  systems  were
 not.   Although  some  differences in SES between areas were noted,  gradients
 between areas existed even when the  groups were divided by  social class,  number
 of children  in  house, and  so on.  Positive associations were found between air
 pollution concentrations and both upper and  lower respiratory illness.   Lower
 respiratory illness was  33 to  56 percent more  frequent  in  the higher pollution
 areas than  in the low-pollution area  (p <0.005).   Also,  decrements in  lung
 function, measured by spirometry tests, were closely  associated with  respira-
 tory disease symptom rates.
      In  a  second report,  Lunn et al.  (1970)  gave results for  11-year-old
 children studied in  1963-64  that were  similar to  those found earlier  for  the
 younger group.  Upper and lower respiratory illness occurred more frequently  in
 children exposed to  annual  average  24-h mean smoke (BS) concentrations of 230
 to 301 ug/m3 and 24-h mean S02 levels of 181-275 ug/m3 than in children exposed
 to smoke (BS) at 97 ug/m3 and  S02  at 123 ug/m3.   This report  also provided
. additional   information  obtained  in  1968 on 68  percent of the  children  who  were
 5  and  6  years old in 1963-64.    By  1968, the reported BS concentrations were
 only about  one-half  those measured  in  1964, S02  levels were about 10 to  15
 percent  below those  of  1964, and the pollution gradient no longer existed; so
                                      3-31

-------
the combined three  higher  pollution  areas were compared with the single origi-
nal low-pollution  area.    Lower  respiratory  illness prevalence measured  as
"colds  going to chest" was 27.9 percent in  the  low-pollution area and 33.3
percent  in  the combined high-pollution  areas,  but  the  difference was not
statistically  significant   (p  >0.05).   Ventilatory  function  results  were
similar.  Also, the 9-year-old children  had less respiratory illness  than the
11-year-old group seen previously.   Becuase 11-year-old children generally have
less respiratory illness than  do 9-year olds, this  represented  an  anomaly  that
the authors suggested may be due to improved air quality.
     It  should  be  noted  that these Lunn et  al.  (1967,  1970) findings  have  been
widely  accepted (WHO,  1979; Holland  et al.,  1979; U.S. EPA, 1982a,b)  as valid.
On the  basis of the results reported, it appears that increased frequency of
lower respiratory  symptoms and decreased  lung function in children may occur
                                                                             O
with long-term  exposures to annual BS levels in the range of 230 to 301 ug/m
and SOp levels  of  181 to 275 ug/m  .   However, these must  be taken  only as  very
approximate observed-effect  levels because  of  uncertainties  associated  with
estimating PM mass  based on BS  readings.   Also,  it cannot now be  concluded,
based on the 1968  follow-up study, that no-effect levels  were demonstrated for
BS levels  in the range of  48 to 169  ug/m  because of:  (1) the  likely insuffi-
cient power of  the study to have detected small changes  given the  size of the
population cohorts  studied, and (2) the lack of  site-specific  calibration of
the BS  mass  readings at the time  of the  later  (1968)  study.   In summary,  the
one study  by  Lunn  et al.  (1967) provided  the  clearest evidence cited in the
1982  EPA criteria  document (U.S.  EPA, 1982a)  for  associations between both
significant pulmonary function  decrements  and  increased  respiratory disease
illnesses in children and  chronic exposure to specific ambient air levels of PM
and S02.
     Since the  earlier criteria review (U.S. EPA, 1982a), results of analyses
of data from the ongoing Harvard study of outdoor air pollution and respiratory
health  status  of  children  in  six  cities in  the eastern  and  midwestern United
States  have been  reported  recently by Ware  et  aV.  (1986),  Between 1974 and
1977, approximately 10,100 white preadolescent children  were enrolled in the
study during three  successive  annual visits  to the  cities.  On the first visit,
each  child  underwent a spirometric examination and a parent completed a stan-
dardized, questionnaire regarding the child's health status and other important
background  information.  Most  of the  children  (8,380) were  seen for a second
                                     3-32

-------
evaluation one year  later.   Measurements  of TSP, the sulfate fraction of TSP
(ISO.),  and  SOp  concentrations  at study-affiliated  outdoor  stations were
combined with data from  other public and private monitoring sites to create  a
record of TSP, ISO.,  and SCL levels in each of 9 air pollution regions during a
one-year period  preceding each evaluation, and  for TSP during each  child's
lifetime up to the time of evaluation.
     Analyzing data  across  all  six cities, Ware et al.  (1985) found that fre-
quency of chronic  cough  (see Figure 5) was significantly associated (p <0.01)
with the average of 24-hr mean concentrations  of all three air pollutants (TSP,
TSO., SOp) during  the  year preceding the  health  examination.   Rates  of  bron-
chitis and a  composite measure  of  lower respiratory illness were  significantly
(p <0.05) associated with annual average particulate concentrations, as well  as
being related to  measures of lifetime  TSP  concentrations.  However, within the
individual cities, temporal  and spatial variation in air pollutant levels and
symptom or illness rates were not significantly  associated.  The history of
early childhood respiratory  illness  for lifetime residents was significantly
associated with average  TSP levels during  the first two postnatal years  within
cities,  but  not between  cities.   Furthermore,  pulmonary function parameters
(FVC and FEV,)  were  not associated with pollutant  concentrations during the
year immediately preceding  the  spirometry  test (see Figure 6) or,  for lifetime
residents, with lifetime average concentrations,  although Ferris  et al.  (1986)
reported a small  effect  on lower airway function (MMEF) related to FP concen-
trations.                                   ;
     Overall, these  results  appear to suggest that  risk may  be increased for
bronchitis and  some  other respiratory disorders  in  preadolescent children at
moderately elevated  TSP, TSO^ and SO^,, concentrations,  which do not appear to
be consistently associated  with pulmonary function decrements.   However,  the
lack of consistent significant associations between morbidity endpoints and air
pollution variables within individual cities argues for caution in interpreting
the present  results.   For example, it might be argued that  the  non-significant
associations within cities but significant symptom increases in relation to air
pollutant gradients  across  the  cities may  reflect spurious  correlations  across
the  cities.   On the other  hand, the  within city variation in  air  pollutant
gradients and/or  size  of study  populations within particular  cities may  not  be
sufficiently  large to  detect associations  between the health  endpoints and air
pollutant variables  included in the analyses.   Also, the PM indices employed in
                                     3-33

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                       CHRONIC  COUGH
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                                100   125   150
 Figure 5   Adjusted frequency of cough for the 27 region-cohorts from the
           Six-Cities Study at the second examination plotted against mean
           •TSP concentration during the previous year, with between-cities
           regression equation.   LEGEND: P=Portage,  T=Topeka, W=Watertown,
           C=Carondolet, L=0ther St. Louis,  R=Steubenville Ridge, V=Steubemn1
           Valley, K=Kinston, H=Harriman.


 Source:  Ware et al. (1985).
                                  3-34 '

-------
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the analyses  (e.g.,  TSP,  etc.) may provide a "diluted" measure of exposure to
the most  highly  toxic PM  components  (e.g.,  FP  or  small  coarse-mode particles).
In  fact,  the reported  stronger associations between TSO^  levels  and other
measures  of  ambient  air FP concentrations are highly  suggestive  of  possible
associations  between  health  effects  observed in the Ware et al.  (1985) study
and exposure  to  small particles in contemporary  U.S.  atmospheres.   Available
data  (Spengler and Thurston, 1983) from air monitors  sampling inhalable parti-
culates (IP;  <15 urn) in the  same  cities included in the Harvard  Six Cities
Study analyses discussed  here indicate IP mass annually averaged  from approxi-
mately 20 to 60  ug/m3.  This  suggests  that the observed health effects noted
above may be  associated with  annual average IP (<15 urn) concentrations below 60
jig/m3. However,  full  interpretation of  the strength and significance of these
findings  is  difficult at this point,  in light of further follow-up of these
children  still being  in progress and the expectation that longitudinal analyses
will  later be carried out which will  relate  health  data to more extensive
aerometric data  (including such data collected in later years).
      In  another  new  American study, by  Schenker et  al.  (1983),  respiratory
symptom questionnaires were  administered to 5557  adult women  in a rural area  of
western  Pennsylvania.   Air pollution data  (including  S02  but not PM measure-
ments) were  derived  from  17  air monitoring  sites  and  stratified in an effort  to
define  low,  medium and high  pollution  areas.   The  means of  4-yr  (1975-1978)
annual  average  S02 levels in each stratum were 62, 66, and 99 ug/m , respec-
tively.   Risks  for respiratory symptoms were  assessed by a multiple logistic
model  that  controlled for  several  potentially  confounding  factors (e.g.,
smoking)  and used estimated  air pollution concentrations  at population-weighted
centroids of 36 study districts  (i.e., the concentrations were derived  from
another  model which weighted observed  monitoring data for distance  from  the
district centroid and corrected for terrain effects).   The  risk of "wheeze most
days  or  night"  in nonsmokers residing in the  high- and medium-pollution  areas
was 1.58 and 1.26 (p = 0.02), respectively,  in  relation to  the low-pollution
area.   For  residents  living in the same  location  for >5 yr, these  relative
risks were 1.95  and  1.40 (p <0.01), and increased, risk of grade 3  dyspnea in
nonsmokers was associated with S02  levels  at  p <0.11.  However, no  significant
association was observed  betv/een  cough or phlegm and air pollution  variables.
The results  of  this  study,  while  suggesting that wheezin'g  may be  qualitatively
associated with ambient  exposure  to S02, are difficult to accept in light of:
                                      3-36

-------
(1) the very  limited  gradient  of  annual-average S02  levels across which health
effects were  reported  to  have  been detected (associations with  higher  level
exposures versus distinctly  lower S02 concentrations would be more credible);
(2) the very  rough  estimation  of  S02  exposure  concentrations  by  means of model
calculations; and (3)  the lack of evaluation of possible PM or short-term S02
peak contributions to the evaluated health effects.
     Several  other  recent studies have been reported that evaluated PM and/or
SO  effects in populations residing in the southwestern United States.   In one,
Chapman et al. (1983) conducted a survey in early 1976 regarding the prevalence
of  persistent cough and phlegm (PCP)  among  5,623 young adults  in  four Utah
communities  stratified to represent  a gradient of  sulfur oxides  exposures.
Community-specific mean S02 levels had been 11, 18,  36 and 115 ug/m  during the
5 years prior to the survey and corresponding mean sulfate levels were 5,  7, 8,
and 14  ug/m3.   No gradients of TSP or suspended nitrates were observed across
the communities.  Aerometric data were obtained from monitors sited at ground
level.  Differences  along the  sulfur  oxides  gradient were tested by chi-square
statistics, and  data  were also analyzed by  constructing .categorical'logistic
regression models that treated PCP as the dependent variable and controlled for
numerous  potentially  important factors (e.g.  smoking,  age,  SES, etc.).   For
nonsmoking  mothers,  PCP  prevalence was 4.2  percent  in  the high-exposure  com-
munity  and  ~2.0  percent in all other communities.   For non-smoking fathers,
the  PCP prevalence  was 8.0 percent in the high pollution community and  3.0
percent elsewhere,  while  the PCP prevalence was  less strongly associated with
ambient sulfur  oxides exposures for  smoking fathers.  Overall,  intercommunity
prevalence  differences were significant at p <0.05  for  all  the above groups
except  smoking fathers.    The  categorical  logistic  regression  model yielded
similar results,  providing evidence  suggestive of increased  cough and phlegm
                                               O                           O
being  associated with annual  average 115 ug/m   S02 levels  and/or 14 ug/m
sulfate  levels.   There is much to argue for acceptance of the reported results
from  this study, including use of  aerometric  data  from monitors  situated in
close  proximity  to  study  subjects' homes and  nearly equivalent  response rate?
on the  health questionnaire across the communities sampled.
      Dodge  (1983) studied the respiratory health and lung function of Anglo-
American  children  (grades  3 to 5) residing in an Arizona smelter community
versus  such  children  residing in another  small  Arizona  community free  of
smelter air pollution.  Cough prevalence was  25.6 percent in the  smelter town
                                      3-37

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children  and 14.3  percent  in the  non-smelter groups  (p <0.05).   Baseline
pulmonary  function  at the outset of the study was equal in  the two groups, and
over  the  four years of the  study,  lung function growth (measured in terms of
FEV-,  after 4 yr. of study minus predicted FEV-^) was also equal between,the two
groups.   During the study, annual  average  S02 levels were  55 and 48 ug/m at
company and state monitoring  sites,  respectively  (highest 24-hr S02  levels were
611 and 524 ug/m3, respectively, at the  company and state sites).  Annual
average TSP was 28 ug/m3 in the smelter community.  These results suggest that
smelter community children had more cough  than the  control group  children but
no evident differences in lung  function.   However,  it  is difficult  to ascribe
the reported effects specifically to S02  or  TSP  (although  the very  low  levels
,of the latter are unlikely to account for  the effects).
      Dodge et  al.  (1985)  more recently reported  on a  longitudinal  study of
children  exposed to markedly different concentrations  of S02 and moderately
different levels of particulate  sulfate (SO]J) in  Southwestern  U.S. towns.  Four
groups of subjects  lived  in  two areas  of  one  smelter  town and  in  two other
towns, one  of  which was  also a smelter town.  In the  highest pollution area,
the children  were  exposed intermittently  to high  S09 levels (peak 3-hr x
                    3
exceeded  2,500 ug/m  or ~1.0 ppm) and moderate particulate  SO^ levels (x = 10.1
ug/m3).   When  children were  grouped by the four observed pollution  gradients,
the prevalence  of  cough  (measured by  questionnaire) correlated significantly
with  pollution levels  (trend chi-square  = 5.6;  p = 0.02).   No  significant
 differences occurred among the  groups  of subjects over 3 years,  and pulmonary
 function  and  lung  growth  over the study were  roughly  equal  over all groups.
The results  tend to suggest that intermittent high level  exposures to S02,  in
 the presence of moderate particulate  sulfate levels,  produced  evidence of
 bronchial irritation (increased  cough) but no chronic effect on lung function
 or lung function growth.   It is difficult to quantitate the S02 levels specifi-
 cally associated with the  observed effects, although the intermittent  high
 level exposures to ~1.0  ppm (3  hr averages) mentioned earlier  are likely
 implicated.  Note that S02 levels for the  higher polluted smelter town annually
 averaged 103'± 282 (S.D.) ug/m3 (indicating wide variability in the one hr mean
 levels)  versus 14  ug/m3  in the  lesser polluted town.  Other measured  air
 pollutants,  e.g. TSP,  differed little  between the high and low  pollution areas
 (24-hr TSP  x = 52 and 58 ug/m3,  respectively).   The observation of increased
                                      3-38

