SERIES 'RESPIRATORY EFFECTS OF AIR POLLUTION' Edited by P. Paoletti … · Edited by P. Paoletti...

Eur Respir J, 1996, 9, 1029–1054DOI: 10.1183/09031936.96.09051029Printed in UK - all rights reserved

Copyright ERS Journals Ltd 1996European Respiratory Journal

ISSN 0903 - 1936

Epidemiological studies of the respiratory effects of air pollution

M.D. Lebowitz

Epidemiological studies of the respiratory effects of air pollution. M.D. Lebowitz. ERSJournals Ltd 1996.ABSTRACT: Environmental epidemiological studies of the health effects of air pollu-tion have been major contributors to the understanding of such effects. The chroniceffects of atmospheric pollutants have been studied, but, except for the known res-piratory effects of particulate matter (PM), they have not been studied conclu-sively. There are ongoing studies of the chronic effects of certain pollutant classes,such as ozone, acid rain, airborne toxics, and the chemical form of PM (includingdiesel exhaust).

Acute effects on humans due to outdoor and indoor exposures to several gases/fumesand PM have been demonstrated in epidemiological studies. However, the effectsof these environmental factors on susceptible individuals are not known conclu-sively. These acute effects are especially important because they increase the humanburden of minor illnesses, increase disability, and are thought to decrease produc-tivity. They may be related to the increased likelihood of chronic disease as well.Further research is needed in this latter area, to determine the contributions of thetime-related activities of individuals in different microenvironments (outdoors, inhomes, in transit). Key elements of further studies are the assessment of total expo-sure to the different pollutants (occurring from indoor and outdoor sources) andthe interactive effects of pollutants.

Major research areas include determination of the contributions of indoor sourcesand of vehicle emissions to total exposure, how to measure such exposures, and howto measure human susceptibility and responses (including those at the cellular andmolecular level). Biomarkers of exposures, doses and responses, including immuno-chemicals, biochemicals and deoxyribonucleic acid (DNA) adducts, are beginningto promote some basic knowledge of exposure-response, especially the mechanisms.These will be extremely useful additions to standard physiological, immunological,and clinical instruments, and the understanding of biological plausibility. The out-comes of all this work will be the management of risks and the prevention of res-piratory diseases related to air pollution.Eur Respir J., 1996, 9, 1029–1054.

Correspondence: M.D. LebowitzPulmonary & Crit. Care Med. Sec.Dept of MedicineRespiratory Sciences CenterRoom 2332 AHBCTucsonArizona 85724USA

Keywords: Air pollutionasthmachronic bronchitisenvironmentepidemiology

Received: December 28 1996Accepted for publication January 3 1996

This work was supported by USA-NHLBISCOR Grant HL14136.

Previously published reviews of this series1. Sandström T. Respiratory effects of airpollutants: experimental studies in humans.Eur Respir J 1995; 8: 976–995.2. Chitano P, Hosselet JJ, Mapp CE, FabbriLM. Effects of oxidant air pollutants onthe respiratory system: insights from experi-mental animal research. Eur Respir J 1995;8: 1357–1371.3. Heyder J, Takenaka S. Long-term canineexposure studies with ambient air pollu-tants. Eur Respir J 1996; 9: 571–584.

This review of epidemiological studies of the respira-tory effects of exposures to air pollutants follows excel-lent reviews of experimental studies in animals and humansthat have recently appeared in the Journal [1–3]. It hasrelied both on prior reviews of the topic and on the exten-sive literature of the major research reports. It includes,as requested, evaluations of the exposure-response rela-tionships for different respiratory effects and some riskassessment, and also attempts to look at the importantissues and hypotheses awaiting further research.

Historically, the clearest evidence for an associationbetween air pollution and health outcomes in populationswas from acute mortality epidemics. There were a num-ber of well-known acute air pollution episodes [4–10].These episodes had greatly increased concentrations ofsulphur oxides (SO2) and particulate matter (PM), andoften increased acidity, usually due to unfavourable meteo-rological conditions and air stagnation. A very signifi-cant increase in daily mortality occurred, primarily amongpersons with prior cardiac and respiratory disease. These

epidemics led to the subsequent epidemiological inves-tigations of environmental health effects.

Some guidelines for epidemiological investigations

In order to understand exposures to contaminants andthe resulting health impacts, it has been suggested [11,12] that one needs to evaluate: 1) the type of viable andnonviable particles; 2) the various sources of contami-nants and the physicochemical factors leading to expo-sures; 3) the chemical nature of the complex mixtures inthe air and the atmospheric physical (including meteo-rological) interactions; 4) the nature and mechanisms ofthe morbidity effects associated with the contaminants,including the range and distribution of sensitivity in thepopulation; and 5) the methods of evaluation. Epidemio-logical methods provide the opportunity to study pollu-tants and interactions in complex environments withinthis framework. Assessments differ with the different

SERIES 'RESPIRATORY EFFECTS OF AIR POLLUTION'Edited by P. Paoletti and U. Costabel

M.D. LEBOWITZ1030

mechanisms (allergic, infective or irritant/toxic). Epidemio-logical investigators can study effects of real-life expo-sures in various population subgroups, even though itmay be difficult to attribute the specific adverse healtheffects observed to concentrations of any one pollutant.Epidemiology also needs to resolve the methodologicalproblems relating to the measures of exposure, the mea-sures of effect (and avoidance of bias), and the use ofcovariables and confounding variables [4–6, 12–14].

Without adequate exposure data, epidemiological stud-ies may be of little use in studying such refined issues[8, 15, 16]. Personal exposure factors, including time-activity patterns, may cause a given subject to experi-ence pollution levels very different from those measuredat a nearby fixed monitoring station [8, 12, 15]. Forinstance, exposure to sources of indoor pollution maybe critical, given that the majority of time is spent in-doors, and those exposures may have deleterious respi-ratory health effects, as will be discussed [8, 10, 16].

The epidemiological evaluation of the pathogenesisand natural history of respiratory diseases requires exami-nation of human susceptibility and sensitivity of speci-fic subgroups to air pollution [4, 5, 7, 11–15, 17–24].Susceptibility may have been innate (e.g. genetic) and/or induced by events/exposures (infectious, allergenicand/or irritant); physiological and immunological mark-ers of susceptibility and sensitization continue to be found.Those who are susceptible usually hyperrespond whenexposed. Asthmatics are excellent examples of indivi-duals who were susceptible to air pollutants; and once sen-sitized or inflicted with the disease, they are susceptibleto the effects of many environmental (and nonenvironmen-tal) triggers. Furthermore, differences between smokersand nonsmokers suggest that smokers are less responsivethan nonsmokers. Smokers have altered lung functionand an increase in mucus, both of which could influencedose in the different regions of the lung. They also havesmaller airway calibre, predisposing them to bronchialresponsiveness. Age also determines susceptibility; chil-dren appear to be more susceptible. The elderly may bemore susceptible, due mainly to existing disease. Pre-existing conditions are often manifestations of susceptibi-lity, which typically implies that the individual is endowedwith some physiological or biochemical characteristicthat may lead to an enhanced response. The underlyingcharacteristic is not usually idiosyncratic, but shared byothers, usually a small fraction of the population. Like-wise, it is possible that some subgroups have host char-acteristics that protect them or permit them to adapt toexposures. Also, factors associated with lower socioe-conomic status, including crowding and nutrition, maypredispose individuals or increase risk. Even withoutobvious susceptibility, approximately 10–20% of healthysubjects will have symptomatic or lung function respons-es to irritants [5, 13, 14].

Pollutant factors of importance

The deposition of gaseous pollutants depends on theirreactivity, whether they are freely gaseous or adsorbedon particles, and whether they are inhaled through thenose or mouth. Highly reactive-hydroscopic gases (e.g.SO2) are absorbed almost entirely in the nose during

normal nasal breathing; on the other hand, ozone (O3)readily can reach the alveoli. Exercise during exposureincreases the pollutant effect on ventilatory function.Deposition also depends on enlargement of aerosols andany neutralization that occurs in the airways. Meta-bolism will also determine the fate of some gaseous pollu-tants [8, 10, 14, 25]. Deposition of PM and associatedeffects depend on the size of particles as well as on thetype of breathing; tracheobronchial deposition occurs witha fraction of 0.14–0.36 for 10 µm aerodynamic diame-ter (Dae) particles, 0.09–0.27 for 12 µm Dae; it is 0.12under maximally deep inhalation of 16.4 µm Dae. "...there can be a significant deposition of particles >10 µmDae" [5]. Lesser deposition can occur even with largerparticles, including pollen [26].

Short-term exposures and acute effects

Mortality

Acute mortality responses appear to occur in nonepi-demic conditions as well as epidemic. Table 1 providesa compendium of the studies of short-term mortality asso-ciated with air pollutants and meteorology.

Sulphur oxides and particulates. The best-known episodeof mortality associated with sulphur oxides (SOx) andPM was the London fog of December 1952. About 4,000excess deaths occurred, predominantly attributed to bron-chitis/pneumonia [4, 5, 10]. Subsequent episodes inLondon were also documented (table 1), and multiple re-analyses have occurred and been reviewed [5, 10, 29,30, 42, 50]. Some analyses indicate that acidic sulphurmay have played a role [10] (Environmental ProtectionAgency (EPA), in press). A study of the Donora episodeof 1948 also found excess mortality in those with exist-ing disease [51]. There may also have been effects inchildren (op cit. [18]).

In New York City, excess deaths were also found insome episodes, mostly among persons 45 yrs of age andolder, due to influenza, pneumonia and cardiopulmonarycauses; these studies, negative studies, and reanalyseshave been presented and reviewed [4–6, 9, 10, 32]. Simi-lar analyses have been conducted at other times in othercities under conditions of lower pollution; the quantita-tive studies are presented in table 1 and the qualitativestudies have been reviewed previously [53]. Episodesof the duration and intensity reported before the early1960s no longer seem to occur in the cities of the UnitedStates and Western Europe, but probably occur in EasternEurope.

As noted above, not all quantitative studies agree onresults even with the same or similar data bases for thesame locations. This occurred even with inclusion ofweather variables, lag effects, and controls for effects ofother pollutants in the analyses of the death certificatefiles. Some studies, as noted, have found PM to be theremaining significant pollutant, whilst others have foundSOx to be more important; some have found sulphate(the particulate SOx) to be the key pollutant [53]; andconflicting results concerning the effects of acidity con-tinue to appear [46, 54]. Some qualitative studies using

EPIDEMIOLOGICAL STUDIES OF AIR POLLUTION EFFECTS 1031T

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5]);

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ted

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; #:

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m O

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& A

bbey

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m E

PA P

MC

rite

ria

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umen

t (1

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iron

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tal

Prot

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n A

genc

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ate

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ter

with

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eter

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: co

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ed:

med

ian.

different general linear models (GLMs) also demonstratesome disagreement of results for the same cities, thoughmost are in agreement when PM or SO2 concentrationsare above the World Health Organization (WHO)/Euro-pean (EURO) [10] lower limits of such effects, shownin table 1, which are similar to those shown by EPA [4].However, current estimates include estimates below thecurrent standards and guidelines (table 2), which deservefurther discussion.