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cough but  lack  of lung function changes  in  children comports well with the
findings of Ware et al. (1986).
     Lebowitz et  al.  (1982)  studied 117 families in Tucson, Arizona,  selected
from a  stratified sample  of  families  in geographical  clusters from a  represen-
tative  community  population  included  in an ongoing epidemiologic study.   Both
asthmatic and non-asthmatic  families  were evaluated over a  two  year  period,
using daily  diaries;  and  the health data obtained were related to various in-
dices of environmental  factors  derived from  simultaneous  micro-indoor and  out-
door monitoring in a  representative  sample  of  houses for  air  pollutants,
pollen, fungi, algae and climate.  Macromonitoring of air pollutants and pollen
was carried  out simultaneously.   The data were  mainly evaluated in terms of
statistical techniques employing contingency tables and frequency distributions
using SPSS programs.  Two-month averages of indoor TSP ranged from 2.1 to 169.6
ug/m3.  Cyclone  measurements of respirable particulate (RSP) ranged from below
readable limits up to 28.8 ug/m3.  CO and NOX measurements were also taken, but
no  S02  monitoring was reported.  Suspended particulate matter and pollen were
reported to  be  related to symptoms in  both asthmatics and non-asthmatics, but
the authors  reported  that the statistical analyses  used  were all qualitative
(becase of low  sample  size)  and statistical significance was  not computed.
     In a  recently published Canadian  study,  Pengelly et al. (1986)  reported
results for  an  ongoing  study of associations  between particle  size and respira-
tory  health  in  children of  Hamilton, Ontario.   From 1979 to  1982, a  cohort of
approximately 3500 elementary school children was studied  by determining  each
child's health  history and  respiratory symptoms by  means of a  questionnaire
administered to their parents.   Also,  pulmonary function tests  were  conducted
on  the  children at school.   Particle  size and concentrations  were determined  by
using  two networks distributed across  the  city, one consisting  of  7 to 9
Anderson 2000 Cascade impactors  and another  of 27 hi-vol  TSP samplers.   Smoking,
use of gas  for cooking,  SES and other potentially  confounding  factors were
assessed  by parental  questionnaire and controlled for in statistical analyses,
i.e.,  stepwise  multiple regression techniques (linear for continuous dependent
variables  and logistic for binary dependent  variables).
      In the  present report,  Pengelly  et al.  (1986) focused  on two indicators  of
respiratory  health (cough and bronchitis  episodes) and two indicators  of
pulmonary  function (peak  expiratory  flow or PF and MEF?5),  both  adjusted for
body size.   Logistic regression analyses  found no significant  associations
                                      3-39

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 between  cough or bronchitis episodes and air pollution indices, 'correcting for
 other  factors.   Both peak flow and MEFyg (adjusted for height) were reported to
 be  significantly associated with the presence of fine particles.  However, the
 fine fraction (FF) was estimated by  adding results for samples collected by the
 lower  stages  of  a cascade impactor (nominally reflecting sizes <3.3 urn).  Based
 on  particle bounce  problems associated with this  impactor (see discussion in
 Chapter  1)  and comparison measurements made by the authors in Hamilton between
 dichotomous fine (<2.5 urn) and the cascade FF,  additional  coarse material  >3.3
 pm  was probably also included in the  FF measured by Pengelly et al.  (1985).
 Overall  the FF mass was more than double the dichotomous sampler fine  mass.
     Also  since preparation of  the earlier  criteria review  (EPA,  1982a),
 additional  analyses of health effects  relationships to PM  and SO  air  pollution
                                                                J\
 in  European  cities have  emerged.    Some  of the new  European  work  includes
 longitudinal  analyses reported by van  der Lende et al. (1986) as being conduct-
 ed  in  regard to evaluating relationships between prevalence  of respiratory
 symptoms and  pulmonary function decline and variations in  air pollution in two
 areas  of The Netherlands.   That is,  health measurements  were  obtained from
 cohorts  of  approximately  2000 men and women (aged 15 to 64 years),  residing in
 a highly polluted area (Vlaardingen) or a non-polluted rural area (Vlagtweddej,
 with subjects being  followed and examined  at  intervals  of three years.   Over
 the course  of the study,  air pollution  levels  (PM measured as British smoke,
 SOg, etc.)  remained consistently very  low in the latter area, whereas  pollution
 levels declined  over  time in the former, highly polluted  area.  Van der Lende
 et  al.   (1986)  noted  that in  a  previous publication, they  reported  both  a
 significantly higher  prevalence  of respiratory symptoms in  the polluted area
 and also a  greater  decline there in pulmonary function (based on four consec-
 utive  studies over  a 9-year period).   In  the present update paper  (van der
 Lende  et al.,  1986),  further findings  are provided regarding associations
 between  respiratory  symptoms and pulmonary function  decline and air pollution
 after  six  consecutive studies  covering a 15-year period.  The results, termed
 "preliminary" by the authors,  provide some indications of  more respiratory
•symptoms and  greater  pulmonary function declines in the polluted area than the
 control, non-polluted area.  However, as currently  available,  the  reported
 results  do  not  allow for any quantitative conclusions  to be clearly drawn
 regarding PM  levels associated with  observed health effects.
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     In  another study  (PAARC,  1982a,b),  relationships  between  atmospheric
pollution  and  chronic or recurrent respiratory diseases were  evaluated from
1974 to  1976 as part of a French  national  survey  in  28  areas of  7  cities and a
newly  industrialized region.   The  following  pollutants were measured:  S0?
(specific-SP and acidimetric-AF  methods); suspended  particles  (smoke and
modified OECD  gravimetric methods);  nitrogen  oxides (NO and NOp measured  by
modified Griess-Saltzmann  method);  and  sulfates (measured  by colorimetry after
reduction).  Samples were obtained over 24 hr. periods, but for the gravimetric
measures (48 to 96  h), from 1974-76 except for one summer month each year  and
except for the sulfates which were  determined only during  the  last half of the
study and  only in  one part of the study zones.  Twenty-eight study zones were
defined  to include  2-4 groups  of ~1000 people in different cities exposed to
pollution that  differed as much as  possible in quality  and quantity (estimated
from earlier aerometric data  from 1971-72).   Zones included populations situ-
ated within 0.5 to 2.3 km (x = 1.3 km) of air monitoring stations located 2-4 m
above ground level  in the center of  each  zone.   National  meteorological ser-
vices  supplied climatic  data (e.g.,  temperature   and  humidity)  taken  at a
station  best characterizing each  city (usually an airport, sometimes far from
the zones  investigated),  and  laboratory analyses  for the air pollutants mea-s-
ured were  carried  out by laboratories in  each city  studied  but for sulfates
done at  a  single laboratory.   Means for daily data for the pollutants studied
were calculated for  1974-76 (where values came  from  data accumulated over
several  days,  it was assumed  the pollution was the  same on each  day).  The
                                                                             o
extreme  mean daily  concentrations from various zones were:  13  and 127 ug/m
for S02  (AF),  22 and 85  ug/m3 S02  (Sp);  18 and 152  ug/m3  (smoke); 45 and 243
ug/m3 (gravimetric), 7 and 145 ug/m3 (NO); and 12  to 61 ug/m3 (N02).
     As  for health  evaluations,  ventilatory  function was measured in both  men
and women aged 25 to 59 and children aged 6 to 10  and respiratory symptoms  were
ascertained by standardized questionnaire.   The  results presented  by PAARC
(1982a,b) were  for  ~20,300 subjects from 20 zones (response rates varied from
70 to >90 percent in the  included zones).   Analyses of covariance were used for
FEV results'  and logistical regression  for the analysis of symptoms scores,
taking into account  control factors such as smoking and socioeconomic status.
It should  be noted  that efforts were made to standardize  the  health endpoint
measurements by  common training  of personnel  carrying  out testing in various
zones and use of standard protocols.
                                     3-41

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     The results of  the  study were reported by PAARC (19825)  as  follows:   (1)
among both male and female adults, S0£ concentrations are significantly  associ-
ated with the prevalence of lower respiratory disease (LRD) symptoms;  (2)  among
children, S02  is  associated with the prevalence of  upper  respiratory disease
(URD) symptoms; (3)  for  both adults and children,  FEV1<0 varied negatively in
relation to  elevations  in S02 levels;  and (4)  no other  pollutants were  associ-
ated with ventilatory function or the prevalence of respiratory symptoms.   More
specifically,  S0£  concentrations were significantly correlated (r >0.44)  with
incidence of cough,  expectoration, and LRD symptoms in men and with LRD inci-
dence in women (r =  0.49);  and S02 correlated  (r = 0.53) significantly with URD
in  children.  It  was  noted  that,  whereas the above  results emerged from
analyses  including data  drawn from across cities, the gradient of S02 effects
on  symptom rates was not always evident within the same  city  (an  analogous
situation  to  findings reported  by Ware  et al.,  1985,  from  data from six
American  cities).   Similarly, the gradients emerging from regressions  across
cities  for relationships between  S02  and FEV-L Q measures  for men (r =  -0.52),
women  (r = -0.67) and children  (r = -0.70) were not always evident from data
within  all  individual  cities.    In contrast to the S02 results, very  mixed
correlations (some positive and  some  negative, but none  significant) were  found
between symptoms  and measures of PM (smoke or gravimetric) and nitrogen oxides
(NO,  N02).   Also, oddly,  the correlations between FEV-,^ Q and PM or  nitrogen
oxides  measures were positive (some significantly  so for NO or  N02);  i.e., they
implied improved  lung function  as airborne particle or nitrogen oxides levels
increased.
      The results  from the PAARC (1982a,b) study are interesting but challenging
 in terms of interpretation.  The study appears to have  ensured  that aerometric
 data from the sampling stations used would be reasonably well representative of
 the surrounding study populations in the various zones, a definite strong point
 of the  study.  Similarly, efforts to  standardize  measurements  of  health end-
 points across the different cities is another strong point.  Also,  in  the case
 of the  S02  measurements, analytical  techniques were used and  periodic inter-
.comparisons made  between laboratories  such that the aerometric data and result-
 ing correlations  with  symptoms and FEV decrements are  probably credible.   Much
 less  confidence  can be placed  in the data  derived for particulate matter,
 however,-in view of the use of smoke readings and/or gravimetric readings that
 varied  for  48 to 96 h  periods  as the basis  for generating estimated particle
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concentrations  to  compare across cities.  It is very dubious that an adequate
comparison could be made, then, across cities in terms of relationships between
either  symptoms or pulmonary  function measures  and PM estimates; analyses
relating  such  health  endpoints to PM  measures  within  individual  cities (not
reported  in  PAARC, 1982a,b) might be  more credible, but this remains  to  be
evaluated.   The very  anomalous results obtained for nitrogen oxides are diffi-
cult  to explain or understand without more in-depth evaluation  of specific
aspects of the NO  aerometric measurement methods as they were applied in the
                  /\
present study.   Clearly,  the results  obtained  for the nitrogen oxides are not
believable in  light of other existing  literature.
      In another European  study (CEC, 1983) reported  since the 1982 EPA criteria
.document was prepared, various health  endpoints in children (6-11 yrs old) were
evaluated  in relation to air pollution  in  19 geographic areas  located  in
several different  European  Community countries.  Data were obtained on 22,337
children and included information on respiratory symptoms obtained by question-
naire and  pulmonary  function measurements (peak expiratory flow rate measured
by Wright  peak flow meters).   Efforts  were made to standardize health measure-
ments and protocols across all study areas.  S02 concentrations were determined
(using six different analytical methods) and particulate pollution was measured
by smoke  methods  in  some countries and by unspecified  gravimetric methods  in a
few other  ones.  Side by side monitors were set up at  20 sites to help provide
a basis for calibration across sites;  these 20  "comparison" monitoring stations
standardly used the British smoke method for PM and acidimetric  method  for
SOp.  Significant  associations emerged  from  analyses  within some individual
countries, but differed  greatly from  one  country  to another.   In three coun-
tries, a  composition  variable called chronic non-specific lung disease (CNSLD)
was highly significantly  correlated positively with  smoke, but the magnitude of
the effects  differed  by  a factor of about seven.   The range of annual smoke
levels was about  the  same in all three countries, about 15-40 ug/m .  In four
countries, there were  significant associations  with S02, but two  of these  were
negative.   In  those with positive correlations annual  median  SO, levels  were
           3                                                                 3
60-160 ug/m,  and  for those with negative associations they  were  20-120 ug/m ,
making  it  likely  that the SOp results reflected chance variations rather than
actual pollution effects.  However, no significant relationships between health
effects and  particulate  pollution were found when  data from across countries
were  pooled.   The  reported results are difficult to interpret.  The CEC (1983)
                                     3-43

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report noted that  annual  average  levels of  smoke greater than 140 |jg/m  in the
presence of SO*  at  >180 ug/m  have been found by other studies to be levels
above which consistent positive associations between health effects  and  air
pollution are detectable.   These  levels  are higher than any measured in  the
present study, and this might explain the lack of consistent effects  observed
from city to city or when data were analyzed across all  cities.   The results  of
analyses for  data within  a given city  may warrant further, more  detailed
evaluation and  may yield useful  information on  quantitative  exposure-effect
relationships.   However,  given  the great difficulty noted by the  CEC (1983)
report in deriving bases for comparing air  quality measurements  for PM and 50^
across different cities it is dubious that  useful  quantitative conclusions can
be drawn from analyses of data combined  across cities.  This is  especially the
case in view of  only limited calibration  of smoke  readings against  gravimetric
measurements by collocated gravimetric devices in the various countries.
     Muhling et  al.  (1985)  also  studied  the relationship between  croup  and
obstructive bronchitis  of German  children taken to clinic versus the level  of
air pollutants of  their residential  areas.   They show  in  this  retrospective
study that the  incidence of these two diseases was  greater  in the area with
higher S02  and  dustfall levels.   Several important  confounding  factors  were
examined (i.e.,  infection incidence,  meteorological  parameters,  social status,
and distance from  clinic).   Quarterly average values of S02 and dustfall  were
provided by the  county of Nord Rhein in  Westphalia.   The  authors state that
their results clearly  show that the disease frequency depended on whether the
children lived in  an area of high or  low S02 and dustfall levels, but noted
that it cannot  be clearly stated  whether or not  the  measured emissions are the
actual cause of any  increased morbidity.
     Wojtyniak et  al.  (1984) using a multivariate analysis method showed that
among men reporting  persistent cough  or  phlegm,  the  prevalence  of exacerbation
of these symptoms  was  much greater in residents of more highly polluted parts
of Cracow,  Poland.  In women, the prevalence of  exacerbation  of symptoms was
associated with  indoor air pollution resulting from coal combustion  from coal
stoves.  This extensive longitudinal  survey used questions based  on  the  MRC
questionnaire.  An extensive monitoring network of 20 sampling stations covered
the entire area of the  city.  Most important confounding factors were examined.
                                     3-44

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     In summary, of the  numerous  new studies published on morbidity  effects
associated with long-term  exposures to  PM or  SOX,  only a  few provide
potentially  useful  results  by which  to derive  quantitative conclusions
concerning exposure-effect  relationships  for the subject pollutants.  The Ware
et al.  (1985)  study,  for example, provides  evidence of  respiratory  symptoms in
children  being associated with particulate  matter exposures  in  contemporary
U.S. cities  without evident threshold across a range of TSP levels for -25 to
150  ug/m3.   The increase  in symptoms  appear  to occur without  concomitant
decrements in  lung  function among the same  children.  The  medical  significance
the  observed  increased  in  symptoms unaccompanied'by  decrements  in  lung
function  remains  to  be  fully evaluated  but is of  likely health concern.
Caution  is warranted, however,  in  using these findings for  risk assessment
purposes  in view  of  the  lack of  significant associations  for  the  same
variables  when assessed  from data  within individual cities  included  in  the
Ware et al.  (1985) study.
     Other  new  American  studies  provide   evidence  for:   (1)  increased
respiratory  symptoms  among young adults in association with annual-average S02
levels  of -115 ug/m3  (Chapman et al.,  1983);  and (2) increased prevalence of
cough  in  children  (but  not  lung  function  changes)  being associated with
intermittent exposures  to  mean  peak 3-hr  S02  levels of  -1.0 ppm  or annual
average levels of -103 ug/m  (Dodge et  al.,  1985).
      Results  from  one  European  study  (PAARC,  1982a,b)  also  suggest the
likelihood  of lower   respiratory disease symptoms and  decrements in  lung
function in adults (both male and  female) being associated with annual average
S0? levels  ranging without evident threshold  from about  25  to 130 ug/m .  In
addition that  study  suggests  that  upper respiratory disease  and lung function
 decrements  in  children  may also  be associated with annual-average S02 levels
 across the  above  range.   Further  analyses would probably  be necessary to
 determine whether  or not  any thresholds for  the  health effects reported by
 PAARC (1982a,b) exist within the stated range  of annual-average S02 values.
                                      3-45

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        CHAPTER 4.  CONTROLLED HUMAN EXPOSURE STUDIES OF SULFUR DIOXIDE
                                HEALTH EFFECTS
     Since  the  completion of the 1982 EPA criteria document (U.S. EPA, 1982a)
and  the  first addendum to it (U.S.  EPA,  1982c),  numerous scientific articles
have been published in the peer-reviewed literature or accepted for publication
in regard  to  controlled human exposure studies providing important additional
information pertinent  to  development of criteria for primary (health related)
NAAQS for  S02.   This  chapter of the present addendum summarizes and evaluates
the newly available studies and discusses their relationship with certain other
key  studies and conclusions  from Chapter 13 of the 1982 criteria document and
the  earlier addendum.   Several  of  the  key issues discussed in the  previous
addendum have been further investigated.  Those discussed here are

     (1)  Differences  in  subject  characteristics,  medication,  and restriction
          from  medication which may have considerable impact upon the differ-
          ences in results reported by different laboratories.
     (2)  Concentration (SOp^response  relationships  in  sensitive individuals
          under various conditions  of exercise activity  level or  other  form of
          hyperpnea.
          Possible enhancement  of  S02-induced bronchoconstriction  by  cold
          and/or dry air and by mouthpiece breathing.
(3)

(4)
          Mechanisms of action  of SOp-induced  bronchoconstriction  in  sensitive
          (asthmatic) individuals.
     The majority of  subjects  used in the studies summarized in this addendum
were asthmatic.'  Asthma is a heterogeneous disease  classification  which  in-
cludes  a  broad  range of subjects.  The  least  severe asthmatic may have  had
asthma  diagnosed by  a  physician during  childhood  (by an  unknown  set of
criteria) .and  have  been mainly  symptom-free  since  childhood and rarely, if
ever, requires medication.  On the other end of the spectrum are individuals  who
                                      4-1

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may  be  on chronic bronchodilator therapy (theophylline),  who may use chromolyn
(disodium  chromoglycate) prior  to  activity, and may also  require  steroids.
Pulmonary  function  tests (spirometry and airway resistance) are used to define
the  clinical status  of an  asthmatic  at the time the studies are performed.
Since airway obstruction  in asthma is variable and  often  intermittent,  and
given that the physiologic status is highly  influenced by the quantity and type
of medication being  used,  tests of  lung function cannot be used  alone  to
determine the severity of the disease at any one time.
     In addition  to the diversity of clinical status, there was a broad range
of selection  criteria used to define asthma in  various  laboratories and from
study to  study.  In  some of  the early studies, a clinical definition of asthma
(i.e., diagnosed  by a physician) was the selection criterion. In an effort to
provide more descriptive information about the subjects,  other criteria such as
a positive response  (i.e,  much  more reactive than "normal"  subjects)  to a
pharmacologic stimulus such  as methacholine or histamine  was used as a criteri-
on for  selection.   A positive (bronchoconstriction)  response to an exercise
test (5 to 10 min at 85 percent of maximum) or to an SOp inhalation challenge
was also  used to  select subjects.  The  use  of these  descriptive criteria is
sometimes useful in comparing results between laboratories.
     One further  point  which relates to severity  of  asthma is  the  ability of
the subjects  to safely  withhold  their medication  for a  particular  period of
time.  There was considerable variation between laboratories in the duration of
time for which certain types or general classes of medication were restricted.
     A number of  the characteristics  of the  subjects  who participated  in
studies described in  this  addendum are summarized in Table 3 along with other
information on aspects of protocols employed in the studies.
4.1.  NORMAL SUBJECTS EXPOSED TO SULFUR DIOXIDE
     The pulmonary function  effects  of S02 in normal healthy adult volunteers
have  usually  been much  less than those  seen in SOp-exposed subjects with
clinically documented asthma.   The  newly available information supports this
conclusion in general but also suggests that  some  mild  effects which are  of
little if  any acute  health importance may be  observed  in normal  subjects  at
concentrations below 5.0  ppm.   The  1982 criteria document  presented  the con-
clusion that the probable lowest-observable-effects level in normal healthy
                                      4-2

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subjects is 5.0  ppm  S02 at rest.  The first addendum to the criteria document
further suggests that  normal  subjects  are  approximately one order of magnitude
(i.e., tenfold) less sensitive to S02 exposure than asthmatics.
     Bedi et al  (1984) studied subjects exposed to  1.0 and 2.0  ppm S02  in  an
environmental  chamber  (22°C,  40  percent RH) for 2h (V£ = 40 L/min for 3 to 30
min exercise periods with  intervening  10 min  rest).   In the initial  9 subjects
tested at both  1.0 ppm and 2.0 ppm S02, these investigators reported a modest
(10.3  percent)  but  significant  increase  in  SRaw following both exposure
concentrations.   Further investigation  with a total of 22 subjects at 1.0 ppm
using the same protocol failed to substantiate this finding.  Given the trivial
increase in SRaw (well within daily variations),  the  finding  in the initial
group  probably  occurred by chance.   Folinsbee et al.  (1985)  also reported
exposure of normal  subjects  to 1.0 ppm S02 in a study in which the effects of
combined exposure  to ozone and S02 were examined.   The exposure protocol  for
this study was  the same as the  Bedi et al.  (1984) study and included many  of
the same  subjects.  There were  no significant changes  in  forced expiratory
spirometry or airway resistance  as a result  of  1.0  ppm S02 exposure reported
for these subjects.
     Stacy et al. (1983) exposed subjects to 0.75 ppm S02 alone and in combina-
tion with several  particulate pollutants.   During the 4-h exposures, subjects
walked on a treadmill on two occasions (VV approximately 55 L/min).  There were
no significant effects of this S02 (or S02 plus particulate) exposure on either
forced expiratory spirometry or airway resistance.
     Schachter et  al.  (1984)  compared the responses of asthmatics and normals
(4M,  6F)  to SOp.  Three  of  the normals were  reportedly atopic  (i.e., they
probably had some  history of allergy).  There were  no significant effects  in
normal subjects  at any of the concentrations  tested (0.25,  0.50, 0.75, and 1.0
ppm S02). Measurements were made for 60 min following a 10-min bicycle exercise
period (vV estimated at 35 L/min by measurement at the same workload on another
occasion) in  S02; the  S02 level  was maintained for the  first 30 min post-
exercise.  At the higher SOp concentrations (0.75 and 1.0 ppm) the subjects did
experience upper respiratory symptoms (these included unpleasant taste and odor
and sore throat, symptoms associated with extrathoracic airways).
     Koenig and Pierson (1985)  in a  review  of several  studies  from their
laboratory .reported  a  decline (6 percent) in FEV1 Q following exposure to 1.0
ppm S09  in 8  healthy  normal  adolescents.   These  subjects  were  exposed via
                                      4-7

-------
mouthpiece to either  1 ppm S02, 1 mg/m   NaCl  aerosol,  or their combination.
Resting exposure  of 30  min was followed by 10  min  of  exercise (V^ =  39.9
L/min).  The  apparent decrease in FEV-j^ Q occurred 2 to 3 min  following the
exercise period in  S02.   However,  the FEV-j^  Q decrease following saline  aerosol
was 4  percent and  the absolute post-exposure FEV1  Q values  were identical
(i.e., 2.89 liters).  Furthermore,  the authors used  repeated  pair t-tests  in
their  analysis without correction  for multiple comparisons  (e.g.,  Bonferroni).
These  data  should be  subjected to a more  rigorous  statistical analysis to
ascertain their significance.   Even if these  FEV-j^ 0 data were statistically
significant, the  differences  between the air exposure and S02 exposure are so
small that they are of no clinical importance.
     Exposure to  a  mixture of S02  (1 ppm) and  ammonium  sulfate (528 ug/mO was
studied in  20  normal  subjects by  Kulle  and associates  (1984).  The subjects
were young  adult  nonsmokers (10M,  10F) with normal  spirometry and no allergic
or  respiratory disease history.  Four hour exposures  occurred  in an environmen-
tal  chamber (22°C, 60 percent  RH) and included two  15-min exercise periods
(mild-100 watts,  v"E estimated 40  L/min  [4  to  5  times rest]).  There were  no
significant effects on spirometry  or airway resistance after exposure to either
S02 alone,  ammonium sulfate alone, or their combination.  There was no change  .
in  the response  to a methacholine  inhalation  challenge following any  of  the
exposures.  There were reports of upper  respiratory symptoms which were most
prevalent with  the combination  exposure.  This  study  further supports the
absence of pulmonary function effects of  S02 at  1.0  ppm  in normal  subjects.
     Wolff  et  al. (1984) exposed  nine steel workers, two of whom  were  classi-
fied  as asthmatic, to 5 ppm S02  or S02 plus carbon dust  for 2.5 h in an
environmental chamber (22°C,  50 percent RH).   The exposure included five 4-min
exercise  periods  (vV  not reported).   Mucociliary  clearance measurement
exhibited no  consistent pattern of change.   Histamine reactivity  (percent drop
in  FEV, Q at threshold dose)  showed a  tendency  to increase  slightly (37
percent;  28 percent excluding asthmatics).  There were no notable  changes in
pulmonary  function among  the  normal  subjects.  Symptomatically  the subjects
found  the S02 p-lus  carbon dust  exposure  more  unpleasant than  S02 alone.
      In summary,  these studies of S02 exposure  in  normal  healthy adults  and
adolescents demonstrate  minimal,  if any,  significant pulmonary function effects
of S0? exposure  at 0.25  to 2.0 ppm with exposure  durations  ranging from 10
minutes to  four  hours including exercise periods, with  work outputs  sufficient
                                       4-8

-------
to increase ventilation  to 35  to  55 L/min.   The  only effect of  any  consequence
was the increase in upper respiratory symptoms, which was chiefly the result of
the unpleasant taste/odor of sulfur dioxide.
4.2  CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS EXPOSED TO S02
     In addition  to  studies of asthmatics,  Linn et al.  (1985b) have studied 15
patients  (ages  49 to 68) with  COPD  (mild to severe — airway reactivity and
reversibility  not characterized) exposed to S02  (0.4,  0.8 ppm).   One-hour
exposures  in an  environmental  chamber (22.5°C, 86 percent RH)  included  two
15-min exercise periods (v"E = 18 L/min).   In contrast to many previous studies
of mild  asthmatics,  most of these patients  regularly used bronchodilators and
were permitted  their use up to  4 h  prior to study.  There were no effects of
S02 exposure in this subject group and no trends indicative of change  in any of
the measured functions  (including SRaw, spirometry, and arterial oxygen satura-
tion).   It should be noted that little  if any effect would be anticipated in
asthmatics  under these exposure  conditions.  The  authors suggested that these
COPD patients may be less reactive to  S02 than  younger asthmatics, although, as
the  authors discuss,   given  the low  dose rate of exposure  and the marked
differences in medication  status,  this  conclusion may be premature.   The
ventilations  achievable by COPD  patients are  limited by the  severity  of their
disease.   It is  conceivable  that patients  with  less  severe COPD able to
exercise  at a  higher intensity  and able  to withhold medication may demonstrate
responses to S02 which are similar to or  even greater than those of young
asthmatics.
 4.3  FACTORS AFFECTING THE PULMONARY RESPONSE TO S02 EXPOSURE IN ASTHMATICS
 4.3.1  Dose-Response Relationships
      Important considerations in  assessing  the response to any inhaled gas or
 aerosol include the  concentration of the substance  in  the  inspired air,  the
 rate of exchange  of ambient air with the lung (ventilation), and the duration
 of exposure.  The  concentrations  to which asthmatics have been exposed in  more
 recent studies  (since  1981) range from 0.10  to  2.0 ppm S02 although interest
 has  focused on the  range from 0.2  to 1.0  ppm.   A broad range  of  exposure
 durations has been utilized ranging from 3  min  to 6 h, although the primary
                                       4-9

-------
focus  has  been  on 5  to  10-min  exposures  which incorporate hyperpnea.
Ventilation rates  have  ranged from 8 to 10  L/min at rest to 60 to 70 L/min
(exercise or voluntary eucapnic hyperpnea), although most interest has centered
on moderate  (VE  = 35 to 50  L/min)  to heavy (V,  >  50  L/min)  exercise levels
which  in warm humid  environments provoke,  at most, only mild to moderate
exercise-induced  bronchoconstriction.  Results  from the recently published
studies  are summarized  in  Table 4.
     Schachter  et al.  (1984) performed a concentration-response study  in a
group  of 10  normal subjects  (see  Section 4.1 above)  and  a group of 10 asthmatic
subjects exposed in an environmental chamber  (23°C, 70 percent RH) to 0, 0 25,
0 50  and 1.0  PPm S0?.   Subjects  rested  briefly and then exercised for  10
rinuU.  at 450  kpm (V, =  35  L/min).  In addition, subjects were exposed to 1.0
ppm SO, at rest.  A significant  decline in  FEV1>0  followed both the  0.75  ( 8.3
 percent) and  1.0 (-13 percent)  ppm exercise  exposures  in these asthmatics  ^
 This was accompanied by a significant increase (54 to 68 percent at  1.0  ppm)  in
 airway  resistance (interrupter method).   There were also some changes  (these
 did not occur consistently  at  all  concentrations  or time -Intervals after
 exposure) in  maximum  expiratory  flow which mainly occurred at the two highest
 concentrations.   The  recovery was rapid and  pulmonary  function was  within 5
 percent of baseline  (and  no longer  significantly different) by  10 mm
 postexercise  even though S02 exposure continued.   As other  investigators have
  reported, there  was a  considerable range  of response among these subjects, with
  3 or  4 subjects  demonstrating  no appreciable  response  to  S02  at any
  concentration while some others showed  trends  indicative of a dose-response
  (SO,-FEV,  n)  relationship beginning as early as 0.25 ppm.   The responses of
  asthmatics'seen  in this  study  may appear less severe than  those seen by o her
  investigators at similar S02 concentrations,  although comparisons  are difficult
  because of the different measurements made; the relatively small  changes in  Raw
  may be partially due to the use of the interrupter method.   However, a number
  of other factors could account for the  discrepancies  between this and other
  recent studies  of  asthmatics.   First, the subjects were  not P^selected for
'  the presence of'airway hyperreactivity to  SO,,  cold air, exercise   hi stamina or
   methacholine,  an approach  frequently used  by  others.  Second  the moderate
   workload and unencumbered  oronasal  ventilation  probably resulted in a  lower  SO,
   delivery io  the reactive airways  than would  occur with mouth  breathing.
                                        4-10

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     In a subsequent paper, Witek et al.  (1985b) described the symptoms  experi-
enced by the  subjects  in the Schachter et al.  (1984) study.  Both asthmatics
and normal subjects  experienced  increased respiratory symptoms following S02
exposure.  Normal  subjects complained  chiefly of upper airway (nose and mouth)
symptoms of  odor or unpleasant  taste; these symptoms were not increased by
exercise.   Normals experienced  no  significant  lower  respiratory symptoms.
There was  an  increase in  lower  respiratory symptoms in asthmatics at 0.75 and
1 0 ppm S09,  although the  significance of this trend is not clear (p = 0.09).
Upper airway  symptoms tended to  be  elevated  in  both asthmatics and normals, but
more consistently in normals.   The  lower  respiratory symptoms increased with
exercise in the  asthmatics and were significantly correlated  (r = 0.67, p <.05)
with the decrease in FEV,  Q.  In contrast, exercise did not affect symptoms in
normals.   The authors stated that  even the asthmatics' symptoms were generally
mild and required no therapy.
      Linn  and coworkers (1983D) also evaluated the responses of  naturally
 breathing asthmatics  exposed  to S02  in an environmental chamber  (23°C,  85
 percent RH)  while performing 5 min of moderately  heavy exercise  (V£ = 48
 L/min)   Twenty-three  mild asthmatics  (some of whom were  hyperreactive  to
 methacholine and  all  of whom were reactive to 0.75 ppm S02) were exposed four
 times, once each to 0, 0.20, 0.40, and 0.60 ppm.  Significant increases in SRaw
 occurred after  clean  air exposure due to exercise-induced bronchoconstriction.
 The SRaw  increase after 0.20 ppm was  not significantly  larger than after clean
 air,  but the SRaw following exposure to the two  higher concentrations was
 significantly elevated.   SRaw demonstrated  a significant  trend to increase with
 increasing  SO,  concentration but this trend was not linear; the mean increases
 in  SRaw after 0.2, 0.4 and 0.6 ppm S02, over those seen with clean air, were
 0 54,  2.03, and  6.77  cm H-O-sec.  The  response  data  are suggestive of a
 threshold concentration  for response to  SO,,.   There is a strong possibility of
  a concentration threshold for  S02 at low concentrations  and ventilations since
  the scrubbing of  SO,  by the upper airway mucosal  surfaces may be  so efficient
  that  only a relatively small  quantity  of SO, reaches the reactive portions  of