The studies by certain groups using Poisson & GEEstatistical methods appear to give consistent estimates ofmortality excesses related to exposure to PM, as seen intable 2. The use of these methods as well as other GLMsin theoretically similar data sets which did not yield simi-lar results (table 1), has raised questions about the useof certain models [42]. Disagreements have also arisenas to the biological plausibility of the results as well asaspects of causality [55–57], and the appropriateness ofthe exposure assessments. Current discussions have fav-oured the likelihood that the elderly, cardiopulmonarycases are the most likely to be affected.

The associations may not be simple linear relation-ships, and other determinants of day-to-day changes inmortality make it difficult to specify a pollutant con-centration at which excess deaths begin to occur [4, 12,57]. Many intervening factors, such as temperature ex-tremes, influenza epidemics, holiday weekends, and sea-son of the year, have strong effects on the day-to-daynumber of deaths and may enhance or minimize the effectof air pollution [12, 31, 57–60]. Thus, there is still noagreement as to how many deaths may be attributedspecifically to the air pollutants [4, 5, 61]. There is littledisagreement that the effects of temperature still pre-dominate.

Ozone/oxidants, nitrogen dioxide and carbon monoxide.Temporal analyses of mortality associated with ozone(O3) or total oxidants (Ox) have been less frequent, thoughozone has been incorporated in some of the PM studies.In these latter studies, the effect of ozone is often asstrong as that of PM [52]. Studies in various localeshave found high temperatures to be the primary sourceof mortality, though O3 is sometimes concurrent in lin-ear model solutions with temperature and other pollu-tants [10, 13, 37, 41, 62]. There has been a study in LosAngeles that showed significant associations both of O3

and nitrogen dioxide (NO2) with total and cause-specificmortality [42]; PM was not significant. No lowest obser-ved effect levels (LOELs) have been defined for acutemortality associated with O3 or NO2.

Two studies have shown associations of carbon mon-oxide (CO) with mortality in the Los Angeles area; bothcontrolled for temperature and other pollutants. The first[63] showed only the effect of CO on cardiovascularmortality. The second [40] showed effects both of COand PM on total and cardiovascular mortality.

Summary of current knowledge. Air pollutants togetherwith temperature can cause increases in short-term mor-tality. The issues of such mortality increases have beendiscussed frequently in the past few years (e.g. [52]).Recent findings have generated hypotheses, and there hasbeen agreement that further studies are needed usingappropriate exposure and response measures, and thatstatistical analyses have to be replicated using the samedata sets as used in the prior analyses and investigations.The major statistical issues addressed have indicated thatnone of the methods utilized were invalid per se. Use ofany of the methods needs to include their appropriateuse, the nature and number of variables and of cases,and the nature of temporal trends. Independence and co-linearity of observations and confounding need to beaddressed further, as should testing of assumptions, het-erogeneity, and "sensitivity" (ibid.). As prior differencesin results could be related to any of these factors (ibid.,[6, 55–57]), reanalyses are underway to examine such fac-tors; preliminary results differ quantitatively but not qua-litatively from prior results [64]. New study designsshould have the ability to explore nonlinear thresholdmodels [55]. Evaluation continues of mortality effects inthose (especially the elderly) with existing cardiopul-monary diseases; it is likely that some small shorteningof life (or increased morbidity and disability) could occurunder the circumstances described in studies showingsignificant associations.

Interpretations have too often depended on data fromstationary monitors when individuals' exposures are notreflected by such measurements. Furthermore, the sizeand species of the particulate should be critical aspectsof the exposure measurements, especially as differentparticles produce different physiological and pathologi-cal responses. It was concluded that one needed epide-miological studies that utilized appropriate monitors (with

M.D. LEBOWITZ1032

Table 2. – PM10-acute respiratory and cardiovascular mortality effects studies based on various PM measures*

Original PM Mean % change 95% CImeasurement equivalent per 10 µg·m-3

Health outcome Location (lag) PM10 PM10 equivalent

Respiratory mortality Birmingham, AL, USA PM10 (3 day) 48 1.5 -5.8–9.4Utah Valley, UT, USA PM10 (5 day) 47 3.7 0.7–6.7Philadelphia, PA, USA TSP (2 day) 40 3.3 0.1–6.6Santa Clara, CA, USA COH 35 3.5 1.5–5.6

Cardiovascular mortality Birmingham, AL, USA PM10 (3 day) 48 1.6 -1.5–3.7Utah Valley, UT, USA PM10 (5 day) 47 1.8 0.4–3.3Philadelphia, PA, USA TSP (2 day) 40 1.7 1.0–2.4Santa Clara, CA, USA COH 35 0.8 0.1–1.6

*: EPA Summary, unpublished, 1995. PM: particulate matter; PM10: particulate matter with aerodynamic diameter ≤10 µm; 95%CI: 95% confidence interval; TSP: total suspended particulates; COH: hydrocarbon; EPA: Environmental Protection Agency; lag:number of days between air pollution and increase in mortality.

EPIDEMIOLOGICAL STUDIES OF AIR POLLUTION EFFECTS 1033

respect to simplicity, reliability and quality of data) forpersonal exposure assessments within studies designedto focus on the dose-response nature of the PM and otherpollutant effects [52, 56].

Exacerbations of chronic respiratory diseases

PM/SOx and chronic obstructive pulmonary disease(COPD). Some studies of the daily symptom status ofpatients with COPD show relationships between diseasestatus and air pollution concentrations at relatively highconcentrations of sulphur dioxide and particulates [4, 5,65–68], as seen in table 3. Low temperatures can exerta greater effect than air pollution [98]. An extensive seriesof studies on the effects of air pollution on bronchiticpatients was conducted in the UK between 1955 and1970 [65–68]. They showed that exacerbations of dis-ease were associated with high concentrations of smoke(>250 µg·m-3) and SO2 (>500 µg·m-3), although theywere associated with relative increases rather than abso-lute concentrations. Furthermore, in the UK, examina-tion of sickness absence records, of rates of physicianconsultation and of daily records of hospital admissionsthrough the emergency service, showed associations withperiods of heavy air pollution [4, 5]. With decreasing con-centrations of pollutants in the UK, it has been diffi-cult (since 1969) to relate bronchitics' symptom status tovariations in air pollution (Waller, personal communi-cation).

In Barcelona (Spain), SUNYER et al. [99] demonstra-ted that patients with COPD had significantly increa-sed frequencies of visits to emergency rooms related toPM and SO2 during winter, and SO2 predominantly insummer; the increases in visits related to 25 µg·m-3 SO2were 6 and 9%, respectively; other variables were con-trolled in analyses, and the reliability of diagnoses wasconfirmed. In Ontario (Canada), BURNETT et al. [100]found increases for respiratory hospital admissions inthose aged over 65 yrs of 2.8–3.2%, related to 13 µg·m-3

increases in sulphate, after controlling for O3, tempera-ture and season. (A reliability study of COPD hospitaladmissions in nearby Quebec [101] found a 75.5% cor-respondence with national health insurance data). Onlystudies covering an entire catchment area are consideredto show an accurate relationship between admission ratesand air pollution, and clinical studies in general do notappear to represent events in an entire community. Thereliability of the diagnosis in USA hospitals is usuallyconsidered to be less than elsewhere [5, 13].

Higher annual sulphate levels in the USA have alsobeen associated with increased symptoms in cardiopul-monary patients, and symptoms of acute and chronic res-piratory diseases in children and adults [102]. Childrenwith chronic respiratory disease symptomatology in TheNetherlands had decreased peak flow, increased wheezeand increased bronchodilator use associated with totalsuspended particulates (TSP) >110 µg·m-3 in winter[89–90].

PM/O3 and COPD. Various studies in the USA of res-piratory disease hospital admissions have shown rela-tionships with particulate matter with an aerodynamicdiameter ≤10 µm (PM10) and often with O3 after con-trolling for temperature; increases ranged 1.2–13% in the

elderly per 50 µg·m-3 PM10, and 3.5–57% for COPD per100 µg·m-3 PM10 [103–106]; the lack of known catch-ment areas for the hospitals weaken such findings (seebelow). In a field study of adults with symptoms of COPD[21], O3 was significantly related to peak expiratory flow(PEF) after adjustment was made for smoking, relativehumidity, TSP, and gas-stove use, as was TSP after alladjustments; and there was an substantial O3-TSP inter-action.

Asthma. Asthmatics appear to be more susceptible toshort-term peak concentration of air pollutants, althoughthere is a broad range of sensitivity [4, 17, 107, 108].Oral breathing produces larger and quicker effects, asdoes exercise. Air pollution may also enhance the asth-matic patient's reactivity to other stimuli. Recent studieshave reported a pollutant-induced enhancement of theeffect of pharmacological bronchoconstricting agents atrelatively low concentrations of NO2, O3, and SOx, aloneor together (ibid; [11, 85, 109]). Sulphate, sulphuric acidand nitrate affect asthmatics more in experimental stud-ies, especially as potentiators of exercise or bronchocon-strictor challenges; other chemicals may also act aspotentiators. In addition, these pollutants may act as pot-entiators for exposure to allergens and their effects inallergic asthmatics [8, 11, 85, 110, 111]. Thus, the sen-sitivity of asthmatics to external stimuli, indicates thatvarious air pollutants, allergens, and weather conditionsare important classes of the many that can precipitateattacks.

PM/SOx and asthma. In Donora, during the 1948 air pol-lution episode, 88% of those persons with asthma repor-ted respiratory symptoms during the episode, a rate twicethat of the general population [51]. Increased hospitali-zation was found to be related to SO2 in Vancouver,Canada [112]. In Seattle, PM was found to be similarlyrelated [44], but not in Detroit [105]. SAMET et al.[113] also found very little effect of air pollutants onasthma Emergency Room (ER) visits. Other studies haverecorded increased ER visits for persons with asthmaduring air pollution episodes and during other times ofincreased air pollution concentrations ([4, 5].

Increased rates of asthma attacks and reduced lungfunction were noted in epidemiological studies duringepisodes, or days of higher levels of sulphur oxides/PM(tables 3 and 4). Lagged effects of outdoor PM and tem-perature in asthmatics have been seen in various loca-les. Sulphates are more likely than sulphur dioxide aloneto be responsible for many of the adverse health effectstypically associated with SO2, even after rates were adjust-ed for temperature. The studies conducted in several UScities suggest that even 8–15 µg·m-3 (for 24 h) is asso-ciated with the acute effects [102]. COHEN et al. [73]found such relationships for asthma attack rates (repor-ted and confirmed) in all physician diagnosed asthma-tics in one town. Temperature and pollutants also had asynergistic relationship to attacks. Suspended sulphateshowed the strongest relationship; however, suspendednitrate, SO2 and TSP individually, as well as in combi-nation, explained a significant portion of the residual.MOSEHOLM et al. [147] also reported the effects of NO2,SO2 and weather in Denmark; medication use was also

M.D. LEBOWITZ1034T

able

3.

–

Acu

te s

ympt

oms

asso

ciat

ed w

ith a

ir po

lluta

nts

Exp

osur

es

µg·

m-3

#Fi

rst

auth

or

Yea

r

[

Ref

]

Loc

atio

n

SO2

TSP

PM2.

5/B

S

PM10

O3*

N

O2

Res

ults

HA

MM

ER

1976

[6

9]

New

Yor

k, U

SA

286

145

RSP

ann

ual

x

Incr

ease

in

LR

I in

chi

ldre

n w

ithL

OV

E19

81

[70]

L

OE

L†

LO

EL

28

–43

[SO

410

–14]

in

crea

ses

abov

e th

ese

leve

ls

POPE

1991

[7

1]

Salt

Lak

e lo

w

11–1

95lo

wlo

w

Sign

ific

ant

20%

inc

reas

e in

UR

I in

C

ity,

USA

no

nast

hmat

ic c

hild

ren;

LR

I N

S;

tem

p. i

n m

odel

(w

inte

r)PO

PE19

92

[72]

Sa

lt L

ake

low

7–

251

low

lo

w

Sign

ific

ant

20%

inc

reas

e in

LR

I, 2

9%C

ity,

UT

, U

SA

incr

ease

in

coug

h in

sym

ptom

atic

child

ren;

win

ter;

tem

p. b

ut n

ot o

ther

AP

in m

odel

s (N

Sin

asy

mpt

omat

ic c

hild

ren)

CO

HE

N19

72[7

3]C

umbe

rlan

d,20

015

0[S

O4]

[NO

3]In

crea

se i

n as

thm

a at

tack

s w

hen

WV

, U

SAL

OE

L†

LO

EL

thes

e le

vels

exc

eede

d in

tera

ctio

n w

ithlo

w t

emp;

SO

4an

d N

O3

effe

cts

also

HA

MM

ER

1977

[74]

Bir

min

gham

,26

180–

220

Incr

ease

in

LR

I in

chi

ldre

n w

ith

AL

, U

SAL

OE

L†

LO

EL

incr

ease

s ab

ove

thes

e le

vels

ZA

GR

AN

ISK

I19

79[7

5]N

ew H

aven

,x=

8x=

73.1

[SO

4x=

12.5

;8–

461

Sign

ific

ant

incr

ease

in

sym

ptom

s in

CT

, U

SA(2

0–14

8)1.

5–35

.7]

asth

ma/

alle

rgy

and

smok

ing

adul

ts r

elat

edto

O3

and

pH o

f T

SP, n

ot r

elat

ed t

o SO

4O

STR

O19

91[7

6]D

enve

r, C

O,

?0.

5–73

??

No

sign

ific

ant

incr

ease

in

coug

h in

adu

ltU

SAas

thm

atic

s†O

STR

O19

93[5

3]So

uthe

rn C

A,

?(S

O4:

2–

CO

H:

4–26

20–5

49?

Sign

ific

ant

48%

inc

reas

e (5

0–10

0 µ

g·m

-3

USA

36)

(6 d

ay)

SO4

and/

or 0

.1 p

pm O

3) i

n L

RI

inno

nsm

okin

g ad

ults

; no

sign

ific

ant i

ncre

ase

in U

RI:

tem

p; o

ther

AP,

sto

ves

NS

SCH

WA

RT

Z19

94[7

7]6

citie

s in

Med

ian

Med

ian

Med

ian

Med

ian

Med

ian

Sign

ific

ant

51%

inc

reas

e in

cou

gh a

ndU

SA 1

984–

1988

=10

.5=

18=

30=

36.9

=24

.410

3% i

ncre

ase

in L

RI

in P

M a

nd 2

AP

90th

%=

4790

th%

=37

90th

%=

5390

th%

=54

90th

%=

45m

odel

s; t

emp.

, ci

ty i

nclu

ded

in m

odel

;22

% i

ncre

ase

in c

ough

with

30

ppb

incr

ease

in

ozon

eH

AM

ME

R19

74[7

8]L

os A

ngel

es,

?78

–980

?Si

gnif

ican

t in

crea

se i

n co

ugh,

inc

reas

edSC

HW

AR

TZ

1989

[79]

CA

, U

SAch

est

disc

omfo

rt, i

n yo

ung

adul

ts r

elat

edSC

HW

AR

TZ

1990

[80]

to O

xbu

t no

t to

NO

2, T

SP,

CO

†

WH

ITT

MO

RE

1980

[81]

Los

Ang

eles

,x

51–1

2159

–294

Sign

ific

ant

incr

ease

in

asth

ma

atta

cks

inC

A,

USA

juve

nile

-adu

lt as

thm

atic

s; S

Ox

and

NO

xhi

ghly

cor

rela

ted

with

TSP

MA

RG

OL

IS19

94[8

2]O

rang

e C

ount

y,<

79M

edia

n=0.

05–0

.30

Upp

erSi

gnif

ican

tly i

ncre

ased

sym

ptom

s (a

ndC

A,

USA

SO4

5.7;

ppb

thir

dde

crea

sed

PEF)

in

adul

t as

thm

atic

s≤1

06

h <

29≥1

50re

late

d to

SO

4an

d N

O2,

con

trol

ling

for

othe

r A

P, t

emp.

, se

ason

, m

edic

atio

ns,

polle

n an

d fu

ngi

KR

ZY

ZA

NO

WSK

I19

92[8

3]T

ucso

n, A

Z,

Med

ian=

≤187

29–1

8125

.1±

Incr

ease

in

alle

rgic

and

irr

itant

Q

UA

CK

EN

BO

SS19

91[8

4]U

SA<

81(x

=42

)pp

b. 1

h10

.2sy

mpt

oms

and

AR

Is a

bove

56

ppb

O3

LE

BO

WIT

Z19

92[8

5]75

th%

=<

105

18–1

61in

depe

nden

tly a

nd in

tera

ctiv

e w

ith te

mp.

ppb

8 h

and

with

PM

10>

50 µ

g·m

-3in

door

AP,

and

cova

riat

es;

inde

pend

ent

incr

ease

in

sym

ptom

s w

ith P

M10

; PE

F de

crea

se(3

.8%

per

100

ppb

) al

so s

igni

fica

nt(w

ith n

o th

resh

old)

see

next

pag

e fo

r de

fini

tions

.


able

3.

–

Con

t.....

...

Exp

osur

es

µg·

m-3

#Fi

rst

auth

or

Yea

r

[Ref

]

Loc

atio

n

SO2

TSP

PM2.

5/B

S

PM10

O3*

N

O2

Res

ults

LE

BO

WIT

Z19

84[2

1]L

EB

OW

ITZ

1985

[23]

Tuc

son,

AZ

,(S

O4

57–3

8918

0–23

931

9–41

3W

heez

e an

d co

ugh

incr

ease

rel

ated

to

LE

BO

WIT

Z19

85[8

6]U

SAan

nual

=(1

h)

TSP

, O

3an

d N

O2

inde

pend

ently

in

LE

BO

WIT

Z19

87[8

7]3.

39–4

.69)

adul

t as

thm

atic

s, c

ontr

ollin

g fo

rsi

gnif

ican

t ef

fect

s of

tem

p.,

RH

, in

door

AP,

pol

len;

int

erac

tions

with

tem

p.us

ually

sig

nifi

cant

; N

Sin

nor

mal

s;in

crea

sed

rhin

itis,

cou

gh,

sore

thr

oat

in a

llerg

ies

seen

with

TSP

; tim

ein

/out

inc

lude

dV

ED

AL

1987

[88]

Che

stnu

t≤1

76 (

1 h)

CO

H ≤

1.3

≤129

≤79

(1 h

)N

o si

gnif

ican

t re

latio

nshi

p w

ithR

idge

, PA

, U

SA,

units

(1

h)sy

mpt

oms

(or

PEF)

LA

WT

HE

R19

70[6

5]L

ondo

n, U

K50

0–60

0B

S=25

0–50

0?

Incr

ease

in

bron

chiti

cs' s

ympt

oms

1954

–196

4w

ith t

hese

lev

els;

tem

p. i

mpo

rtan

tH

OE

K19

93[8

9]W

agen

inge

n,≤1

05≤1

10≤1

27A

RI

NS;

tem

p. i

n m

odel

(w

inte

r)N

LR

OE

ME

R19

93[9

0]W

agen

inge

n,>

110

Sign

ific

ant

incr

ease

in

coug

h in

NL

sym

ptom

atic

chi

ldre

n in

win

ter

rela

ted

to T

SPD

USS

EL

DO

RF

1994

[91]

Net

herl

ands

?4–

137

?N

o si

gnif

ican

t in

crea

se i

n co

ugh

inad

ults

nea

r st

eel

mill

†

MA

KIN

O19

75[9

2]T

okyo

, Ja

pan

-266

? hi

gh≤4

5 O

x≤2

07*

Sign

ific

ant

incr

ease

in

sym

ptom

s in

MIZ

OG

UC

HI

1977

[93]

child

ren

inde

pend

ently

rel

ated

to

Ox,

SO2,

TSP

and

tem

p.SH

IMIZ

U19

76[9

4]O

saka

, Ja

pan

<15

96*

<37

3 O

x<

226*

Sign

ific

ant

incr

ease

in

sym

ptom

s in

child

ren

rela

ted

to S

O2,

TSP

; w

eath

erin

mod

els

S CH

WA

RT

Z19

91[9

5]5

Ger

man

Med

ian=

Med

ian=

Med

ian=

Sign

ific

ant

26%

inc

reas

e in

AR

I in

Com

mun

ities

9–48

17–5

614

–>50

child

ren;

TSP

NS

with

NO

2in

mod

el;

1983

–198

590

th%

=w

eath

er i

n m

odel

41–1

18V

ON

MU

TIU

S19

95[9

6]L

eipz

ig,

Ger

man

y20

–90

40–2

50N

Ox:

Si

gnif

ican

t in

crea

se i

n U

RI

in c

hild

ren

40–5

00re

late

d to

SO

2, N

Ox,

TSP

, co

ntro

lling

for t

emp.

, ET

S; w

ith p

ossi

ble

inte

ract

ions

FOR

SBE

RG

1993

[97]

Pite

a, S

wed

en1.