    6 ^Roglfet  al.  (1985) studied 27 mild  asthmatics (methacholine  sensitive,
  not using  cromolyn or steroid  medication).  Exposures  were to 0.0,  0.25, 0.50,
  and 1.0  ppm SO, in an environmental chamber (26°C, 70  percent RH) utilizing
  natural  breathing while performing treadmill  exercise  (V£  = 41 L/min)   The
  increases  in  SRaw post-exercise  associated  with  these exposures  were 48,  63,
                                       4-20

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93,  and  191  percent  respectively;  the  increases  at the  two  highest
concentrations were  significantly  greater than with  air.  The  data  reported by
Roger et  al.  (1985)  were further analyzed (Horstman et al., 1986) in order to
determine  individual S02-SRaw  dose-response relationships.   This  analysis
included  previously  unreported  data on exposure to 2 ppm in subjects who were
non-responsive  to   lower  concentrations.   From  interpolation  of  the
dose-response plots, the concentration of  S02  which provoked a  100  percent
increase  in SRaw (PCS02) was determined  for  each  subject.  All S02 responses
were corrected for the response observed with clean air, i.e., exercise-induced
bronchoconstriction.   For the  most reactive  80 percent of the  subjects  the
PCSOp ranged from 0.28 to 1.38 ppm;  it was greater than 1.95 ppm  (and therefore
.basically indeterminate) in  the  remaining 20  percent of  subjects.   (This
percentage of  SOg-insensitive asthmatics  is  in general agreement with Linn et
al.s 1984b)   The median PCS02  in  all subjects  and under these conditions was
0.75 ppm; 25  percent (i.e., 6) of the subjects had a PCS02 less than 0.50 ppm,
the  lowest being 0.28 ppm.   The dose-response relationships relate only to the
level  of exercise used  in  this  study.   Different dose-response relationships
would  be  expected  for  different  exercise  levels  or different exposure
durations.

4.3.2   SO^-Induced Versus Non-Specific Airway Reactivity
      It is well established  that  most asthmatics  are highly  reactive to  bron-
chial   inhalation  challenge with  histaminergic  (histamine) and  cholinergic
 (acetylcholine,  carbachol,  methacholine) agents.   Clear  evidence has  also
emerged that asthmatics  are  substantially more reactive to S02.  The relation-
 ship between  S02-induced bronchoconstriction and non-specific airway reactivity
 has been examined or  alluded to in a number  of studies (Horstman et  al., 1986;
Witek et al.,  1985a; Sheppard et al., 1983).   Airway reactivity to methacholine
 and to histamine are well correlated (r = 0.70) (Chatham et al., 1982).   Metha-
 choline reactivity was more highly correlated with exercise-induced bronchocon-
 striction and was  better able to  distinguish between  normals and asthmatics
. (Chatham et al., 1982).
      Witek et  al.  (1985a)  reported that  the  methacholine  reactivity of  a group
 of 8 asthmatics was highly (r = 0.86, p <0.05) correlated with their reactivity
 to S02.   The  subjects were  a  subgroup of  8 of the  10 subjects  used in the
 Schachter et  al.  (1984)  study (see Schachter  et  al.,  1984, for protocol
 details).  The  dose of methacholine  required to  produce  a 20 percent drop in
                                      4-21

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 the maximal expiratory flow  at  40 percent VC  above  RV  on  a partial  expiatory
 maneuver (MEF40 percent-P) was  determined.   From the MEF40 percnet-P vs. SO,
 response relationship, the S02  concentration  required  to  produce a 20  percent
 drop was  determined.   The relationship between  the methacholine provocative
 dose and the  SO, provocative concentration was determined by  rank Correlation.
 This  study suggests  that there  is  a relationship between  methacholine
 reactivity and severity of S02-induced bronchospasm.
      On the  other hand,  Koenig and  Pierson  (1985)  concluded  in their recent
 review  article  that the response to  a methacholine challenge was  not a good
 predictor  of  the degree of S02-induced bronchoconstriction  in asthmatics   They
 suggested  that a positive response to an exercise challenge was more likely to
 predict a positive response  to SO,.   Linn et al. (1983b) present subject data
  (their  Table 1) for methacholine  reactivity, exercise response  (SRaw  change),
  and SO, response  (SRaw change),  which are sufficient to allow calculation of
  correlation coefficients between these three variables.   The rank-order cor-
  relation coefficient between methacholine reactivity and  SO,  response  was 0.38,
  between exercise  response and  SO, response was  0.46,  and between exercise and
  methacholine response  was 0.47  (these calculations  by  the  authors of  the
  addendum).   The  latter two-correlation coefficients were significant  p <05)
  and  this  observation supports the  suggestion  of  Koenig and Pierson  (1985)
  Horstman  et  al.  (1986)  have compared the methacholine reactivity (interpolated
  dose causing a doubling of  SRaw) with the  SO, response  (PCSO,;  see previous
  section).   The methacholine and  S02 responses  were significantly but weakly
  correlated  (r = 0.31).
       The  relationship of histamine  reactivity  to  S02-induced bronchoconstric-
  tion is less well described.  "Tolerance" to SO,  exposure reported by Sheppard
  et al   (1983)  was not accompanied  by any  decrease in histamine  reactivity.
   However,  this does not necessarily indicate the absence  of an  overall  relation-
   ship between histamine reactivity and S02 responsiveness.
        One problem in establishing  the strength of the  relationship  between
   non-specific airway  reactivity  and SO,  response is the  restricted range of  the
.   observations in  these studies which  deal only with the most reactive segment of
   the population, namely  asthmatics.   Inclusion of data  from  normal  objects
   would  undoubtedly result in a higher correlation.  Nevertheless it is  app.re.it
    that  increased SO, responsiveness  in asthmatics  cannot simply be ascribed to
    elevated non-specific airway  reactivity.
                                         4-22

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4.3.3  Oral, Nasal, and Oronasal Ventilation
     For S02 in  particular,  but also for many other  gases  and aerosols,  the
inhalation route  is  an important factor in delivery  of  the substance to  the
lung.  Since 1982,  a number of studies have  been  reported  which specifically
address this issue.   There are important interactions between  the  inhalation
route, which in  many cases is  simultaneous  oral  and nasal breathing (oronasal)
(Proctor, 1981),  and the ventilation rate  is such that  the efficiency of the
oral or  nasal  mucosa in absorbing S02 declines as the air flow increases.  As
noted  in  the  previous addendum (U.S.  EPA, 1982c) the  studies of Kirkpatrick et
al.  (1982)  and Linn et  al.  (1982b  in the earlier Addendum I;  1983b in the
present  reference list)  indicated the importance  of oronasal airway scrubbing
of S02 in mitigating the effects of S02 during nasal or oronasal breathing.
     In.an  effort to further resolve the interaction  between exercise ventila-
tion and route of inhalation  in  asthmatics,  Bethel  et al.   (1983b) studied 9
mild asthmatics  breathing  humidified  air (23°C,  80 percent  RH)  through either a
mouthpiece  or  a divided facemask (ventilation could be measured separately in
nasal  and oral chambers).   Subjects worked  at 250  (V£ = 26  L/min),  500  (V£ = 53
L/min),  or  750 kpm (VE,  62 L/min) and breathed either clean air or  0.50 ppm S02
for  5  min.  Mouthpiece inhalation of  S02 resulted  in  increased  SRaw at  moderate
(231 percent)  and heavy (306  percent) workloads,  but with  facemask breathing,
the  SRaw only increased  at  the heavy workload (219 workload). The oral
component of ventilation  during mask breathing  was  approximately 38 L/min at
the  heavy workload,  similar to the  oral  ventilation of 41 L/min with mouthpiece
breathing at the moderate workload;  the  similarity of SRaw responses in  these
two  cases  is  noteworthy.   From  these  studies  it is apparent  that oronasal
breathing ameliorates some of the  effect of S02  breathing in  asthmatics, but
this effect becomes  less  important as the  exercise workload increases  and both
the  overall ventilation  rises  and the relative  contribution of oral ventilation
 to total ventilation increases.
      Kleinman (1984)  has  modeled the bronchoconstriction  response  to  S02  in
 relation to ventilation,  oral/nasal  partitioning of ventilation,  and  differ-
 ences in  S02  -scrubbing capability  of the  two  upper airways.   This model
 suggests that differences in  response  to S02 can be quantitatively accounted
 for by  differences  in penetration of S02  to target  sites  within the lower or
 thoracic, airways (defined as  structures at or just below the laryngopharynx).
                                      4-23

-------
     Because of the  possible  interference with oral breathing during the face-
mask exposures, Bethel  et al. (1983a) studied 10 mild  asthmatics  exposed  to
0.50 ppm  S02 in an  exposure  chamber (23°C,  80 percent RH)  to  determine  if
freely  breathing  subjects  would  develop  bronchoconstriction  at  this
concentration.  Following  5  min  exercise  at  750  kpm (tf£  unreported,
approximately  50  to 60  L/min),  SRaw increased 39 percent  in clean  air but
increased  238  percent  in 0.50 ppm S02 similar to that previously observed  with
facemask breathing.  Thus mild asthmatics performing moderate to heavy exercise
exhibited  clear  evidence of  bronchoconstriction after  5  min exposure to  0.50
ppm S02 while breathing  unencumbered.
     In a  subsequent study (Bethel  et al., 1985), the  effects of 0.25 ppm  S02
were studied in 19 mild to moderate asthmatics using a similar protocol (23°C,
36  percent RH with  5 min exercise  at 750 kpm).  SRaw  increased from 6.38  to
11.32  post-exercise in clean air and from 5.70  to 13.33  post-exercise  in  0.25
ppm S02.   The slightly  greater  response following S02  exposure was  apparently
significant (p <0.05,  Wilcoxon one-tailed sign  test).   The application of a
signed rank test,  preferable in  this case, would not  confirm this  significance.
However,  when the workload was  increased to  1000 kpm in  9  of the  19 subjects,
the increase in SRaw after clean air exercise  was slightly, but not signifi-
 cantly, greater than  that  after  exercise with  0.25 ppm S02.   The authors
 suggested  that  the threshold concentration  of  S02  which may cause broncho-
 constriction in mild asthmatics  under conditions of  moderate to heavy  exercise
 appears close to  0.25  ppm.  However, the very  small rise  in SRaw at only one
 work output  indicates  that the additional effect of 0.25  ppm S0£ (over that
 produced  by  exercise)  is of minor,  if  any,  clinical significance.   Neverthe-
 less, it  must be stressed  that these asthmatics had relatively mild disease.
     Voenig  et  al.  (1983b) examined the effects of exposure to 0.5  and 1.0 ppm
 S02 combined with a sodium  chloride droplet aerosol in  nine extrinsic adoles-
 cent  asthmatics.   Judging from their medication  requirements,  this group of
 asthmatics would  have  to  be considered more severe than the adult asthmatics
 studied  by several other investigators.  The  exposures were delivered  via
 mouthpiece (22°C,  75+  percent RH)  for 10 min during  moderate treadmill exercise
  (30 min rest exposures were followed by 10 min  exercise).   The  responses  ranged
  from  a 15 percent  decrease  in  FEV1>0 at 0.5 ppm  to a 61  percent decrease in
           i                         .  _...      I  ll.l^^l_~.wu«*iK*it^At/tl*Vll^TH'1C
       at  1.0  ppm.   The response to  1.0  ppm tended to be  greater  but this
difference  between  S02  concentrations  did  not  attain overall  statistical
significance.  Nevertheless,  the effects  of S0£ on lung function  persisted
                                     4-24

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longer after  the  higher concentration  exposure.   FEV-j^ Q,  Vmax50 and Vmax?5
(partial  flow volume curves)  were significantly reduced and total  respiratory
resistance  (forced  oscillation)  was   significantly  increased  following
mouthpiece breathing of  0.5  or 1.0 ppm S02.  Seven  of nine subjects were also
exposed to 0.5  ppm S02 plus  aerosol  delivered  via a facemask (ventilation 5 to
6  times  rest or  30 to  50  L/min).   The  pulmonary function  changes  after
breathing 0.50  ppm S02 plus aerosol via  facemask were not significantly dif-
ferent from  baseline.   However, some of  the  subjects intentionally breathed
through  their nose  rather  than oronasally therefore  the  comparison of the
results  of  this  study with those  of  Bethel   et  al.  (1983a) would  not be
appropriate.                                                                  '-"'
      Previous  studies  (Andersen et al.,  1974)  cited  in the criteria document
have  suggested  that nasal resistance increases  following S02 exposure.   Because
this  could have  an important impact on  the  route of inhalation and/or  the
oronasal  ventilation switch point, Koenig and associates  (1985) examined the
effects  of 0.50 ppm S0£ on  the work of nasal  breathing in a group of moderate
adolescent  asthmatics  (7/10  were  theophylline users).  Subjects were  exposed
to S02  (and  H2S04 aerosol  -  100  ug/m3) either via mouthpiece or  oronasal
 facemask (22°C, 75 percent  RH).   Thirty min  resting exposure was followed by  20
 min of moderate  exercise on a treadmill (V£  = 43 L/min).   Exposure  to  S02  via
 mouthpiece or  facemask  resulted  in an  approximate 30 percent increase  in nasal
 work of breathing (measured with a divided diving mask containing two  pressure
 transducers which  measured  the pressure drop across the nasal  passages).  Due
 to marked inter-  and  intra-individual  variability in these nasal measurements,
 only the increase in  nasal  work of breathing after facemask exposure was found
 to be  statistically  significant.   No increase  occurred  with  clean air or
 sulfuric acid aerosol  exposure.   The decreases  in FEV-,^ n  and Vmax5Q were
 significantly  greater with mouthpiece than with  facemask exposure to  0.50 ppm
 SO
The implications of  this  finding may be of considerable importance.
                                                                              A
  rise  in nasal work of  breathing  could provoke a switch to predominantly oral
  breathing  during exercise at a lower  ventilation,  thus causing more inspired
  air to traverse  the oropharynx  rather than  the  nasopharynx.   Since  oral
  inhalation of S02 results in greater  increases in airway resistance and larger
  declines   in  spirometric tests,  an  increase in  the  proportion  of oral
  ventilation  due  to  nasal   congestion  could  result  in  S02-induced
  bronchoconstriction at  lower concentrations  in  freely breathing exercising
  asthmatics.
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4.3.4  Time Course of Response to SOo In Asthmatics
     Early studies of  SCL  exposure in normal healthy subjects indicated that
the peak  response  occurred early in exposure and  was reduced with continued
exposure.   The  effect of  prolonged or repeated exposure  has  recently  been
addressed in asthmatics.
     Sheppard and  associates  (1983) reported the responses of mild to moderate
asthmatics (n  = 8)  exposed three  consecutive  times  to 0.51 ppm  SOg.  The
subjects performed voluntary eucapnic hyperpnea with 0.5 ppm S02 for 3 min at  a
ventilation which  had  previously caused bronchoconstriction (air  temperature =
22.6°C, RH =  82 percent).   Three  subjects  failed  to  reach the target of  a 60
percent increase  in  SRaw above baseline and consequently performed additional
hyperpnea to produce increased SRaw.   Twice more,  at  30-min intervals,  the S02
hyperpnea was  repeated.   SRaw was measured before  and after each  S02  exposure.
A single bout of S02 hyperpnea was performed on the following day and again one
week  later.  The  first exposure to S02 caused a doubling of SRaw (104 percent
increase).  The second and third  S02 exposures elicited only modest increases
in  SRaw (35 percent,  30 percent respectively).   However,  1-day  and  7 days
later, the response to S02 was similar  (+89, +129  percent)  to that on the first
exposure.
      In  this  study, the relationship of S02 tolerance to histamine-induced
bronchoconstriction  was  examined in a  subgroup of four subjects.  A  baseline
histamine  challenge  test was followed 30 min later by two 3-min periods of S02
breathing  separated  by 30 min (as in the initial  part of the study).   When the
histamine  challenge was repeated  after a  further 30  min,  the  histamine
dose-response  relationship was unchanged despite  the blunted response  to S02
inhalation.   This study demonstrated that  repeated exposure of asthmatics to
0.5 ppm S0£ by mouthpiece  at 30-min intervals resulted in a blunted S02 re-
sponse (tolerance) which persisted for at  least 30 min but was absent after 24
h  and was not  associated  with any change  in airway  reactivity to histamine.
The implications  of this study  for response  mechanisms  are discussed  in
Section 4.3.
      Linn et al.'  (1984c) also studied  the  effect  of repeated S02  inhalation in
14  mild to moderate asthmatics who were exposed to 0.6 ppm S02 for 6 h on each
of  two consecutive days.  These were compared with similar clean  air  exposures.
They performed two  5-min  bouts  of exercise (V"E = 50 L/min), one immediately
 upon entering the exposure chamber (22°C and 85 percent RH) and a second bout 5
 h later.   SRaw was  measured immediately post-exercise  and at hourly  intervals
                                      4-26  .    .  •'.