3–12

.9B

S=7.

4–55

.8Si

gnif

ican

t in

crea

se i

n dy

spno

ea i

n1.

0–21

.4as

thm

atic

s re

late

d to

BS;

tem

p. a

ndR

H i

n m

odel

#: 2

4 h,

unl

ess

othe

rwis

e no

ted;

*:

1 h

daily

max

imum

val

ues

unle

ss o

ther

wis

e st

ated

; †:

fro

m E

PA C

rite

ria

Doc

umen

ts;

LO

EL

: lo

wes

t ob

serv

ed e

ffec

t le

vel;

x: m

ean;

TSP

: to

tal

sus-

pend

ed p

artic

ulat

es;

PM2.

5: p

artic

ulat

e m

atte

r w

ith a

erod

ynam

ic d

iam

eter

≤2.

5 µ

m;

BS:

bla

ck s

mok

e; R

SP:

resp

irab

le s

uspe

nded

par

ticul

ate

(~PM

3.5)

; C

OH

: co

effi

cien

t of

haz

e; P

M10

:pa

rtic

ulat

e m

atte

r w

ith a

erod

ynam

ic d

iam

eter

≤10

µm

; L

RI:

low

er r

espi

rato

ry i

llnes

s; U

RI:

upp

er r

espi

rato

ry i

llnes

s; N

S: n

onsi

gnif

ican

t; te

mp:

tem

pera

ture

; A

P: a

ir p

ollu

tant

; pp

b: p

arts

per

billi

on;

PEF:

pea

k ex

pira

tory

flo

w;

AR

I: a

cute

res

pira

tory

inf

ectio

n; R

H:

rela

tive

hum

idity

; E

TS:

env

iron

men

tal

toba

cco

smok

e.

M.D. LEBOWITZ1036T

able

4.

–

Acu

te p

ulm

onar

y fu

nctio

n ch

ange

s as

soci

ated

with

air

pollu

tion

Exp

osur

es

µg·

m-3

Firs

tau

thor

Y

ear

[R

ef]

Loc

atio

n

SO2

TSP

PM

2.5/

BS

PM10

O3*

NO

2R

esul

ts

S PE

CK

TO

R19

88[1

14]

Tux

edo,

NY

,?

H2S

O4

≤9?

41–2

43?

Sign

ific

ant

decr

ease

in

spir

omet

ry a

ndU

SAPE

F re

late

d on

ly t

o O

3in

acu

te h

ealth

yex

erci

sing

non

smok

ing

adul

tsSP

EC

KT

OR

1988

[115

]R

ural

NJ,

USA

?H

2SO

4<

19?

78–2

94?

Sign

ific

ant

decr

ease

s in

lun

g fu

nctio

nSP

EC

KT

OR

1991

[116

](1

2 h)

in c

hild

ren

rela

ted

to O

3(1

day

lag

), b

utno

t to

H2S

O4

TH

UR

STO

N19

93[1

17]

Rur

al C

T,

USA

?H

+≤1

10 n

M?

137–

314

?Si

gnif

ican

t de

crea

ses

in P

EF

in a

sthm

atic

child

ren

rela

ted

to O

3: (

effe

ct o

f A

P se

enas

sym

ptom

s al

so),

med

icat

ion,

tem

p. R

Hin

mod

els†

LIP

PLA

M19

83[1

18]

Rur

al P

A a

nd?

≤66

[H2S

O4

(6 h

)≤1

10?

Sign

ific

ant

decr

ease

in

PEF

in c

hild

ren:

LIP

PMA

N19

85[1

19]

NJ,

USA

av ≤

6]≤2

16ot

her

AP

and

tem

p. s

omet

imes

in

BO

CK

1985

[120

]m

odel

s; o

ther

wis

e as

sum

ed n

otL

IOY

1985

[121

]co

nfou

nder

sD

OC

KE

RY

1982

[122

]St

eube

nvill

e,28

0–46

022

0–45

5?

Sign

ific

ant

2–3%

dec

reas

e in

lun

gO

H,

USA

func

tion

in c

hild

ren;

tem

p. i

n m

odel

LE

BO

WIT

Z19

74[1

9]T

ucso

n, A

Z,

low

≤150

≤235

Sign

ific

ant d

ecre

ase

in F

EV

in e

xerc

isin

gU

SAch

ildre

n w

ith i

nter

actio

n w

ith t

emp.

LE

BO

WT

IZ19

85[2

1]T

ucso

n, A

Z,

low

In <

69R

SP I

n <

5074

–235

Sign

ific

ant

decr

ease

s in

dai

ly P

EF

inU

SAO

ut <

170

Out

<12

5ch

ildre

n (T

SP,

O3)

, ad

ults

with

AO

Dda

ilyda

ily(T

SP,

tem

p. g

as s

tove

s) c

ontr

ollin

g fo

rm

eter

olog

y, i

ndoo

r su

rrog

ates

, po

llen,

fung

iQ

UA

CK

EN

BO

SS19

91[8

4]T

ucso

n, A

Z,

low

Med

ian

<81

Out

=29

–181

Out

: m

ean

Sign

ific

ant

decr

ease

in

PEF

in a

sthm

atic

USA

75th

% <

105

≤187

15–4

8ch

ildre

n re

late

d in

depe

nden

tly to

O3,

PM

KR

ZY

ZA

NO

WSK

I19

92[8

3]x=

42In

: m

edia

nan

d N

O2;

tem

p.,

wea

ther

, t-

act.,

In

door

: ≤2

1211

–37

med

icat

ion

in m

odel

NE

AS

1995

[123

]U

nion

tow

n,x=

29.2

x=24

.5x=

35.6

12 h

·day

-1C

hild

ren'

s PE

F si

gnif

ican

tly d

ecre

ased

,PA

, U

SAm

ax=

128.

4m

ax=

88.1

max

=83

.4av

=98

by ≥

1%,

espe

cial

ly i

n th

ose

with

(sum

mer

)H

+x=

102

sym

ptom

s re

late

d to

O3,

H+,

PM t

emp.

nM·m

-3an

d tim

e sp

ent o

utdo

ors

in m

odel

s; c

ough

incr

ease

d 16

% w

ith H

+

SEL

WY

N19

85[1

24]

Hou

ston

, T

X,

low

x=10

≤265

low

No

sign

ific

ant

decr

ease

in

lung

fun

ctio

nU

SAin

hea

lthy

adul

ts w

ith t

emp.

and

RH

in

mod

elJO

HN

SON

1986

[125

]H

oust

on,

TX

,lo

wx=

10-2

49,-

412

low

Incr

ease

d as

thm

a at

tack

s, m

edic

atio

n us

e,H

OL

GU

IN19

85[1

26]

USA

and

othe

r Sx

with

O3

and

decr

ease

d te

mp.

;C

ON

TA

NT

1985

[127

]al

so d

ecre

ased

FE

V1

and

FVC

; SO

2an

dPM

not

in

mod

els

POPE

1991

[71]

Salt

Lak

e C

ity,

low

11–1

95lo

w

low

Sign

ific

ant

decr

ease

s in

PE

F in

ast

hmat

icU

T,

USA

child

ren

rela

ted

to P

M10

: te

mp.

, bu

t no

tot

her

AP,

in

mod

elPO

PE19

93[1

28]

Salt

Lak

e C

ity,

low

≤181

low

low

Sign

ific

ant

decr

ease

in

FEV

in

adul

tsU

T,

USA

rela

ted

to P

M;

tem

p.,

but

not

othe

r A

P,in

mod

else

e ne

xt p

age

for

defi

nitio

ns.


able

4.

–

Con

t.....

..

Exp

osur

es

µg·

m-3

#Fi

rst

auth

or

Yea

r

[

Ref

]

L

ocat

ion

SO

2T

SP

PM

2.5/

BS

PM

10O

3*

N

O2

Res

ults

KO

EN

IG19

93[1

29]

Seat

tle,

WA

,?

5–45

??

Sign

ific

ant

decr

ease

in

spir

omet

ry i

nU

SAas

thm

atic

chi

ldre

n; t

emp.

, bu

t no

t ot

her

AP,

in

mod

el†

LIN

N19

80[1

30]

Sout

hern

CA

,x=

33x=

182

(SO

4x=

16.5

)≥3

00†

x=13

2Si

gnif

ican

t dec

reas

e in

FE

V w

ith e

xerc

ise

LIN

N19

83[1

31]

USA

–428

in n

orm

al a

nd a

sthm

atic

adu

ltsH

IGG

INS

1990

[132

]M

ount

ains

NE

low

PM2.

5x=

24x=

5949

–481

≤75

Sign

ific

ant

decr

ease

s in

spi

rom

etry

in

GR

OSS

1991

[133

]of

LA

, C

A,

child

ren

rela

ted

to O

3; o

ther

AP,

tem

p.,

GR

OSS

1991

[134

]U

SAR

H i

n m

odel

; re

latio

nshi

p im

prov

ed a

thi

gher

O3

leve

lsA

VO

L19

90[1

35]

Foot

hills

SE

low

18–5

411

8–31

4?

No

rela

tions

hip

of l

ung

func

tion

to A

PA

VO

L19

91[1

36]

of L

A,

CA

, U

SAR

AZ

IEN

NE

1987

[137

]R

ural

Ont

ario

,?

?<

216

?Si

gnif

ican

t de

crea

se i

n lu

ng f

unct

ion

inC

anad

ach

ildre

n: F

EV

1w

ith l

agge

d av

SO

4,PM

2.5,

tem

p.,

and

PEF

with

O3,

in

nona

sthm

atic

s. (

Stud

ies

in g

irls

in

anot

her

loca

tion

NS)

†

STU

DN

ICK

A19

95[1

38]

Aus

tria

SO4

[H+

24 h

≤20

xs (

24 h

):Si

gnif

ican

t de

crea

se i

n FE

V ≤

4 da

ys≤1

24xs

: 12

.2–3

2.2]

45–5

6re

late

d to

PM

10,

H+

and

O3

in s

ome

pane

ls o

f ch

ildre

n; P

EF

also

with

O3;

polle

n an

d te

mp.