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between exercise periods.  With  S02 exposure, SRaw was approximately  doubled
following each exercise  bout.  Small  increases  in  SRaw also  occurred following
exercise in clean air.  There were no differences in response between early and
                                                                             . i
late exercise  challenges and  no significant differences  in SRaw  response
between  exposure  days.   SGaw,  but not  SRaw, responses  indicated  smaller
decreases on the second  S02  exposure day (-0.091  sec-cm  H20) than the first
(-0.119  sec-cm H20).   This  difference  was  of  only marginal  statistical
significance and not  of  any  clinical importance.  The results  of this study
indicate that  S02~exercise challenges  separated by 5  h  (between  exercise
periods) produce essentially  similar  responses  and that the responses are not
appreciably different  on two  consecutive days.   The Linn  et al.  (1984c) and
Sheppard et al.  (1983)   studies had  several methodological differences;
respectively, these were free  breathing vs. mouthpiece,  exercise vs.  eucapnic
hyperpnea,  4.5 h vs.  30  min  interexposure  interval, 5 min vs.  3  min exposure
duration, and  0.6 ppm vs. 0.5 ppm  S02  concentration.   Nevertheless,  in each
study, an initial S02 exposure which produced at least a doubling of SRaw was
followed later by a second exposure.   With the shorter 30-min interval in the
Sheppard study, the  response  to  S02 was  blunted.   However, with the longer 5-h
interval in  the  Linn study,  the SO,,  response was  unchanged  from the initial
exposure.   Evidence  from the exercise-induced bronchoconstriction  literature
(Edmunds et al.,  1978;  Stearns  et  al.,  1981) indicates that the refractory
period following exercise induced bronchoconstriction persists for 2  to 4 h.
The refractory period following  S02-induced bronchoconstriction lasts  at least
30 min but less than 5 h.
     Snashall and Baldwin (1982) studied the effect of exposures to 8 ppm S02
repeated at 4 h and 24 h  in 4 normal and 1  asthmatic subjects.  Compared to the
initial  exposures,  S02~induced bronchoconstriction was  reduced  42 percent at 4
h while no difference was observed at 24 h.
     In a more comprehensive examination of repeated exercise during continuous
S02 exposure  in  a  large  subject population (n~28) exposed to 3 different S02
levels with repeated exercise, Roger et al.  (1985) also observed  attenuation of
S02-induced  bronchoconstriction.  The subjects  worked at  a  moderate  workload
(VV =  42 L/min) and breathed freely  (except for 2 min  at the end of exercise
periods 2 and 3). They were not  selected for  S02 sensitivity, were sensitive to
methacholine challenge,  and  used no cromolyn or steroids.   Each subject was
exposed, on three  different  days, to three  S02  concentrations (0.25,  0.50,  and
1.0).  During  each  exposure,  the subject exercised three  times  for 10 min each
                                     4-27

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separated by 15-min  intervals  between  exercise bouts.   SRaw was  measured  pre-
exposure and following  each  exercise period.   After the first exercise, SRaw
increased significantly over that  seen  with clean air (48  percent),   with
exposure to  both 0.5  (+93  percent) and 1.0  ppm S02 (+191 percent).  With
subsequent exercise  bouts in both  0.5  and 1.0 ppm  S0£, the SRaw  increased only
about half as much (third exercise SRaw increase was 52 percent and 116 percent
in 0.5  and  1.0 ppm,  respectively).   This attenuation of response was less than
that  seen  by  Sheppard et  al.  (1983).  Nevertheless,  there were  several
differences  between  the two studies (exposure  duration  3 min vs. 10  min,
inter-exposure  interval 30  min vs. 15 min, mouthpiece  eucapnic  hyperpnea vs.
free  breathing exercise,  S02 sensitive vs.  methacholine  sensitive selection
criterion).  The  subjects  in this study demonstrated a refractoriness to both
exercise in clean air  and  to  exercise  in S02; the latter  was  of greater
absolute magnitude in terms of  less  increase  in SRaw but the relative reduction
in  response from first to   last  exercise  periods was similar for repeated
exercise in  either clean air or S02.
      A  subset  of 10 subjects from  the Roger et al.  (1985) study were  further
studied by Kehrl  and coworkers (1986,  in  press).   The subjects  were selected
for moderate S02  sensitivity (i.e.,  no subjects  non-responsive to  S02 were used
and  the most reactive  subjects were not  studied).  In addition to the three
10-min  exercise periods performed  previously,  these subjects exercised  continu-
ously for  30 min at the same exercise intensity (v"£ = 41 L/min) in an environ-
mental  chamber (26°C,  70 percent  RH)  while exposed to 1,0 ppm S0r  The SRaw
data  for the original  intermittent  exercise exposures were similar to those of
the  original  larger  subject group (SRaw:  baseline 5.4, postexercise-1 14.7,
postexercise-2 12.8, postexercise-3 11.1). After  30 min continuous exercise in
1.0  ppm S02,  SRaw significantly  increased from 5.2 to 17.3 cm  H20-sec.  The
SRaw change was  not significantly different than that seen after  the  first  10
minute exercise  period of  the intermittent  exercise exposure.   This  study
 demonstrated  that  SOg-induced bronchoconstriction  is  elicited  by  10-min
 exposures  but  a further 20 min  of continuous  exercise  resulted  in only a
 slightly  greater increase  in SRaw  which  did  not  attain  statistical
 significance.
      In order  to examine the  time course  of recovery  from S02-induced  broncho-
 constriction  in  asthmatics, Hackney et al.  (1984) exposed 17  mild to  moderate,
 nonsmoking, S02-sensitive asthmatics (not using cromolyn or steroid medication)
 to 0.75 ppm S02 for 3 h.   A secondary objective of 'this  study was to  determine
                                      4-28

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the  usefulness  of  spirometric testing  as an  adjunct or alternative  to
plethysmography under such  exposure  conditions.  The exposure consisted of 3 h
in an environmental  chamber with  a 10-min exercise period (VE = 45  L/min) at
the beginning of  the exposure followed by post-exercise and hourly  SRaw  mea-
surements.  SRaw  was  approximately quadrupled (+263 percent) after  exercise,
returned almost to  baseline at one hour  (+34  percent,  not significant) and was
unquestionably back  to  baseline after 2 h recovery. In an otherwise identical
exposure  sequence  which included spirometric  testing,  the  FEV1 Q was
significantly reduced (-20 percent) post-exercise.   The correlation between the
FEV, Q  and SRaw  changes was  significant  (r = 0.60)  but  accounted for
considerably less than  half the variance,  indicating that the two  measures did
not track  each  other closely in all  subjects.   This  study  demonstrated that
moderate S02/exercise-induced  bronchoconstriction will  be relieved during rest
(over a 1 to 2 h period) even if a low-level S02 exposure is continued.   Second
the authors demonstrated that changes in FEV^ Q are also useful  indicators of
S02 exposure  in  asthmatics, although it is not clear that significant changes
in  FEV, 0  would  occur with less severe  exposure more  typical  of the ambient
environment.

4.3,5  Exacerbation of the  Responses of Asthmatics to SO., by Cold/Dry Air
     It has been well established  that both cold air and dry air can exacerbate
bronchoconstriction  in  asthmatics  (Deal  et al., 1979a; Strauss et al., 1977).
The  precise mechanism(s) for  the effect  are not  universally agreed upon
(Anderson,  1985).   Although direct convective cooling  of the  airway plays a
minor role, the major avenue of heat  loss  is  due to evaporation to humidify the
inspired  air.   Evaporation of  airway surface liquid may also lead  to  other
changes discussed in section 4.4.  The  potential  for  evaporative cooling by
inhaled  air can  be most readily  appreciated from  the determination of  the
absolute  humidity of the inspired air.  Absolute  humidity  (AH)  expresses the
water  content of the air in  mg/L  (g/m3).   The lower the AH, the  greater the
potential  for evaporative cooling.  AH  is  listed,  for  each study, in Table 4.
F6r reference,  the AH of saturated  air  at 37°C (i.e.   BTPS) is  44 mg/liter.
Therefore,  in order to  bring  inspired  air at 0°C, AH  = 1  mg/L  to BTPS,  the
temperature of each liter of air must be increased to 37°C (0.011 kcal) and 43
mg of water must be  evaporated (0.025 kcal)  (calculated from the respiratory
heat exchange equation  of Deal  et  al., 1979b).
                                      4^29

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     Sulfur dioxide  exposure  can occur  during the winter  months when the
ambient air temperature  is  low,  and consequently the water vapor content  is
reduced.  Accordingly, Bethel  and  coworkers  (1984) examined the  separate and
combined effects of  sulfur  dioxide and cold dry air in seven  asthmatics  (mil^
to moderate asthma)  breathing via  mouthpiece.   In  this  study and  the following
study by Sheppard  and coworkers (1984), a series  of  bronchpprovocation tests
were used.  The methods are as follows:

     The subjects  breathed  a test gas mixture for 3 min, then SRaw was deter-
     mined  every  30 s for 2  min.  This  cycle  of 3 min exposure and 2 min SRaw
     testing  was  repeated  until the  desired response was  achieved.   The
     vantnatorv bronchoprovocation  test consisted  of performing  voluntary
     eucapnic hyperventilation at increasing  ventilation levels  (20,  30,  40,
     50  60  etc.  L/min) while  breathing  a single test gas mixture.   The SO^
     h,nnrhnprovocation  test consisted of  breathing (eucapnic  hyperventilation)
      at some fixed  ventilation  and  gas temperature and humidity with succes-
      sively doubling levels  of  sulfur dioxide (e.g.  0, 0.125, 0.25, 0.50, 1.0,
      2.0 ppm S02) used as the stimulus.

 Bethel's subjects performed ventilatory bronchoprovocation tests  with both 0.50
 ppm SO,  in warm humid air and  with no S0£ in cold-dry air (-ll'C, dew point
 -15oC) until  an  increase in SRaw was observed in  order to  determine  the venti-
 lation which caused "little or no  bronchoconstriction" with  either  stimulus.
 At the selected ventilation,  subjects breathed on  a  mouthpiece for 3 min one of
 the following mixtures:  (1)  warm-humid (23°C,  dew  point = 18.4'C) fir, {2) warm
 humid air with 0.50 ppm S02,  (3)cold dry air, (4) cold dry air with 0.50 pp.
 SO     Modest but non-significant increases  in SRaw  followed  each  of  the  first
 three conditions [(1) +3 percent,  (2)  +38 percent,  (3) +18 percent].  However,
  the combination of 0.50 ppm S0£ and  cold dry air  caused a striking increase in
  SRaw  (from  6.94  to 22.35,  or  a  222 percent increase).   In  this  study,  the
  combined effect of breathing cold dry air and 0.50 ppm S02  via  mouthpiece was
 "clearly larger than the sum of the  individual response to either S02 or  cold

  dry ^Sheppard and  coworkers (1984) further explored the  interaction of breath-
  ing  cold  dry air  and SO- via  mouthpiece in  a group of 8 mild asthmatics.  The
  purpose  of  the study was' to determine the  relative contributions of Screwed
  air  temperature  (-20°C) and reduced water vapor content (0  percent  RH).   Using
                                        4-30

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a ventilatory bronchoprovocation  test  with cold dry air, the highest ventila-
tion which did not cause increased SRaw was determined.   The study consisted of
having the  subjects perform  eucapnic  voluntary hyperpnea,  at  the selected
ventilation, 6  consecutive times for  3  min  at a time with  2 min intervals
between efforts.  This  was done on four separate occasions  (different days)
ordered randomly.   On  one occasion, the subject breathed  cold-dry air only;
this did not cause an increase in SRaw.  The three other tests consisted of S02
bronchoprovocation  tests  at the selected ventilation with successive doubling
S02  concentrations  (starting at 0.125 ppm), one with  cold dry  air, one with
warm-dry (22°C,  0 percent RH) air, and  one  with warm-humid (22°C, 70 percent
RH)  air.  The S02 concentration required to produce a doubling of baseline SRaw
(PC100) was  interpolated from the dose-response curve.   The PC100 for cold dry
air  (0.51 ppm) and  for warm dry air (0.60 ppm) were not  significantly different
but  both were  less than the  PC100  for warm humid air (0.87 ppm).  The PC100
measured in  this study may not be a useful effects index because the response
may  be  a function of the cumulative effect of all  S02 concentrations breathed,
as  noted by the authors.   In addition, the authors considered  the possible
mitigating  effect of repeated exposure - tolerance, but the importance of this
is   unclear.   Further   studies   were  performed  using  a   ventilatory
bronchoprovocation  test while breathing either  0.0, 0.1,  or 0.25 ppm S0£  in
warm-dry  air.    From  the ventilation-SRaw dose-response plots  at  each  S02
concentration,  the ventilation producing an 80 percent  increase in SRaw (PV80)
was  determined.   The PV80  at 0.0,  0.1,  and 0.25 ppm S02 were 54.9, 51.1, and
49.3 L/min, respectively.   The differences  in PV80 between 0.1 or 0.25 and
clean air (0.0  ppm) reportedly  reached significance although it was not  clear
 how these  data  were  analyzed  (presumably  repeated measures  analysis  of
variance).   Regardless of whether  or  not  the  difference in PV80 between  clean
 air and 0.1 and 0.25  ppm S02 was  statistically significant, the  magnitude of
 this difference  is  small  and of  no established or obvious clinical  importance.
 Nevertheless,  the  first  part of this study did confirm that breathing dry air
 and cold  air  potentiates  sulfur dioxide-induced  bronchoconstriction.  This
'potentiation could be  an additive  effect  since both cooling (convective and
 evaporative) and drying  of the airway may act  as  direct bronchoconstrictive
 stimuli, per se (Sheppard et al.,  1984).   In  addition,  the  drying of the  upper
 airway also reduces the ability of the oropharynx to scrub S02  from the inhaled
 air and may also cause a concentrating effect of the remaining airway surface
 liquid (see Mechanism section).
                                      4-31     •  •'-