, al

so s

igni

fica

nt m

odel

KA

GA

WA

1975

[139

]T

okyo

, Ja

pan

-133

-400

20–5

90-4

14Si

gnif

ican

t in

crea

se i

n ai

rway

res

ista

nce

KA

GA

WA

1976

[140

]in

chi

ldre

n w

ith O

3, S

O2,

tem

p. o

nly

VA

ND

ER

LE

ND

E19

75[1

41]

Vla

ardi

ngen

, N

L30

0B

S=14

0D

ecre

ase

in l

ung

func

tion

with

1969

–197

2in

crea

ses

abov

e th

ese

leve

ls†

DA

SSE

N19

86[1

42]

Net

herl

ands

200–

500

200–

250

RSP

>20

0Si

gnif

ican

t 3–

5% i

ncre

ase

in l

ung

func

tion

in c

hild

ren

with

RSP

HO

EK

1992

[143

]W

agen

inge

n, N

L≤1

0530

–144

7–20

6≤1

27Si

gnif

ican

t de

crea

se i

n PE

F in

CR

DH

OE

K19

93[1

44]

child

ren;

NS

in a

ll ch

ildre

n re

late

d to

RO

EM

ER

1993

[90]

PM10

, O

3; t

emp.

and

oth

er A

P no

t in

m

odel

J AA

KK

OL

A19

90[1

45]

3 ar

eas

0–10

29–4

4Si

gnif

ican

tly i

ncre

ased

pre

vale

nce

rate

Finl

and

H2S

: of

nas

al s

ympt

oms

and

incr

ease

d co

ugh

(adu

lts)

15–1

00re

late

d to

AP

J AA

KK

OL

A19

91[1

46]

3 ci

ties

in37

–83

H2S

73–1

98m

ax=

48Si

gnif

ican

tly i

ncre

ased

(60

–100

%)

Finl

and

max

=42

.3re

spir

ator

y in

fect

ions

rel

ated

to

AP;

(chi

ldre

n)at

opy,

age

, pa

ssiv

e sm

okin

g, s

ex,

daily

cont

acts

tak

en i

nto

acco

unt;

AP

effe

cts

not

diff

eren

tiate

d

*: 1

h m

ax d

aily

(un

less

oth

erw

ise

note

d);

†: f

rom

EPA

Cri

teri

a D

ocum

ents

; FE

V:f

orce

d ex

pira

tory

vol

ume;

Sx:

sym

ptom

s; F

EV

1: f

orce

d ex

pira

tory

vol

ume

in o

ne s

econ

d; F

VC

:fo

rced

vita

l ca

paci

ty;

CR

D:

chro

nic

resp

irat

ory

dise

ase;

t-a

ct:

time-

activ

ity;

AO

D:

airw

ay o

bstr

uctiv

e di

seas

e.

In:

indo

ors;

Out

: ou

tdoo

rs;

RH

: re

lativ

e hu

mid

ity.

For

fur

ther

def

ini-

tions

see

leg

ends

to

tabl

es 1

and

3.

considered. WHO environmental health criteria (EHCs)have also documented responses related to metal partic-ulate (especially in those sensitized) and to pesticides.

PM and O3/NO2/organics and asthma. BATES and SIZTO

[148] found highly significant associations between ex-cess respiratory admissions, especially asthma (and espe-cially in the young), and average maximum hourly SO4and O3 concentrations, and temperature in SouthernOntario. There appeared to be 24–48 h lags for effects.These correlations were consistent in other years. Otherstudies in the USA confirmed this association with ozone[149–152]. In Helsinki, a combination of temperatureand ozone, as well as other gaseous pollutants, was asso-ciated with increased asthma admissions to hospitals[153], and a combination of temperature and NO2 wasassociated with ER visits in northern Finland [154]. InBirmingham (UK), location near roadways (a surrogatefor NO2) was also associated with hospital admissionsfor childhood asthma [155]. In Mexico City, ER visitsfor childhood asthma increased by 43% per 98 µg·m-3

(50 ppb) increase in ozone, and by 68% if O3 exceeded216 µg·m-3 (110 ppb) for two or more days, controllingfor other pollutants, weather and other factors [156].Asthma attendance was also correlated with spore andpollen counts along with weather factors [157].

Increased rates of asthma attacks and reduced lungfunction were noted in epidemiological studies duringepisodes, or days of higher levels of photochemical oxi-dant air pollution (tables 3 and 4). (Experimental stu-dies also show increased bronchial responsiveness withozone [17]).

WHITTMORE and KORN [81] found significant increa-ses in the probability of asthma attacks in asthmatics inLos Angeles associated with increases of 0.10 ppm (range0.03–0.15 ppm) in oxidant levels; attacks increased on dayswith high TSP, and also cooler temperature. ZAGRANISKI

et al. [75] reported an increased prevalence rate for res-piratory symptoms at about 0.08 ppm (range 0.004–0.235ppm) O3 in patients with asthma in New Haven.

Studies in Tucson [21, 83, 86] showed effects in asth-matics, related to temperature, O3 (0.052–0.12 ppm), andthe two together (clinically significant reductions of 15–24% in PEF); these were related to time-activity (timespent in/out of doors), controlling for other factors. Medi-cation use confirmed the changes. More severe symp-toms usually occurred 1–3 days after significant PEFdeclines. These time-lag effects of ozone (and tempera-ture) have been shown by some other studies [115, 121],but not all [83]. Both 1 and 8 h concentrations of O3have been shown to have significant effects, and to inter-act with PM10 and temperature in producing reductionsin PEF [83]. However, temperature effects were alwaysmore important. In addition, the low humidity in someenvironments probably had a major influence on theeffects seen at concentrations below 120 ppb [86]. Thisgeneral interactive type of relationship has also been seenfor outdoor NO2 and either an indication of gas stoveusage or measured indoor NO2 in asthmatic adults andchildren, in which time spent outdoors was an importantfactor, and medication usage did not prevent the effects[84, 87].

Different forms of particulate, including environmen-tal tobacco smoke (ETS) (and ETS-organic compounds)

indoors also have effects on symptoms and PEF in asth-matics, especially in children [84, 115, 158–161]. It hasalso been demonstrated that there were influences ofindoor particulate matter with an aerodynamic diameter≤2.5 µm (PM2.5) and cigarette smoking on morning PEFin asthmatic children when including previous days' asth-matic medications, an inhibitor of adverse effects on phy-siological status. Thus, nocturnal asthma may well havesignificant physiological decrements associated with en-vironmental stimuli, for which there can be only partialprotection. Indoor formaldehyde (HCHO) exposures haveeffects on symptoms and PEF in asthmatic children; therealso appears to be avoidance of high exposures to HCHOby asthmatics [160]. The impact of bioaerosols (indoorsand outdoors) has also been substantial [8, 16, 162–164],as will be discussed further. The effects of other meteo-rological phenomena have been reviewed previously [17,165].

Summary. Several studies have shown that daily tem-perature variations were often more strongly correlatedwith attack rates, but air pollution still exerted a signifi-cant effect even when temperature-adjusted rates werecomputed. Examination of tables 3 and 4 vis-a-vis asth-matics indicates the LOEL for symptoms and significantPEF reductions of: 157 µg·m-3 (0.08 ppm) O3 based onseveral studies; about 200 µg·m-3 SO2 based on two stu-dies; TSP approximately 80–120 µg·m-3 based on fourstudies; PM10 >50 µg·m-3 based on 1–2 studies; PM2.5>25–75 µg·m-3 based on three studies, but less if pri-marily SO4 effects (as low as 10 µg·m-3 SO4) based onthree other studies. The evidence for NO2 is too con-flicting to determine any LOEL.

The major problems in most studies of exacerbationsof asthma have been the lack of information on time-activity patterns, the possible effects of medications, andthe absence of records for all days on which symptomscould have occurred. Investigators who have been ableto control some of these variables have found consistenteffects of O3 (as well as other pollutants) on asthma andother airway obstructive disease (AOD), though con-trolled exposure studies have not [13, 17]. However, eventhe lack of records for all days, and the presence of medi-cation information implying very good management,have not interfered with the occurrence of effects rela-ted to air pollutants in asthmatics ([88, 83]; Daumer, per-sonal communication). Experimental evidence suggestsa continuum in the dose-response relationship. Peak flowmeasurements have been shown to be most responsiveto pollutant and meteorological exposures as well as tobeneficial effects of medications [166], as also describedabove.

There are some possible long-range effects of bronchialresponsiveness (BR) produced by pollutants (and tem-perature). Several studies [167–169] have shown detri-mental longitudinal effects of BR on lung function,either reduced growth or increased decline. The long-range implications of BR and immunological status havealso been discussed at length [8, 11, 16, 162, 170–172].

In conclusion, a variety of indoor and outdoor pollu-tants, including bioaerosols, have been shown to affectlung function in those with pre-existing disease [8, 10,11, 16, 23, 83–86, 89, 111, 159, 160, 162–164, 166,173–176] as well as symptoms; PEF appears to be a

M.D. LEBOWITZ1038

more sensitive instrument for detecting such changes[166, 177, 178].

Respiratory infections. Air pollution and impaired resis-tance to respiratory infection, shown in animals, has alsobeen seen in studies of humans; a greater incidence ofacute respiratory illness (ARI) supports a probable asso-ciation between increased acute lower respiratory tractdisease (acute bronchitis, pneumonia, other acute chestillnesses) and air pollution [4, 5, 10, 14]. Although im-portant, excess acute lower respiratory illness rates inchildren cannot be accounted for by social class or areadifferences in residential mobility (ibid.).

Atopic status appears to be an additional risk factorfor respiratory illnesses associated with air pollution [179,180]. The role of air pollution as adjuvants to alteredimmunological status, for infections and allergic sensiti-zation, has also been seen in animal models ([181–183];Kagawa, personal communication).

PM/SOx. Several epidemiological studies have obser-ved the increased incidence of acute respiratory illness(spatially and temporally) in populations living in com-munities with more sulphur oxides and particulates [4,6, 69, 102, 184–190]; the quantitative studies are foundin table 3. The frequency and severity of acute lowerrespiratory disease increased with the degree of air pol-lution (ibid.), and appeared to diminish when air qua-lity was improved in the UK [186, 191]. Several recentstudies confirm the effect of various outdoor pollutantson respiratory illnesses and symptoms, especially in chil-dren: PM effects in children in Switzerland [192] andin the US [71]. Several metals have also been associa-ted with acute respiratory infections (ARIs) [25]. IndoorPM has been shown to be a special problem for such ill-nesses in the developing world [193].

Environmental tobacco smoke (ETS). Multiple studieshave found the relationship between ETS and ARIs [159].(There have also been numerous studies showing otherrespiratory effects of ETS in children [159], which arenot discussed here).

NO2. Elementary schoolchildren and infants living in ahigh-exposure community for two or more years alsoexperience increased bronchitis morbidity; this has sug-gested an adverse effect in areas with average NO2 con-centrations of 150–282 µg·m-3 (0.08–0.15 ppm), confirmedby subsequent years of study and analyses by EPA [70,194–197]. In Switzerland, increases in ARIs were foundwith 24 h exposures to ambient NO2 of 150–282 µg·m-3

(NO3 of 3.8 µg·m-3) and no other associated pollutants,adjusting for other factors [192]. QUACKENBOSS et al. [84,176] have found increased respiratory illnesses relatedto monitored PM and NO2, indoors and outdoors, as wellas ETS, controlling for other indoor pollutants and fac-tors. NEES and co-workers [198, 199] found a 40% increasein childhood lower respiratory illnesses (LRIs) per 28µg·m-3 (15 ppb) increase in NO2 in the six city study inthe USA. Some studies [200] have not found such effects,though their NO2 concentrations are often lower.