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     Concurrent studies by Linn and coworkers (1984a) also were directed at the
possible  interaction  of inhalation  of  sulfur dioxide  and cold air.  They
studied a group of 24 mild to moderate SOg-sensitive asthmatics.   A preliminary
study to  determine  the effects of humidity  at cold ambient temperatures in-
cluded eight  subjects  exposed to 0.0, 0.2,  0.4,  and 0.6  ppm S02  at 5°C  under
two humidity  conditions  (81 percent and 54  percent).   The subjects exercised
for 5  min  in an environmental chamber  at a workload selected to  elicit  a
ventilation of  approximately 50 L/min (range 37  to 60)  and breathed naturally.
SRaw showed a  tendency  to  increase  more  from pre-  to post-exposure with
increased  S0£  concentration.   The post-hoc  analyses for  changes  at each
concentration were  not presented, presumably because of the small  sample  size
and the  non-randomized experimental design.  No  effect of  ambient  humidity on
response  to S02 was seen  at the  5°C  air temperature.  However, the difference
in water vapor content at  the low and high humidities was approximately 1.84
mg/L,  approximately 1/20  of the difference in water vapor pressure between
ambient  and  BTPS,  and thus  the  absence  of  a difference should have been
expected.   A second • study  in this same  series  compared  responses  of 24
asthmatic subjects  exposed  to  0.6  ppm  S02 under warm-humid (22°C, 85 percent
RH,  AH = 16.5)  and cold humid (5°C,  85 percent  RH, AH  =  3.4)  conditions.  The
same  exercise  and natural  breathing  procedures as above were followed.
Breathing 0.0 ppm  S02,  subjects  had small non-significant  increases  in SRaw
 under  warm (27 percent) and cold (38 percent) conditions.   0.6 ppm S02 exposure
 under  these  temperature-humidity conditions  produced significant increases  in
 SRaw in  both warm  (132 percent) and cold (182 percent)  conditions.   However,
 the temperature effect,  unlike in the  Sheppard et al.  (1984)  and  Bethel et al.
 (1984) studies, was  not significant although the trend was in the direction  of
 an increased response at the  lower  temperature.   The  temperature difference
 between  cold and warm air was larger in  the Sheppard et al. and Bethel et al.
 studies  (42°C and 34°C, respectively) compared to the Linn et al.  study (17°C).
 However  the  cold-warm  difference  in inspired  air water  content (AH)  were
 similar  for  the three studies (14.8, 12.6, 13.1 respectively).  Nevertheless,
 ft is apparent  that the exacerbation of S02-induced  bronchoconstriction by cold
 air, containing small quantities of water vapor,  is  minimal in freely breathing
 asthmatics exposed during moderately heavy exercise  at 5°C air temperature.
       In  order  to  determine the possible effects  of even colder ambient air
 temperatures,  Linn et  al.  (1984b)  exposed  24  mild S02-sensitive asthmatic?
  (including 11 subjects from  Linn,  1984a) to 0.0, 0.'3, and 0.6 ppm S02 at +21,
                                       4-32

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+7, and -6°C  (RH approximately 78 percent).   The exposure duration was 5 min.
The authors noted  that "only 10-20  percent of clinically  asthmatic  prospective
subjects had  to  be rejected as non-responsive to  S02"  (10 min  exercise  at 40
L/min breathing  0.75  ppm S02).   There was a  significant  effect of  decreasing
air temperature  and  of increasing S02 concentration  on  the post-exercise SRaw.
However, the  authors  reported  that there was no  statistically significant
interaction of  air temperature and S02  concentration for SRaw  although the
interaction was  apparently  significant for SGaw.  The  effect of cold air (in
increasing SRaw  or decreasing SGaw) was most  pronounced  with the 0.0 ppm S02
exposures and minimal with 0.6 ppm exposures.   The results of this study do not
support the hypothesis that S02 acts  synergistically with cold air in freely
breathing, exercising, mild to moderate asthmatics.  The authors concluded that
the cold air  and S02 effects "acted additively at most."  The results for the
7°C and 21°C 0.6  ppm S02 exposures (+207 percent,  +150  percent SRaw) were
similar to  those  seen  in their previous  (1984a)  study (+182  percent, +132
percent SRaw), thus demonstrating the  reproducibility of these studies.
     In order to study the full range  of S02-temperature-humidity interactions,
Linn et al. (1985a) also examined the  effects of warm-dry (38°C, 20 percent RH)
and warm-humid  (38°C, 85 percent RH)  conditions on  22  SOg-exposed (Q.(5 ppm)
asthmatics.  The exposure protocol was similar to the two 1984 studies with a 5
min chamber exercise period and ventilation  of  approximately  50 L/min.   The
experimental design was a three-factor (S02-0.0 and  0.6 ppm; temperature-21 and
38°C; and  humidity-20 percent and  80  percent) factorial  design with repeated
measures across  all  factors.  In this study,  the  major differences would be
anticipated to occur  between  the warm  humid (38°C, 85 percent RH) condition and
the  cooler dryer  condition (21°C,  20 percent RH).   There were  significant
effects  of  temperature,  S02 and  humidity  on  the  delta-SRaw  (pre  to
post-exercise)  response  and significant  temperature-S02 and  humidity-S02
interactions.   The largest clean air  increase in  SRaw  (20 percent)  occurred
with  cool-dry air and the  smallest with warm-humid.  The largest S02 induced
increase in SRaw (204 percent) occurred  under cool-dry  conditions and again the
smallest  change (35 percent) occurred under  warm-humid conditions.  Symptoms
showed  a  similar pattern of  response  after  S02  exposures with lower symptoms
scores  under  warm-humid than cool-dry conditions.   SRaw responses to 0.6 ppm
S0?  under 21°C-humid conditions were  similar for all three Linn et al.  studies
(1984a,  132 percent; 1984b,  150  percent;  1985a, 157 percent).   The  response
under warm humid conditions  was  considerably less.   The  authors discussed the
                                      4-33

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possibility that  they observed a  synergism  between S02 exposure and airway
drying/cooling due to reduced temperature or humidity of inspired air.
4.4  MECHANISM(S)
4.4.1  Mode of Action
     A single unequivocal definition of asthma is not realistic on the basis of
existing knowledge  and  the heterogeneity of the  disease.   The  single  condition
that  is  common to all definitions  of  asthma is  the reversibility of slowed
forced  expiration  presumably  due  to  airway  narrowing  (smooth  muscle
contraction, excess mucous secretion, mucosal edema).  Most current definitions
of asthma also include the concept of nonspecific airway hyperreactivity (e.g.,
methacholine,  histamine).   The present American  Thoracic Society definition of
asthma is:

     A disease characterized by an increased responsiveness of the airways to
     various  stimuli  and  manifested  by  slowing  of forced expiration which
     changes in  severity either spontaneously or with treatment.

It  is  noteworthy that the data summarized in this addendum indicate that asth-
matics  experience  substantial, but transient,  bronchoconstriction  (slowed
forced  expiration) when exposed  to low S02 concentrations (i.e. increased
responsiveness).
      Because  of  its  relatively rapid reversibility, SOg-induced bronchocon-
striction  in asthmatics  is likely the  result of  decreased airway caliber caused
by  contraction of airway  smooth muscle.   The study of  Roger et al. (1985)  in-
dicated  the largest  S02-induced increases  in airway  resistance measured by
plethysmography were associated with  increases  in  the  low frequency  component
of  respiratory  system  impedance measured  by  the  forced  random oscillation
 (noise)  technique.  The interpretation  of this  finding was an  elevated peri-
pheral  resistance associated  with  constriction  of  anatomically peripheral or
 small airways.   However,  narrowing of central  upper airway structures such ,as
 the larynx and  glottis  may accompany  increased  airway  resistance (Cole,  1982)
 and it is possible that some of the increase in  airway  resistance may be due to
 elevated laryngeal or glottal resistance.
      Contraction of airway  smooth  muscle in response to environmental stimuli
 can be  evoked  by intrinsic chemical  and/or physical stimuli  acting via neural
                                      4-34       •   '

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and/or  humoral  pathways.   S02 may either act directly on smooth muscle or may
cause the  release of chemical mediators from tissue,  especially the release of
histamine  from  mast cells.   It is beyond the scope of this  document to provide
even a  brief review of the mechanism  of action of all  the  possible pharmaco-
logic mediators of SOp-induced bronchoconstriction.  However,  some plausible
candidates  include histamine, slow-reacting substance of anaphylaxis,  leuko-
trienes, and prostaglandin  F2-alpha,  all of which are released in the airways
and can cause smooth muscle contraction.
     As reported  in the previous addendum (U.S. EPA, 1982c), both activation of
parasympathetically  mediated  reflexes  (Nadel et al., 1965;  Sheppard et al.,
1980) and  mast  cell degranulation (Sheppard et al., 1981) with consequent re-
lease of chemical mediator  (most likely histamine) play a significant role in
S02-induced  bronchoconstriction.  While the specific  mechanism whereby S02 in-
teracts with the  airways to induce bronchoconstriction has not been elucidated,
two reports  of  studies  relevant to the  mechanism(s)  have appeared since the
previous addendum. These studies assessed the inhibitory effects on SOVinduced
bronchoconstriction of  a  variety of receptor antagonists (drugs that bind ^he
receptors  but do  not stimulate the receptor-induced  response).   Results  from
these studies suggest that mechanisms in addition to reflex  bronchoconstriction
and mast cell degranulation may play a significant part in the responses of the
asthmatic airway  to S02.
     Snashall and Baldwin (1982) studied the effects of atropine and cromolyn
on  relatively mild  bronchoconstriction (Raw  increased  <100 percent  above
baseline) induced by breathing 8 ppm S02 at rest. Both atropine and cromolyn at
least partially blocked S02-induced  bronchoconstriction in  all but one of 11
normal  subjects.  The  degree  of atropine blockade was inversely related to the
magnitude of  the  SOy-induced  response  (r = -0.75), i,e., small responses were
completely blocked, while there was  little blockade  of  large  responses.  For
asthmatics,  atropine enhanced S02-induced  bronchoconstriction  in  three of four
subjects tested;  minimal  blockade was observed in  the remaining  subject.
Cromolyn blocked  the S02-induced  response  in three  of the four  asthmatic
subjects.
     Tan et al.  (1982) exposed resting normal and atopic subjects to 20 ppm and
asthmatics  to  10  ppm S02  to  induce bronchoconstriction.  Both ipratropium
bromide (IB,  an anticholinergic agent  similar to atropine)  afid cromolyn  par-
tially inhibited  the  S02~induced response  in all normal and atopic subjects
tested.  For asthmatics,  IB had little effect on S02-induced  bronchoconstriction
                                     4-35       .  •'.    •

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in five of  nine  subjects  and afforded only partial blockade in the remaining
four subjects. Cromolyn at  least partially inhibited S02-induced bronchocon- ^
striction in  all 18 asthmatics  tested.  Clemastine  (a selective HI receptor
antagonist  without  anticholinergic or antiserotinergic activity) effectively
blocked the SOg-induced response in five of seven asthmatic subjects tested.

4.4.2  Breathing Mode and Interaction With Dry Air
     There  is no question that the magnitude of SOg-induced bronchoconstriction
is  significantly greater with  oral  than  with  oronasal or nasal breathing
(Kirkpatrick  et  al.,  1982).  When S02 is  inhaled by mouth more S02 penetrates
beyond the  pharynx to sites involved  in the  induction of bronchoconstriction
(Bethel  et  al.,  1983b; Kleinman,  1984).  It  is  assumed that because of their
geometry  and  greater relative surface area, the nasal  passages are capable of
effectively removing most S02 breathed  at rest and a large percentage during
conditions  of increased  ventilation (exercise, isocapnic hyperpnea).  While
there is certainly less  relative  surface area  available for S02 scrubbing in
the oral  cavity, other factors  may also  influence  increased .bronchoconstriction
associated  with mouth breathing of S02,  especially at higher ventilation  rates.
      Increased oral ventilation may result in  substantial drying of both upper
 (oral and  pharyngeal  area)  and  lower  (larynx and trachea) airways.   The extent
 of airway  surface  drying will  depend upon the  ventilation (air flow rate)  and
 water content of  inhaled air.   Airway drying could lead to alterations in both
 the quantity and properties of surface liquid in the airways.   Decreased  volume
 of and/or  surface  area of liquid in  the upper airway may result in  decreased
 efficiency of  S02  absorption,  allowing deeper penetration of the gas to  sites
 in  the  intrathoracic airway  more  likely  involved  in  the induction of
 bronchoconstriction.   Decreased quantity of surface liquid in  the  lower  airway
 may  result in a reduced volume  in  which soluble gases such as  S02 can  forip
 solutions.   The chemical interactions of S02  and S02-generated ionic species
 could  be altered by  reduced fluid  volume or by changes  In concentrations of
 other  substances in surface liquid,  which  could alter the equilibria between
 the SO- ionic  species.  Another  factor which  is altered by drying  of airway
  surface liquid is  its  osmolarity.   Hyperosmolar  solutions  can   induce
  bronchoconstriction (Anderson, 1985) and could be associated  with enhancement
  of S09-induced bronchoconstriction.
       Two  laboratories (Cardiovascular  Research Institute, UCSF, and  Rancho  Los
  Amigos  Hospital)  have performed the  bulk of the wofk on  the interaction of  S02
                                       4-36

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breathing  and  inhaled air temperature and humidity.   Although  the results of
the  two  labs have been qualitatively similar,  the mouthpiece breathing studies
(e.g. Bethel et al.,  1983b) have typically yielded more pronounced increases in
airway resistance.   In S02 exposures using oronasal ventilation, interlabora-
tory differences have been smaller.  The use of mouthpiece breathing results in
a more direct  airflow path of lower resistance than does  unencumbered oronasal
breathing  (Proctor,   1981;  Cole,  1982).  Under situations of  unencumbered
oronasal breathing, the mouth may act as an effective organ of air modification
(i.e. warming,  humidifying,  scrubbing of particles and soluble  gases).   During
mouthpiece breathing,  this  effectiveness is  reduced because of the alteration'
in oral  airway geometry.   Thus some of the difference  between laboratories may
be due to  differences in the  amount  of  airway drying  and the volume  of nasal
ventilation, both  of  which would favor greater upper  airway SO« scrubbing in
studies using oronasal ventilation.  Undoubtedly subject selection criteria and
medication also play  an important role in the magnitude  of  response  but such
differences  between study  series  are not obvious (see subject table). Another
possibility, noted incidentally  by Koenig et al.  (1985),  is'that subjects may
deliberately breathe  via  the  nasal airway,  despite  the higher  resistance,  in
order to alleviate both the drying effect due  to  cold  (and/or dry)  air and the
effect of S02 which may be associated with the distinctive odor or taste.
     Cole (1982) notes that approximately 85 percent of adults are preferential
nose breathers who only  resort to  oral  or oronasal  breathing under  the
demanding conditions  of exercise,  nasal  obstruction, or  speech.   This occurs
despite the  fact  that upper airway resistance  via  the nasal airway is about
twice that  via a  mouthpiece.   However,  Bethel et  al.  (1983b)  suggest more
asthmatics may breath  oronasally  and that asthmatics switch from nasal to
oronasal  breathing at a lower ventilation than normals;  this is due  to the
greater prevalence of rhinitis in the asthmatic population.