MELIA and co-workers [201, 202] reported a greaterincidence of lower respiratory illnesses in British chil-dren residing in homes using gas versus electricity for

cooking, in which NO2 monitoring occurred. Illness rateswere adjusted for other significant factors (ETS, age, sex)and other potentially confounding factors. This study andothers have led to major re-evaluations of the role ofNO2, including a meta-analysis by HASSELBLAD et al. [203]confirming the effects in humans [14]; these effectsmirror those found in animal studies [4, 14].

Ozone. Respiratory illness effects have been seen inschoolchildren in Mexico City [204], and adults in LosAngeles (together with sulphate but not particulate haze)[53].

Risk assessments. ARIs appear to be increased by 1.5–2.0times with exposures to PM (including ETS), SO2, NO2.Early childhood LRIs increased by 1.5 (19.4 to 30–34%),2.5 if from the lower socioeconomic status (SES), rela-ted to SO4 and SO2 of 190 µg·m-3, hospitalizations by1.5–2.8 (0/1.1 to 1.0/1.8% for bronchitis or pneumonia,1.1–3.1% for LRIs) with similar concentrations. The levelof NO2 reported to produce acute respiratory illnesses isabout 137 µg·m-3 (1 h) [10].

Implications. These relationships are of particular pub-lic health significance because infections and allergiesof the respiratory tract account for a major portion oftotal acute illness in the general population and exact alarge economic toll in terms of time lost from school orwork, visits to doctors, and admissions to hospitals. Thesum of the studies supports an association with increasedacute lower respiratory illness. The pollutants, or con-centrations, which increase risk of acute illness have usu-ally not been established; though some estimates havebeen made [61]. However, this is difficult given the manyenvironmental and personal factors that contribute to suchrisk [4]. The other reason for concern is that these ill-nesses appear to be related to BR, reduced airway cali-bre, and subsequently to airway obstructive diseases [18,23, 86, 170, 186, 205–211]. The role of ventilatory im-pairment, and BR, cannot be underemphasized [22, 167,169, 170].

Other acute respiratory responses

Nonirritants. The effects of carbon monoxide (CO) stemprimarily from its affinity with oxygen-carrying haemo-proteins, which causes a leftward shift and steeper slopeof the oxyhaemoglobin dissociation curve and decrea-ses the amount of such haemoprotein available for oxy-gen transport. The ultimate effect is a tissue deficit ofoxygen, such that normal function may not be sustained.In the absence of CO exposure, carboxyhaemoglobin(COHb) concentrations are approximately 0.5%. (A pack-per-day cigarette smokers may achieve COHb saturationsof 4–7%). For nonsmokers, exposure to CO at a con-centration of 10 mg·m-3 (9 ppm) for 8 h or to a con-centration of 40 mg·m-3 (35 ppm) for 1 h (the presentUS primary air quality standard) is calculated to causean increase in COHb concentrations to 1.5% during theinterval of exposure. At higher elevations, the oxygendissociation curve shifts further to the left. During heavymuscular exercise, the oxygen consumption rate of thewhole body places maximal stress on the oxygen trans-port system, and the ability of the cardiovascular system


to transport oxygen to exercising muscles is a determi-nant of the maximal sustained rate of work that a nor-mal person can perform [212]. Thus, CO has been shownto have predictable effects on healthy young men under-going strenuous exercise; over the range of COHb concen-trations of 5–20%, a linear relationship existed betweenincreasing COHb and decreasing maximal oxygen con-sumption. Respiratory function may suffer. Nitrogenoxides, specifically NO, can also diffuse into the circu-latory system, form met-haemoglobin, and by further de-priving cells of oxygen, can have similar effects; therelative potency of met-Hb is about one-third that ofCOHb [213].

Short-term irritant-related symptoms. In Donora, duringthe 1948 air pollution episode, 43% of the general popu-lation reported respiratory symptoms during the episode[51]. Irritation of the nose and throat are the most com-mon outcome of almost all air pollutants; cough can oftenbe induced, and sometimes wheeze [4, 5, 8, 13, 14, 25,61]. The quantitative studies of effects on acute symp-toms are displayed in table 3. Many qualitative studieshave been reported (ibid.). Symptoms may temporarilyimpair performance of normal activities even in healthysubjects. Wood smoke, indoors and out, other forms ofparticulate indoors (especially ETS), and indoor formal-dehyde (HCHO) exposures have acute effects on symp-toms, especially in children [108, 115, 159, 161, 176,214].

Short-term irritant-related reductions in function. A widevariety of human airway responses to most of the pol-lutants has been demonstrated, as seen in table 4. (Thesereflect findings in controlled exposure studies of most ofthe pollutants). There is evidence that they can also causebronchoconstriction (ibid.; [107]). In general, these effectsare reversible, and do not necessarily constitute a riskof disease in healthy subjects.

Several field studies have also shown more prolongeddecreases in pulmonary function during and followingpollution episodes, mostly in children, when exposed torelatively high levels of SO2 [24, 66–68, 122, 139, 140];these exposures usually occur with the presence of somePM, and temperature can also play an important role.The levels of reduction can be clinically significant (morethan 15% decline), but reverse quickly when exercise isstopped or the exposure is removed.

In general, decrements occur in normal children andadults above 110 µg·m-3 PM10 (in the presence of SO2),3,760 µg·m-3 of NO2 (560 µg·m-3 in asthmatics, thus the1 h Air Quality Guideline (AQG) of 400 µg·m-3) [10,71]; above 150–200 µg·m-3 of ozone for 1 h (above100–250 for 8 h).

Decrements related to short-term (1 h) and longer (6–8 h) ozone exposure have also been amply demonstra-ted [4, 13, 61, 215, 216], and recent studies continue toconfirm these results (table 5). In general, these acutefunctional changes in healthy children and young adultsoccur with 1 h O3 concentrations of 0.08–0.15 ppm, andless (>0.06 ppm) for the longer (6–8 h) exposures.

Tolerance and/or adaptation. Humans respond physio-logically to complex environments containing pollutants(exogenous stimuli which usually produce adverse changes)

by adaptive strategies that should be suitable, but maynot be under all circumstances. Recovery from irritantexposures in healthy subjects is generally complete with-in hours, although the recovery period may be longer forsubjects with the most severe responses, and some clini-cally severe responses can occur at higher doses [58].The susceptibility of the humans so exposed is of criti-cal importance to early responses and adaptability, andinfluence changes that help determine later physiologi-cal responses to the same or similar stimuli. For manyof the current pollutants of concern, such as most volatileorganic compounds, either as gases or in particle form(such as from solvents, cleaners and maintenance pro-ducts, and sidestream tobacco smoke), the mechanismsof response are so complex and poorly understood thattoxicological and also some controlled exposure studiesare required first. Furthermore, some pollutant classesmay be well-characterized, but occur in concentrationssufficient for study only in occupational settings (e.g.asbestos, some volatile organic compounds, some mine-ral fibres); the adverse health effects of these pollutantclasses are, therefore, best characterized in occupationalstudies [12, 171].

Although others have found adaptation to ozone incontrolled human exposure studies, no such changes havebeen seen in epidemiological or physiological studies inthe field. This is probably due to prolonged exposure toambient ozone and/or other pollutants, and lagged effectson lung function (supra vida). The studies described doshow some relative adaptation has occurred to high tem-peratures and low relative humidity.

Sometimes, active smokers appear to have adapted tothe effects of irritants, as seen in their lesser reactivityto ozone in chamber studies [5]. It may occasionally bethe case for passive smoking as well, since it appears toinhibit the effects of ozone in children [121].

Chronic respiratory diseases

Mortality

Sulphur oxides and particulate matter. Non-time seriesanalyses of geographic differences in mortality havefavoured an association of sulphur oxides (including sul-phates) and PM with mortality, although there has beenno general agreement from such studies [4, 5, 10, 25].The nature of ecological analyses, and their fallacies andbiases, have been reviewed elsewhere [4, 8, 12, 25, 52,279].

A recent study of childhood mortality in different re-gions of the Czech Republic [280] found a 3.16 excessrelated to TSP, a 5.41 excess related to SO2, and a 2.73excess related to NO2. A significant correlation betweenbronchitis mortality and the acidity of precipitation (pH)has been found in the UK [281]. A recent analysis oflongitudinal data on large populations in six US citiesin which individuals' data were utilized [54] found thattotal and cause-specific mortality in the different citieswas related to the PM concentrations in those cities afteradjusting for personal factors. The consistency of thefindings for PM is significant, in spite of the fact thatother factors might have accounted for some of the

M.D. LEBOWITZ1040


able

5.

–

Rel

atio

nshi

p of

chr

onic

ter

m e

xpos

ures

to

spec

ific

pollu

tant

s to

chr

onic

res

pira

tory

dis

ease

(an

nual

mea

sure

men

ts u

nles

s ot

herw

ise

stat

ed)

Exp

osur

es

µg·

m-3

#Fi

rst

Loc

atio

nau

thor

Y

ear

[R

ef]

(po

pula

tion)

SO2

TSP

PM

2.5/

BS

P

M10

O3*

NO

2R

esul

ts

CH

APM

AN

1973

[217

]U

rban

Are

as28

6 (2

4 h)

145

SO4

≤50

low

Incr

ease

d pr

eval

ence

rat

es o

f ch

roni

cH

AM

ME

R19

76[6

9]U

SA(≤

617)

(24

h)br

onch

itis,

sm

okin

g, o

ther

fac

tors

in

(adu

lts)

(≤24

4)m

odel

sC

HA

PMA

N19

76[2

18]

Bir

min

gham

,26

(24

h)

180–

220

RSP

≥45

(NO

xlo

w)

Incr

ease

d pr

eval

ence

rat

es o

f sy

mpt

oms

HA

MM

ER

1977

[74]

AL

USA

(24

h)L

OE

Lan

d de

crea

sed

FEV

rel

ated

to

PM;

othe

r(c

hild

ren)

fact

ors

in m

odel

sSH

Y19

73[2

19]

USA

69–1

6072

–114

86–1

66D

ecre

ased

FE

V w

ith T

SP/s

ulph

ate;

(chi

ldre

n)ot

her

cova

riat

es i

n m

odel

NO

2N

S

SCH

WA

RT

Z19

89[2

20]

USA

??

<78

-150

Dec

reas

ed l

ung

func

tion

rela

ted

to(c

hild

ren)

LO

EL

NO

2, O

3, (

45 m

L/2

8.3

µg·

m-3

NO

2);

16–2

31ot

her

fact

ors

in m

odel

s†SP

EIZ

ER

1980

[221

]6

City

Stu

dy,

90th

%=

39–1

14PM

15?

Est

. 7–

49M

argi

nally

sig

nifi

cant

inc

reas

es i

nW

AR

E19

84[2

22]

USA

55 p

pb20

–59

indo

orre

spir

ator

y ill

ness

es u

nder

age

2 y

rsD

OC

KE

RY

1989

[223

](c

hild

ren)

Stub

envi

lle(3

3 ex

cess

and

decr

ease

s in

lung

func

tion;

com

bine

dN

EA

S19

90[1

98]

if g

as s

tove

)sy

mpt

oms

sign

ific

antly

inc

reas

ed b

y N

EA

S19

91[1

99]

47%

; ot

her

fact

ors

in m

odel

sW

AR

E19

84[2

24]

6 C

ities

, U

SA90

th%

=39

–114

PM15

<42

.5V

ery

larg

e, s

igni

fica

nt in

crea

ses

in L

RIs

,W

AR

E19

86[2

22]

(chi

ldre

n)55

ppb

20–5

9co

ugh

and

bron

chiti

s w

ith T

SP,

PM15

DO

CK

ER

Y19

89[2

25]

(not

PM

2.5)

, ag

e, s

ex,

SES,

mat

erna

lN

EA

S19

94[2

26]

smok

ing

in m

odel

s; o

ther

AP

NS;

bron

chiti

s an

d L

RI

incr

ease

d 13

–18%

CH

APM

AN

1985

[227

]U

tah,

USA

11–1

1539

–108

SO4

5–14

NO

30.

9–75

–95%

inc

reas

ed c

hron

ic r

espi

rato

ry(c

hild

ren)

3.5

sym

ptom

s re

late

d to

SO

2; s

mok

ing

inm

odel

DO

DG

E19

80[2

28]

Ari

zona

, U

SA4–

8637

–72

low

low

Sign

ific

ant l

ower

lung

func

tion

with

TSP

;D

OD

GE

1983

[229

](c

hild

ren)

SO2

NS;

oth

er f

acto

rs i

n m

odel

sL

INN

1976

[230

]L

A v

sSF

, C

A?

??

65–1

30N

o si

gnif

ican

t di

ffer

ence

in

lung

USA

(no

nsm

okin

gfu

nctio

n; n

o in

door

mea

sure

men

ts;

adul

ts)

com

plic

ated

out

door

exp

osur

esD

ET

EL

S19

81[2

31]

Sout

hern

CA

, U

SAlo

w76

–133

78–3

9253

–226

*In

crea

sed

sym

ptom

s an

d so

me

DE

TE

LS

1987

[232

](a

dults

)SO

44.

5–(x

of

24 h

)ev

iden

ce o

f de

crea

sed

lung

fun

ctio

n,D

ET

EL

S19

91[2

33]

13.5

(x

ofbu

t on

ly s

mok

ing

cont

rolle

d fo

r an

dT

ASH

KIN

1994

[234

]24

h)

spec

ific

AP

not

dete

rmin

ed a

nd h

igh

refu

sal

rate

s in

fol

low

-up

exam

sA

BB

EY

1993

[41]

Cal

ifor

nia

<57

–>40

0<

60–>

200

[SO

4<

6–>

15]

<19

6–>

491

<94

–>37

6Pr

eval

ence

and

inc

iden

ce r

ates

of

AB

BE

Y19

93[2

35]

(non

smok

ing

chro

nic

bron

chiti

s an

d as

thm

aA

BB

EY

1995

[236

]ad

ults

)si

gnif

ican

tly r

elat

ed t

o T

SP a

nd o

zone

;ot

her

AP

NS;

tim

e-ac

tivity

, ex

-sm

okin

g,pa

ssiv

e sm

okin

g, S

ES,

age

, ge

nder

,oc

cupa

tiona

l ex

posu

re i

n m

odel

sP E

AR

LM

AN

1971

[194

]C

hatta

noog

a,lo

w?

x ≤2

86Si

gnif

ican

t in

crea

sed

resp

irat

ory

P EA

RL

MA

N19

71[1

95]

TN

, U

SAup

to

1971

sym

ptom

s in

197

2, n

ot i

n 19

73 (

22–

LO

VE

1982

[70]

(chi

ldre

n)N

O3

≤4.1

40 µ

g·m

-3N

O2)

HN

O2=

?19

72:

43–9

1se

e en

d of

tab

le f

or d

efin

ition

s

M.D. LEBOWITZ1042

MO

STA

RD

I19

81[2

37]

Ohi

o, U

SA21

–77

x (9

mo)

:(S

O4

x (9

mo)

:x=

54Si

gnif

ican

t in

crea

se i

n re

spir

ator

yM

OST

AR

DI

1981

[238

](c

hild

ren)

51–5

511

–12)

(27+

)sy

mpt

oms;

sm

all

decr

emen

ts i

n lu

ng(N

O3

4–5)

func

tion;

no

indo

or m

easu

rem

ents

; co

nfou

nder

s in

mod

els

KR

ZY

ZA

NO

WSK

I19

90[1

60]

Tuc

son,

AZ

,lo

wIn

med

ians

:In

<23

5In

TW

A w

ith t

ime-

activ

ities

and

act

ual

QU

AC

KE

NB

OSS

1989

[84]

USA

8.9–

35.7

med

ians

:m

edia

ns:

mea

sure

men

ts o

f PM

; PM

-ET

S,Q

UA

CK

EN

BO

SS19

91[1

76]

75th

% 7

7.8

17.5

–80.

811

.5–3

6.8

HC

HO

-ET

S, N

O2,

pol

len

asso

ciat

edL

EB

OW

ITZ

1990

[85]

(wee

kly)

Out

<60

75th

%w

ith s

igni

fica

nt i

ncre

ase

in p

reva

lenc

eL

EB

OW

ITZ

1992

[161

]75

th%

105

17.7

–47.

2ra

tes

of b

ronc

hial

res

pons

iven

ess;

LE

BO

WIT

Z19

93[1

75]

(wee

kly)

Out

: 34

–48

HC

HO

-ET

S al

so a

ssoc

iate

d w

ith a

sthm

aan

d ch

roni

c br

onch

itis;

SE

S, m

edic

atio

n,al

l A

P, m

eteo

rolo

gy,

age,

sex

in

mod

els

NE

RI

1975

[239

]O

ntar

io,

<85

0<

500

Dec

reas

ed l

ung

func

tion

and

incr

ease

dC

anad

ax=

46–5

2x=

90–9

3pr

eval

ence

rat

es o

f ch

roni

c br

onch

itis

(LO

EL

)B

EC

KL

AK

E19

75[2

40]

Mon

trea

l,15

–123

84–1

31N

o di

ffer

ence

s be

twee

n ar

eas

in l

ung

AU

BR

Y19

79[2

41]

Can

ada

(adu

lts)

func

tion

afte

r sm

okin

g co

ntro

lled

INFA

NT

E-

1993

[242

]M

ontr

eal

??

Pers

onal

Incr

ease

d pr

eval

ence

rat

e of

ast

hma;

RIV

AR

D(c

hild

ren)

1–>

28SE

S an

d E

TS

in m

odel

sST

ER

N19

94[2

43]

Can

ada

low

SO4

1.9

vsx=

18–2

3>

156

low

No

incr

ease

in

chro

nic

sym

ptom

s;(c

hild

ren)

6.6

low

er f

unct

ion

in m

ore

pollu

ted

com

mun

ities

LA

MB

ER

T19

70[2

44]

Bri

tain

90B

S=70

Incr

ease

d pr

eval

ence

rat

es o

f L

RIs

;(c

hild

ren)

incr

ease

d br

onch

itis

prev

alen

ce r

ates

(adu

lts)

>10

0>

100

and

low

er l

ung

func

tion

LU

NN

1967

[187

]B

rita

in18

1–27

5B

S=23

0–30

1In

crea

sed

prev

alen

ce r

ates

of

sym

ptom

sL

UN

N19

70[2

45]

(chi

ldre

n)94

–253

48–1

69an

d fu

nctio

n; n

o ef

fect

s se

enM

EL

IA19

77[2

01]

Eng

land

19–1

45B

S=12

–73

16–5

30In

crea

sed

prev

alen

ce r

ates

of

resp

irat

ory

ME

LIA

1981

[202

](c

hild

ren)

Indo

ors

dise

ase;

mos

t co

nfou

nder

s co

ntro

lled

KE

RR

EB

IJN

1975

[246

]N

ethe

rlan

ds15

0B

S <

30In

crea

sed

coug

h, b

ut l

ung

func

tion

(chi

ldre

n)(L

OE

L)

NS

FISC

HE

R19

85[2

47]

Net

herl

ands

??

15–3

00D

ecre

ased

lun

g fu

nctio

n re

late

d to

FISC

HE

R19

86[2

48]

(adu

lt fe

mal

eN

O2

in m

odel

sR

EM

IJN

1985

[249

]no

nsm

oker

s)D

IJK

STR

A19

90[2

50]

Net

herl

ands

??

?22

–42

No

incr

ease

d re

spir

ator

y sy

mpt

oms

orH

OU

TH

UIJ

S19

87[2

51]

(chi

ldre

n)23

–72

lung

fun

ctio

n de

clin

eB

RU

NE

KR

EE

F19

90[2

52]

SAW

ICK

I19

69[2

53]

Cra

cow

,x=

45,

x=90

,In

crea

sed

CO

PD; o

ther

fac

tors

in m

odel

;S A

WIC

KI

1977

[254

]Po

land

125

170

late

r, J

edry

chow

ski

(com

mun

icat

ion)

sh

owed

rel

atio

n to

mod

elle

d ac

id;

larg

er(a

dults

)ve

ntila

tory

dec

lines

tho

ught

rel

ated

to

occu

patio

nal a

nd e

nvir

onm

enta

l exp

osur

esan

d sm

okin

g ha

bits

. (K

RA

ZY

ZA

NO

WSK

Iet

al.,

1990

[28

4])

RU

DN

IK19

78[2

55]

Nea

r C

raco

w14

8–18

0B

S 15

0–22

7In

crea

sed

resp

irat

ory

sym

ptom

s in

boy

s

see

end

of t

able

for

def

initi

ons

Tab

le 5

. –

C

ont..

......

...

Exp

osur

es

µg·

m-3

#Fi

rst

Loc

atio

nau

thor

Y

ear

[R

ef]

(po

pula

tion)

S

O2

TSP

P

M2.

5/B

S

PM10

O3*

NO

2R

esul

ts


PAA

RC

1982

[256

]Fr

ance

??