4.4.3  Tolerance (Attenuation of Response) to SOg With Repeated Exposure
     Attenuation of SOn-induced  bronchoconstriction with  repeated S0« exposure
(With eucapnic  hyperpnea)  was  not  associated with a decrease in airway respon-
siveness to  histamine  (Sheppard et al., 1983).  This  indicates  that this
attenuation  of  response was  not related to decreased responsiveness of airway
smooth muscle  or  decreased responsiveness  of vagal reflex  pathways.   These
authors did  suggest that  depletion of mediators  or a  selective inhibition of
S02-sensitive afferents might  be  involved in this phenomenon.  For equivalent
                                     4-37       -  •'

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total  exercise time,  Kehrl  et  al.   (1986)  observed greater  SO^-induced
bronchoconstriction with continuous as compared to intermittent exercise during
SO*  exposure.   These findings suggest  that  mediator depletion or selective
inhibition  of  afferents, as well  as exercise-induced release of endogenous
bronchodilators (epinephrine) are  probably not related to the attenuation of
response with  repeated  exposure  (or repeated intermittent  exercise  during
exposure).
     The results obtained by Kehrl et al.  (1986) are highly suggestive that the
attenuation of  SC^-induced bronchoconstriction is  related  to events that  occur
during the  post-exposure/post-exercise  recovery periods  rather than  events
occurring during the  exposure  per se.  It is  likely that  during the  recovery
periods, there is some mechanism that first helps alleviate bronchoconstriction
and  may  then prepare  the  subject for  subsequent challenge.  Without the
recovery period,  the continuing  stimuli  of  high  ventilatory  rates and S02
exposure overwhelm  any  attenuating  process  resulting in unremitting  or  in-
creasing bronchoconstriction.  Since drying of the upper airways  with  resultant
changes in  surface  liquid  quantities and properties  has been  strongly impli-
cated in the positive interactions between ventilation and  SCL exposure, per
haps a  corollary mechanism  may  account for the attenuation of  SO^-induced
response.
     It is  clear that increased  evaporation  of water from airway mucosal  sur-
faces must  occur  during exercise or  hyperventilation (Anderson,  1985).   The
continuance of  increased production  and/or secretion of airway surface liquid
during recovery periods  may  result in decreased delivery of SOy during subse-
quent inhalation of  SOp.  Whether or not SOp has any effect on surface liquid
quantity is unknown.   Increased  liquid in the lower airways  would  prevent
severe alterations in surface liquid properties postulated to occur when SOp  is
dissolved in this  liquid.   Protection from subsequent challenges would be a
time-dependent  phenomenon  and  would resolve  as the  factors  governing airway
surface liquid homeostasis gradually return to normal.
     Attenuation of bronchoconstriction has been reported for exercise (Stearns
et al., 1981) and hyperpnea of cold, dry air  (Bar-Yishay et al. 1983,  Wilson  et
al., 1982) repeated at short time intervals,  suggesting that the attenuation  of
S09-induced bronchoconstriction may be secondary to this decline in respons
                                                •
                                     4-38

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4.5 CONCLUSIONS
     Studies which have  been  published in  the  scientific  literature  since  1982
support many of  the  conclusions reached in the criteria document and th'e pre-
vious addendum.
     The new studies  clearly  demonstrate that asthmatics are much more sensi-
tive to S0«  as a group.   Nevertheless, it  is clear  that there  is  a broad range
of sensitivity to  SO* among asthmatics exposed under simiTar conditions.  Re-
cent studies also  confirm that normal healthy subjects, even with moderate to
heavy, exercise,  do not experience effects  on  pulmonary function due  to S02
exposure in  the  range of 0 to 2 ppm.   The  minor  exception may  be  the annoyance
of the  unpleasant smell or taste  associated  with S02.  The suggestion  that
asthmatics are about  an order of magnitude more  sensitive than normals is  thus
confirmed.
     There is  no longer any question  that  normally breathing  asthmatics per-
forming moderate to  heavy  exercise  will experience  S02-Induced  bronchoeon-
striction when breathing SOg  for at least 5 min at concentrations less than 1
ppm.   Durations  beyond 10 min do not  appear to cause substantial  worsening of
the effect.  The lowest concentration at which bronchoconstriction is clearly
worsened by SO* breathing depends on a variety of factors.
     Exposure  to less than 0.25 ppm  has  not  evoked group mean  changes in
responses.    Although  some individuals  may  appear  to  respond  to  Sp2
concentrations less  than 0.25  ppm,  the  frequency of these responses  is npt
demonstrably greater  than with clean air.   Thus  individual responses cannot be
relied  upon  for  response estimates,  even  in the most reactive segment of  the
population.
     In the  S02  concentration range from 0.2 to 0.3 ppm,  six  chamber  exposure
studies were performed with asthmatics performing  moderate to heavy exercise.
The evidence that S02~induced bronchoconstriction  occurred at this concentra-
tion with  natural  breathing under  a  range  of ambient conditions was  equivocal.
Only with oral mouthpiece breathing of dry  air (an  unusual breathing mode  under
exceptional  ambient  conditions) were small effects  observed on a test of ques-
tionable quantitative relevance  for criteria development purposes.  These  find-
ings are  in accord with  the  observation that the most  reactive subject  in the
Horstman et  al.  (1986) study had a PCS02 (S02 concentration required to double
SRaw) of 0.28  ppm.
     Several  observations of  significant  group mean  changes  in SRaw have
recently been  reported for asthmatics exposed to 0.4  to  0.6 ppm  SO,,.  Most if
                                     4-39

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not all studies,  using  moderate to heavy exercise levels  (>40  to 50 L/min),
found evidence of  bronchoconstriction  at 0.5 ppm.  At a lower exercise rate,
other studies (e.g.,  Schachter  et  al., 1984) did  not produce clear evidence of
SQp-induced bronchoconstriction  at 0.5  ppm  S02.   Exposures which  included
higher ventilations,  mouthpiece  breathing,  and inspired air with a  low water
content resulted  in  the greatest  responses.   Mean  responses ranged from 45
percent (Roger et  al.,  1985)  to 280 percent  (Bethel et al., 1983b) increase in
SRaw.  At  concentrations  in  the range of 0.6  to  1.0 ppm,  marked  increases in
SRaw are observed  following  exposure.   Recovery is generally complete within
approximately 1 h  although the  recovery  period may be longer for  subjects with
the most severe responses.
     It is  now evident  that for S02-induced bronchoconstriction  to  occur  in1
asthmatics  at concentrations  less than 0.75  ppm,  the exposure must  be
accompanied by hyperpnea.  Ventilations  in the range of 40  to  60 L/min have
been  most   successful;  such  ventilations  are  beyond  the usual  oronasal
ventilatory switchpoint.
     There  is no longer any question that oral breathing (especially via mouth-
piece)  causes exacerbation of  S02~induced  bronchoconstriction.   New studies
reinforce the concept that the mode of breathing is an important determinant of
the  intensity of  S02-induced bronchoconstriction  in  the following order:  oral
> oronasal >  nasal.
     A  second exacerbating factor strongly implicated  in recent reports  is  the
breathing  of  dry  and/or cold air  with S02-   It has been  suggested  that the
reduced water content and not cold, per se,  could be  responsible for much  of
this  effect.  Airway drying may contribute to the S02  effect by decreasing  the
efficacy of S02  scrubbing by the  surface liquid of the oral and  nasal airway.
Drying  of  airways  peripheral  to the 1aryngopharynx may result  in  decreased
surface liquid volume to buffer  the effects of S02-
      The new  studies  do not provide sufficient additional  information to estab-
lish whether the intensity of the S02-induced bronchoconstriction depends  upon
the  severity of the  disease.   Across  a  broad clinical  range from "normal"  to
moderate  asthmatic there  is  clearly a  relationship between the  presence  of
asthma  and sensitivity to S02.  Within the asthmatic population, the relation-
ship of S02  sensitivity to the  qualitative clinical severity of asthma has not
been studied systematically.   Ethical  considerations  (i.e., continuation of
appropriate medical treatment)  prevent the  unmedicated  exposure of the  "severe"
asthmatic  because of his  dependence  upon drugs for control of his asthma.  True
                                      4-40      •  •'

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determination of sensitivity  requires  that the interference with S02 response
caused by  such medication be  removed.   Because of these mutually exclusive
requirements, it is unlikely that the true S02 sensitivity of severe asthmatics
will be determined.   Nevertheless,  more severe asthmatics  should be studied.
Alternative  methods to  those  used  with  mild  asthmatics,  not  critically
dependant on  regular  medication,  will  be  required.  The  studies to  date  have
only addressed the "mild to moderate" asthmatic.
     Consecutive S02  exposures (repeated within 30 min or  less) result in a
diminished  response compared  with the initial  exposure.  It  is  apparent  that
this refractory period lasts at least 30 min but that normal reactivity returns
within  5  h.  The mechanisms and  time  course  of this effect are not clearly
established but refractoriness does not appear to be related to an overall
decrease in bronchomotor responsiveness.
     From the review of studies included in this addendum,  it is clear that the
magnitude  of response (typically bronchoconstriction) induced by any given SD2
concentration was  variable among individual  asthmatics.   Exposures to S02
concentrations of  0.25 ppm or  less, which did not  induce  significant group mean
increases  in airway resistance also did not cause symptomatic bronchoconstric-
tion in  individual  asthmatics.  On  the  other  hand, exposures to  0.40 ppm S02  or
greater  (combined  with moderate  to  heavy exercise)  which  induced significant
group  mean increases in  airway resistance,also  caused  substantial bron-
choconstriction in some invididual  asthmatics.  This bronchoconstriction was
associated with wheezing  and  the  perception  of  respiratory  distress.   In
 several  instances  it was necessary to  discontinue  the exposure and provide
medication.  The significance  of these  observations is that some S02-sensitive
 asthmatics are at  risk of experiencing  clinically significant (i.e., symptoma-
 tic)  bronchoconstriction  requiring termination  of  activity and/or medical
 intervention when  exposed to  S02 concentrations of 0.40 ppm  or greater when
 this exposure is accompanied by at least moderate activity.
                                      4-41

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                         CHAPTER 5.  EXECUTIVE SUMMARY
     In general,  studies  published in the scientific literature since 1981-82
support many of  the conclusions reached in the  earlier criteria  review (U.S.
EPA, 1982a,c).   Some  of the key findings emerging from the present evaluation
of the  newly  available information on health effects associated with exposure
to PM and SO  are summarized here.
            f\
5.1  RESPIRATORY TRACT DEPOSITION AND FATE
     Studies published since preparation of the earlier criteria document (U.S.
EPA, 1982a) and the previous addendum (U.S. EPA, 1982c) support the conclusions
reached at  that  time  and provide clarification of several  issues.   In  light  of
previously available data, new literature was reviewed with a focus towards (1)
the thoracic deposition  and clearance of  Targe particles,  (2)  assessment of
deposition during oronasal  breathing,  (3) deposition in possibly  susceptible
subpopulations, such,  as  children,  and (4) information that  would  relate the
data to refinement  or interpretation of ancillary issues,  such as inter- and
intrasubject variability in deposition,  deposition  of monodisperse  versus
polydisperse aerosols, etc.
     The thoracic deposition of  particles  >10  urn  D_Q and their  distribution  in
                                           """        36
the TB and P regions has been studied by a number of investigators (Svartengren,
1986; Heyder, 1986;  Emmett et al., 1982).  Depending upon the breathing regimen
used, TB deposition ranged from 0.14 to 0.36 for 10-um D3a particles,  while the
                                                        36
range for 12-jjm  D30 particles  was 0.09 to 0.27.  For particles 16.4 urn D=Q,  a
                  36                                                     3.6
maximally deep inhalation pattern resulted in TB deposition of 0.12.  While the
magnitude of deposition in various regions depends heavily upon minute ventila-
tion, there  is,  in  general,  a  gradual  decline  in  thoracic  deposition for large
particle sizes, and there can  be significant  deposition of particles  greater
than 10 urn  D_.  particularly for individuals  who  habitually breathe  through
             36                    *
their mouth.   Thus, the  deposition  experiments wherein subjects inhale througb
                                      5-1

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a mouthpiece are  relevant  to  examining the potential of particles to penetrate
to the  lower respiratory tract and pose  a  potentially increased risk.  In-
creased risk may  be due to increased  localized dose or to the exceedingly long
half-times for clearance of larger particles (Gerrity et al., 1983).
     Although experimental  data  are  not currently available for deposition  of
particles in the  lungs of children,  some trends are evident from the modeling
results of  Phalen  et  al.  (1985).  Phalen and  co-workers  made  morphometric •'
measurements in replica lung casts of  people aged 11 days  to  21 years and
modeled deposition  during  inspiration as a function of  activity level.  They
found that,  in  general, increasing age is associated with decreasing particu-
late deposition efficiency.   However, very high flow rates and large particu-
late sizes  do  not exhibit consistent age-dependent differences.  Since minute
ventilation  at  a given state of  activity is  approximately linearly related to
body mass,  children receive a higher TB  dose of particles than do adults  and
would appear to be  at  a greater  risk, other  factors (i.e., mucociliary clear-
ance, particulate losses in the  head, tissue  sensitivity, etc.) being equal.
 5 2  SUMMARY OF  EPIDEMIOLOGIC FINDINGS  ON  HEALTH EFFECTS  ASSOCIATED WITH
      EXPOSURE TO  AIRBORNE PARTICLES  AND SOX
      Newly available reanalyses of data  relating mortality in London to short-
 term (24-h)  exposures  to PM (measured as smoke) and  S02 were evaluated and
 their results compared with earlier findings and conclusions discussed in U.S.
 EPA (1982a).  Varying  strengths and weaknesses were evident in relation to the
 different individual  reanalyses  evaluated and  certain questions remain un-
 resolved concerning most.  Regardless  of the above considerations,  the following
 conclusions appear warranted  based  on the earlier criteria review  (U.S. EPA,
 1982a) and present evaluation of newly available analyses of the London mortal-
 ity experience:   (1)  markedly increased mortality occurred, mainly  among the
 elderly  and chronically  ill,  in  association  with BS and S02 concentrations
 above  1000  ug/m3, especially during  episodes when  such pollutant  elevations
 occurred for.several consecutive days; (2) the relative contributions of BS and
 S02  cannot  be clearly distinguished  from those of each  other,  nor can the
 effects of  other  factors  be clearly delineated, although it appears likely that
 coincident  high   humidity  (fog)  was  also  important  (possibly in  providing
                                        5-2

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 conditions leading to  formation  of H2$04 or other  acidic  aerosols);  (3) in-
 creased risk of  mortality is associated with exposure to BS and S02 levels in
 the range of 500 to  1000  ug/m3,  clearly  at  concentrations  in  excess of ~700  to
 750 ug/m ; and  (4) less certain  evidence suggests possible slight  increases  in
 the risk of mortality  at  BS  levels  below 500 ug/m3, with no specific threshold
 levels having yet been demonstrated or ruled out at lower  concentrations of  BS
 (e.g., at 150 ug/m ) nor  potential  contribution of other plausibly confounding
 variables having yet  been  fully evaluated.
      In addition  to  the  reanalyses of London  mortality data, reanalyses of
 mortality data from  New York City  in relation to air pollution reported by
 Ozkaynak and  Spengler (1985)  were evaluated.  Time-series analyses  were  carried
 out on a subset  of New York City data included in a prior  analysis by Schimmel
 (1978) which was critiqued during  the  earlier criteria  review (U.S.  EPA,
 1982a).   The reanalyses by Ozkaynak and  Spengler (1985)  evaluated 14 years
 (1963-76)  of  daily measurements of  mortality (the sum of heart, other circula-
 tory,  respiratory, and cancer mortality),  COH,  S02,  and  temperature.   In
 summary,  the  newly available reanalyses of New York City data raise possibili-
 ties  that, with additional  work,  further  insights may emerge  regarding
 mortality-air pollution relationships in  a large U.S.  urban area.   However, the
 interim  results reported thus  far  do not  now permit definitive determination  of
 their  usefulness  for  defining exposure-effect relationships, given the above-
 noted  types of caveats  and limitations.
     Similarly,  it is  presently  difficult to  accept  findings reported  in
 another  new study of  mortality associated with relatively  low levels of S0?
 pollution  in  Athens,  given questions regarding  representativeness of  the
 monitoring data  and the statistical  soundness of  using deviations of mortality
 from an  earlier  baseline relatively distant  in  time.   Lastly,  a newly reported
 analyses  of  mortality-air   pollution relationships  in Pittsburgh (Allegheny
 County,  PA) was  evaluated  as  having utilized inadequate  exposure  characteriza-
 tion and  the  results  contain sufficient internal  inconsistencies, so that the
 analyses are not useful for delineating mortality relationships with either S0?
 or PM.                                                                         Z
     Of  the  newly-reported analyses of short-term PM/SOX  exposure-morbidity
 relationships  discussed in this  Addendum,  the  Dockery et  al.  (1982)  study
provides the best-substantiated and  most  readily interpretable  results.  Those
results, specifically,  point  toward  decrements  in  lung function  occurring  in
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association with acute,  short-term  increases  in PM and S02 air pollution.  The
small, reversible  decrements appear to  persist for 1-2 wks  after  episodic
exposures to these pollutants across a wide range,  with no clear delineation  of
threshold yet being  evident.   In some study periods effects  may have been due
to TSP and  S02  levels ranging up to 422 and 455 ug/m3, respectively.  Notably
larger decrements  in lung function  were discernable for  a subset of children
(responders) than for others.  The precise medical  significance of the observed
decrements per se or any consequent long-term sequalae remain to be determined.
The nature  and  magnitude of lung function  decrements  found  by  Dockery et al.
(1982), it should be noted, are also consistent with: observations of Stebbings
and Fogelman  (1979)  of gradual recovery in  lung function of children during
seven days  following a high PM episode  in  Pittsburgh,  PA (max  1-hr TSP esti-
mated at  700  ug/m3); and a report by Saric et al.  (1981) of 5 percent average
declines in FEV-j^ Q being associated with high S02 days (89-235 ug/m3).
     In regard  to  evaluation of long-term exposure effects,  the 1982 U.S. EPA
criteria document (1982a) noted that certain  large-scale "macroepidemiological"
(or "ecologic" studies as termed by some) have attracted attention on the basis
of  reported  demonstrations  of associations  between mortality and  various
indices of  air  pollution, e.g.,  PM  or SOV levels.   U.S.  EPA  (1982a) also noted
                                         x\
that  various  criticisms  of then-available ecologic studies made it  impossible
to  ascertain  which findings may be  more valid than others. Thus,  although many
of  the  studies  qualitatively suggested positive associations between mortality
and chronic exposure to certain air pollutants in the United States, many key
issues remained unresolved concerning reported associations  and whether they
were  causal or  not.
      Since  preparation of  the earlier  Criteria Document (U.S. EPA,  1982a)
additional  ecological  analyses have been reported regarding  efforts to  assess
relationships between mortality and long-term exposure  to particulate matter
and other air pollutants.  For  example,  Lipfert  (1984) conducted a series of
cross-sectional  multiple regression analyses of 1969  and 1970  mortality rates
for up to 112 U.S.  SMSA's,  using the same basic  data  set as Lave  and Seskin
(1978)  for 1969 and taking into account various demographic, environmental and
lifestyle variables  (e.g., socioeconomic  status  and smoking).   Also, the
Lipfert  (1984)  reanalysis  included  several  additional  independent  variables:
diet;  drinking  water variables; use  of  residential  heating  fuels;  migration;
and SMSA growth.   New dependent  variables  included age-specific mortality rates
                                       5-4

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with their accompanying  sex-specific  age variables.   Both linear and several
nonlinear (e.g.,  quadratic  or linear splines testing  for  possible  threshold
model specifications) were evaluated.
     It became  quite  evident from the results obtained that the air pollution
regression results  for the  U.S.  data sets  analyzed by Lipfert (1984)  are
extremely sensitive to  variations  in the  inclusion/exclusion of  specific
observations (for central city versus SMSA's or different subsets of locations)
or additional explanatory variables  beyond those used in the earlier Lave and
Seskin analyses.  The  results are also highly dependent upon  the  particular
model specifications  used,  i.e.  air pollution coefficients vary in  strength  of
association with  total  or age-/sex-specific mortality depending upon the form
of the specification  and the range of explanatory variables  included in the  '
analyses.   Lipfert1s overall conclusion was that the sulfate regression coeffir
cients are not  credible  and, since sulfate  and TSP interact with each other  in
these regressions, caution is warranted for TSP coefficients as well.
     Ozkaynak and Spengler   (1985) have  also newly  described  results  from
ongoing attempts  to  improve upon previous analyses of mortality and morbidity
effects of air  pollution in the United States.   Ozkaynak  and  Spengler  (1985)
present principal findings  from a cross-sectional analysis of  the  1980 U.§.
vital statistics and available air pollution data bases for sulfates, and fine,
inhalable and total  suspended particles.   In these  analyses,  using multiple
regression methods, the  association between  various  particle measures and 1980
total mortality were estimated for 98 and  38 SMSA subsets by  incorporating
recent information on  particle  size  relationships and a set of socioeconomic
variables to control  for potential confounding.   Issues of model misspecifica-
tion and spatial autocorrelation of the residuals were also investigated.
     The Ozkaynak and  Spengler  (1985) results for 1980 U.S.  mortality provide
an interesting  overall  contrast to  the findings of Lipfert (1984)  for 1969-70
U.S.  mortality  data.   Whereas Lipfert found TSP  coefficients  to be most con-
sistently statistically  significant  (although varying widely  depending upon
model  specifications,  explanatory variables  included,  etc.),  Ozkaynak and
Spengler found  particle mass measures  including coarse particles  (TSP,  IP)
often to  be  non-significant  predictors  of  total mortality.   Also, whereas
Lipfert found the sulfate coefficients  to be even more unstable than the TSP
associations with mortality  (and questioned the credibility of the  sulfate
coefficients),   Ozkaynak  and  Spengler found  that particle exposure  measures
                                      5-5

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related  to  the respirable  or toxic  fraction  of the aerosols (e.g., FP or
sulfates) to  be most  consistently and significantly associated with annual
cross-sectional mortality rates.   It  might be tempting to hypothesize that
changes  in  air quality  or other  factors  from the  earlier data  sets  (for
1969-70) analyzed  by Lipfert (1984)  to the  later  data  (for 1980)  analyzed by
Ozkaynak and  Spengler  (1985, 1986) may at  least partly  explain their contrast-
ing results,  but  there is at present no basis  by which  to  determine  if this is
the case or which set of findings may or may not most accurately characterize
associations  between mortality  and chronic PM  or  SO exposures  in the United
                                                     /\
States.  Thus conclusions  stated in  U.S  EPA  (1982a)  concerning  ecologic
analyses still largely apply here  in regard to mortality PM/SO  relationships.
     The present Addendum also  evaluated a growing  body of new  literature on
morbidity effects  associated with chronic  exposures to airborne particles and
sulfur oxides.  In summary, of  the numerous new studies published  on morbidity
effects  associated with  long-term exposures to PM  or  SO  ,  only a  few may
                                                         J\
provide potentially  useful  results by which to derive quantitative conclusions
concerning  exposure-effect  relationships for the subject pollutants.  A study
by Ware  et  al.  (1986), for example,  provides evidence of'respiratory symptoms
in children being  associated with particulate  matter exposures in  contemporary
U.S. cities without  evident threshold across a  range of TSP  levels  of ~25 to
         o
150 ug/m .   The increase  in symptoms appears  to  occur without  concomitant
decrements  in lung function among the same children.  The  medical  significance
the observed  increased in  symptoms  unaccompanied by decrements  in  lung  of
function renjains  to be  fully evaluated but  is of  likely health concern.
Caution  is  warranted,  however, in using these findings for  risk  assessment
purposes in view of the lack of significant associations for the same variables
when assessed from data within  individual  cities  included in the  Ware et al.
(1985) study.
     Other  new American  studies provide evidence for:   (1) increased respira-
tory symptoms  among  young adults  in  association with annual-average  SO, levels
            3
of ~115  ug/m   (Chapman et al.,  1983);  and  (2)  increased prevalence of cough in
children (but not lung function changes)  being associated with  intermittent
exposures to mean peak 3-hr S02 levels of ~1.0 ppm or annual average S02 levels
of ~103 ug/m3 (Dodge et al., 1985).
     Results  from  one  European  study (PAARC,  1982a,b) also suggest the likeli-
hood of  lower respiratory disease symptoms and decrements  in lung function in
                                      5-6

-------
 adults (both male  and female) being associated with annual average S02 levels
 ranging without evident threshold from about 25 to 130 ug/m3.  in addition that
 study suggests that  upper  respiratory disease and lung function decrements in
 children may also be associated with annual-average S02 levels across the above
 range.  Further analyses would  probably be necessary to  determine whether or
 not any thresholds for  the health effects reported by  PAARC (1982a,b) exist
 within the stated range of annual-average S02 values.
 5.3  SUMMARY OF  CONTROLLED  HUMAN EXPOSURE  STUDIES  OF SULFUR DIOXIDE HEALTH
      tr r tv> I o
      The  new studies clearly  demonstrate  that asthmatics are much more  sensi-
 tive to S02 as a group.  Nevertheless, it is  clear that  there is a broad range
 of sensitivity to S02  among  asthmatics exposed under similar conditions.   Re-
 cent studies also confirm that  normal healthy subjects,  even with moderate to
 heavy exercise,  do  not experience effects on  pulmonary  function  due to S0?
 exposure  in the range of 0 to 2 ppm.  The minor exception may be the annoyance
 of the unpleasant smell  or  taste associated  with S02>   The suggestion  that
 asthmatics  are about an order of magnitude more sensitive than normals is thus
 confirmed.
      There  is  no longer any question  that normally  breathing asthmatics per-
 forming moderate to  heavy  exercise will  experience  S02~induced bronchocon-
 striction  when breathing S02 for  at least 5 min at concentrations  less than 1
 ppm.   Durations  beyond  10 min do  not appear to cause  substantial worsening of
 the  effect.  The lowest concentration at which bronchoconstriction is clearly
 worsened by S02 breathing depends  on a variety of factors.
      Exposure  to less  than  0.25  ppm  has  not evoked  group  mean changes  in
 responses.  Although  some  individuals  may appear to respond to S02 concentra-
 tions  less  than  0.25 ppm,  the frequency of these responses is not  demonstrably
 greater than with clean air.   Thus individual  responses  cannot be relied upon
 for response estimates,  even in the most reactive segment of the population.
      In the  S02  concentration  range from 0.2 to 0.3 ppm, six chamber exposure
 studies were performed  with  asthmatics performing moderate to heavy exercise.
The evidence that S02-induced  bronchoconstriction occurred at this concentra-
tion  with  natural  breathing  under a  range  of ambient  conditions  was equivocal.
Only with oral  mouthpiece breathing of dry air (an unusual breathing mode under
                                      5-7

-------
exceptional ambient conditions) were  small effects observed on a test of ques-
tionable quantitative relevance for criteria development purposes.   These  find-
ings are  in  accord with the observation that the most reactive subject  in the
Horstman  et  al.  (1986)  study had  a PCS02  (S02  concentration required to double
SRaw) of 0.28 ppm.
     Several  observations  of significant  group  mean changes  in  SRaw have
recently  been  reported  for asthmatics exposed to 0.4 to 0.6 ppm S02-   Most if
not all  studies,  using  moderate to heavy  exercise levels  (>40 to 50 L/min),
found evidence  of bronchoconstriction at 0.5 ppm.   At  a lower exercise rate,
other studies  (e.g.,  Schachter et al.,  1984) did not produce  clear  evidence  of
S02-induced  bronchoconstriction at 0.5  ppm S02.  Exposures  which  included
higher ventilations,  mouthpiece breathing, and inspired air  with a low water
content  resulted in  the  greatest responses.  Mean  responses ranged from 45
percent  (Roger  et al.,  1985) to 280 percent (Bethel  et al., 1983b)  increase  in
SRaw.  At concentrations  in the  range of  0.6  to 1.0 ppm,  marked  increases in
SRaw are observed following exposure.  Recovery  is  generally complete within
approximately  1 h although the recovery period may be longer  for  subjects with
the most severe responses.
     It  is now evident that  for  S02~induced bronchoconstriction  to occur in
asthmatics at concentrations less than 0.75 ppm,  the exposure must be  accom-
panied by hyperpnea.   Ventilations in the range of  40 to 60 L/min have  been
most  successful; such ventilations are beyond  the  usual oronasai ventilatory
switchpoint.
     There is  no longer any question  that  oral breathing (especially via  mouth-
piece)  causes  exacerbation of S02-induced  bronchoconstriction.   New studies
reinforce the concept that the  mode of breathing is  an  important determinant of
the  intensity of S02-induced bronchoconstriction in the following order:   oral
> oronasai > nasal.
     A  second exacerbating  factor strongly  implicated in recent reports  is  the
breathing of dry and/or  cold air with S02.  It  has been  suggested that the
reduced  water content  and not  cold,  per  se, could  be responsible for much  of
this  effect. -Airway drying may  contribute  to the S02 effect by decreasing  the
efficacy of S02  scrubbing by the surface liquid of  the oral  and  nasal  airway.
Drying   of airways peripheral to  the laryngopharynx may result in decreased
 surface  liquid volume to  buffer the effects of SOg.
                                       5-8

-------
      The new studies do not provide sufficient additional  information to estab-
 lish whether the  intensity  of the  S02-induced  bronchoconstriction depends upon
 the severity of the  disease.   Across a broad  clinical range from "normal" to
 moderate asthmatic  there  is clearly a  relationship  between the presence of
 asthma and sensitivity to S02<  Within  the asthmatic population, the  relation-
 ship of S02 sensitivity to  the qualitative clinical severity of asthma  has not
 been studied systematically.   Ethical  considerations (i.e., continuation of
 appropriate medical  treatment)  prevent  the unmedicated exposure of the "severe"
 asthmatic  because  of his dependence upon drugs  for control  of his asthma.  True
 determination  of sensitivity requires that the interference with SO^ response
 caused by  such  medication be removed.   Because  of these  mutually exclusive
 requirements, it is  unlikely that the true S02  sensitivity  of severe  asthmatics
 will  be determined.   Nevertheless, more  severe asthmatics  should be  studied.
 Alternative methods  to those  used  with  mild asthmatics,  not critically
 dependant  on regular medication, will be  required.   The studies to date have
 only  addressed the "mild to  moderate" asthmatic.
      Consecutive S02 exposures  (repeated within  30 min  or less) result  in a
 diminished  response  compared with  the initial  exposure.  'It is apparent that
 this  refractory period  lasts  at least 30 min but  that normal reactivity  returns
 within  5 h.  The mechanisms  and time course  of this effect are  not  clearly
 established but  refractoriness does  not appear to be related  to an  overall
 decrease in bronchomotor responsiveness.
      From the review of studies included in this  addendum,  it is clear that the
 magnitude of response (typically bronchoconstriction)  induced by any  given SO,,
 concentration was  variable  among  individual  asthmatics.   Exposures  to S0?
 concentrations of 0.25 ppm or less, which did not  induce significant group mean
 increases in airway  resistance  also did not cause symptomatic bronchoconstric-
 tion  in individual  asthmatics.  On  the other hand, exposures to 0.40 ppm S02 or
 greater (combined with  moderate to heavy  exercise) which  induced significant
 group  mean  increases  in  airway  resistance,also  caused substantial  bron-
 choconstriction  in  some invididual  asthmatics.    This bronchoconstriction  was
 associated  with  wheezing and the  perception of  respiratory distress.   In
 several  instances  it was  necessary to  discontinue the exposure and  provide
medication.   The significance of these  observations is that some S02-sensitive
asthmatics  are at  risk  of  experiencing clinically significant (i.e.,  symptoma-
tic)  bronchoconstriction  requiring termination of activity and/or  medical
                                      5-9

-------
intervention when exposed to  S02 concentrations of 0.40 ppm or  greater when
this exposure is accompanied by at least moderate activity.
                                     5-10

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                            CHAPTER 6.  REFERENCES
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Dockery, D. W.;  Ware,  J.  H.; Ferris, B. G., Jr.; Speizer, F. E.; Cook, N. R.;
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*These  references  were cited  in the First  Addendum and are  included here for
clarification  of correct journal volume and pages.
                            U.S. GOVERNMENT PRINTING OFFICE: 1986 - 646-014/40014


                                      6-16

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