12–1

6N

o ef

fect

s; n

o in

door

mea

sure

men

ts†

PAA

RC

1983

[257

](a

dults

)R

AM

AC

IOT

TI

1977

[258

]G

enev

a,10

–60

?In

crea

sed

chro

nic

bron

chiti

s, p

reva

lenc

eSw

itzer

land

rate

s an

d de

crea

sed

PEF

with

SO

2an

d(a

dult

men

)sm

okin

gB

RA

UN

-19

89[2

59]

Switz

erla

nd?

??

25–5

2In

crea

sed

resp

irat

ory

sym

ptom

s w

ithFA

HR

LA

ND

ER

(chi

ldre

n)(O

ut)

NO

2≥3

0 µ

·m-3

outd

oors

†

6–91

(In

)G

SCH

WE

ND

-19

89[2

60]

Switz

erla

nd?

??

x 26

.2 v

sB

ronc

hial

rea

ctiv

ity i

ncre

ased

in

EIG

EN

MA

NN

(chi

ldre

n)36

.2no

nast

hmat

ic c

hild

ren†

SCH

MIT

ZB

ER

GE

R19

93[2

61]

Aus

tria

n A

lps

12–2

0?

200–

286

15–3

3D

ecre

ased

lun

g fu

nctio

n an

d in

crea

sed

(chi

ldre

n)(p

roba

bly

asth

ma

(O3)

; SE

S, i

ndoo

r su

rrog

ates

,hi

gh)

age,

sex

in

mod

els

KU

EH

R19

91[2

62]

Sout

hern

Ger

man

y?

?I/

OIn

crea

sed

prev

alen

ce r

ate

of a

sthm

a(c

hild

ren)

mea

sure

-w

ith h

ighe

r in

door

NO

2in

dexe

d to

gas

men

tsst

oves

: E

TS

in m

odel

†

VO

NM

UT

IUS

1992

[263

]L

eipz

ig a

nd<

350

<28

018

6x

39Si

gnif

ican

tly i

ncre

ased

pre

vale

nce

rate

sM

unic

h,<

25<

7023

658

of c

hron

ic b

ronc

hitis

in

Lei

pzig

and

of

Ger

man

y(m

onth

ly)

(lig

ht(3

0 m

in)

asth

ma

in M

unic

h; o

ther

fac

tors

(chi

ldre

n)sc

atte

r)co

ntro

lled

ZA

PLE

TA

L19

73[2

64]

Cze

chos

lova

kia

>24

0>

240

Dec

reas

ed p

ulm

onar

y fu

nctio

n(c

hild

ren)

(24

h)(2

4 h)

(flo

ws)

S PIN

AC

I19

85[2

65]

Tur

in,

Ital

y60

–200

110–

150

Initi

ally

, lo

wer

fun

ctio

n w

ith h

ighe

rA

RO

SSA

1987

[266

](c

hild

ren)

50–1

1080

–110

pollu

tion

data

; la

ter,

no

diff

eren

ce;

adju

sted

for

ET

S, S

ES

PET

RIL

L19

66[2

67]

Gen

oa,

Ital

y53

–404

80–8

50hi

ghSi

gnif

ican

tly i

ncre

ased

chr

onic

(a

dults

)(2

4 h)

(24

h)br

onch

itis

with

SO

2; w

eath

er,

othe

r A

Pan

d ot

her

fact

ors

in m

odel

s; a

ll lo

w S

ES

SAR

IC19

81[2

68]

Cro

atia

≤550

x=20

0[S

O4=

3–42

]Si

gnif

ican

t dec

reas

e in

lung

fun

ctio

n an

d(c

hild

ren)

(24

h)(2

4 h)

–360

(24

h)in

crea

sed

sym

ptom

s w

ith T

SP >

130,

SO2

>60

ann

ual

av;

indo

or,

and

othe

rfa

ctor

s in

mod

elP E

RSH

AG

EN

1984

[269

]H

elsi

nki,

Finl

and

??

5–70

CO

PD c

orre

late

s w

ith N

O2;

tem

p. i

n(a

dults

)m

odel

; no

cov

aria

tes†

GO

RE

N19

88[2

70]

Isra

el?

??

x=In

crea

sed

resp

irat

ory

sym

ptom

s;(c

hild

ren)

23 v

s 62

conf

ound

ers

cont

rolle

d†Sp

ekto

r19

91[1

15]

Cub

ata,

Bra

zil

?64

–104

??

Lun

g fu

nctio

n m

easu

res

sign

ific

antly

(chi

ldre

n)de

crea

sed

rela

ted

to P

M10

(abo

ut 1

00m

L·s

-1pe

r 50

µg·

m-3

)†T

SUN

ET

OSH

I19

71[2

71]

Osa

ka,

Japa

n0.

5–4.

6du

stSO

2si

gnif

ican

tly r

elat

ed t

o ch

roni

c(a

dults

)µ

g·10

0fa

llbr

onch

itis

(not

dus

t fa

ll);

smok

ing,

cm-2

daily

othe

r fa

ctor

s in

mod

elY

OSH

IDA

1976

[272

]Ja

pan

110–

120

LO

EL

SO4

40–1

20In

crea

sed

prev

alen

ce r

ates

of

asth

ma

S UZ

UK

I19

78[2

73]

Japa

n (a

dult

58–9

712

2–43

4In

crea

sed

chro

nic

resp

irat

ory

sym

ptom

s,fe

mal

es)

also

rel

ated

to

age

see

end

of t

able

for

def

initi

ons

Tab

le 5

. –

C

ont..

......

...

Exp

osur

es

µg·

m-3

#Fi

rst

Loc

atio

nau

thor

Y

ear

[R

ef]

(po

pula

tion)

S

O2

TSP

P

M2.

5/B

S

PM10

O3*

N

O2

Res

ults

M.D. LEBOWITZ1044

YA

NO

1990

[274

]Ja

pan

(adu

lt?

119–

341

No

incr

ease

in

chro

nic

sym

ptom

s†fe

mal

es)

(win

ter)

NIT

TA

1993

[275

]T

okyo

, Ja

pan

64–7

724

h:

45–

Sign

ific

ant

incr

ease

of

≥35%

in

chro

nic

(adu

lt13

0 (N

O=

resp

irat

ory

sym

ptom

s at

hig

her

NO

2fe

mal

es)

97–1

26 p

pb)

leve

ls;

mod

els

incl

uded

age

, sm

okin

g,du

ratio

n of

res

iden

ce,

SES,

hom

ehe

atin

g; o

ther

AP

not

incl

uded

HE

1993

[276

]W

uhan

, C

hina

8–24

536

–648

51–2

07N

Ox

4–24

43.

8% l

ower

FE

V1

asso

ciat

ed w

ith A

P,(a

dults

)as

wer

e sy

mpt

oms;

eff

ects

of

spec

ific

AP

not

diff

eren

tiate

dX

U19

91[2

77]

Bei

jing,

Chi

na18

–128

261–

449

Sign

ific

antly

red

uced

lung

fun

ctio

n re

late

d(a

dults

)to

SO

2or

TSP

, an

d in

door

hea

ting;

othe

r fa

ctor

s in

mod

els

TA

M19

94[2

78]

2 di

stri

cts

of4–

177

43–1

33R

SP 3

0–68

15–4

9Si

gnif

ican

tly i

ncre

ased

bro

nchi

alH

ong

Kon

gre

spon

sive

ness

, esp

ecia

lly in

non

whe

ezin

g;(c

hild

ren)

nona

sthm

atic

s, m

ostly

in

boys

; ad

just

edfo

r SE

S, h

ouse

typ

e, p

assi

ve s

mok

ing;

effe

cts

of d

iffe

rent

AP

not

dete

rmin

ed*:

mea

n of

dai

ly m

axim

um 1

h u

nles

s ot

herw

ise

stat

ed;

†: f

rom

EPA

Cri

teri

a D

ocum

ents

. SE

S: S

ocio

econ

omic

sta

tus;

TW

A:

time-

wei

ghte

d av

erag

e; H

CH

O:

form

alde

hyde

; E

TS:

env

i-ro

nmen

tal

toba

cco

smok

e; C

OPD

: ch

roni

c ob

stru

ctiv

e pu

lmon

ary

dise

ase;

RH

: re

lativ

e hu

mid

ity;

I/O

: In

door

/Out

door

rat

io.

For

furt

her

defi

nitio

ns s

ee l

egen

ds t

o ta

bles

1,

2 an

d 4.

Tab

le 5

. –

C

ont..

......

...

Exp

osur

es

µg·

m-3

#Fi

rst

Loc

atio

nau

thor

Y

ear

[R

ef]

(pop

ulat

ion)

SO

2T

SP

P

M2.

5/B

S

PM

10O

3*

NO

2R

esul

tsobserved association. In contrast to the six city study, inthe longitudinal study in California with data on indi-viduals, including individual estimates of exposure [41],no association was found with all cause or cause-spe-cific mortality (table 1).

Though previous reviews did not conclude that airpollution could cause lung cancer [4, 5, 12], two recentstudies have indicated an association [50, 282], raisingthe issue once again.

Chronic respiratory morbidity

Only PM is definitely known to produce chronic res-piratory disease, for which AQGs have been written [61,39], but there is evidence that ozone [13], and NO2 [10]may also produce such diseases. Table 5 presents the quan-titative results concerning chronic effects, as obtainedwhen available from the multiple studies mentioned below.It should be noted that the role of the indoor environ-mental contaminants, especially due to combustion prod-ucts and bioaerosols (including allergens), is also consideredquite substantial by itself [8, 16].

PM/SOx. Respiratory symptoms and deterioration in lungfunction in populations (studied cross-sectionally or longi-tudinally), and longitudinal changes, are greater in thosethat reside in polluted areas than those residing in clea-ner areas [4, 6, 8, 9, 12, 13, 15, 25, 41, 61, 102, 179,186, 215, 218, 223–225, 228, 229, 235, 244, 263, 283–288]. The pollutant mix invariably contains PM but alsooften contains SO2, NO2, or O3. The effects of specificspecies of PM have not been delineated, though SO4 andH2SO4 have been implicated specifically in chronic obstruc-tive lung disease (COPD) [10, 236, 243, 289].

Childhood chronic bronchitis was more associated withtypical SO2 and PM pollution in Germany [263], as hadbeen found in the UK [4, 5, 191, 244]. It is thought thatthis may be the case in the parts of Central and EasternEurope that are still polluted primarily by PM and SO2.Chronic lung conditions in children and adults in less-developed countries are thought to be related to indoorcombustion products [12, 15, 17, 18].

PM/NOx. Geographic differences occur in the prevalencerates of asthma as well, based on more recent studies [5,13]. For instance, there is an increased level of asthmaeven when risk factors for asthma in different commu-nities may be similar, when there is more pollution frompower plants [290], or when there is more pollution fromauto exhaust [41, 235, 263]. The relationship of asthmaprevalence (and immunological changes) to auto exhaustwas also noted by ZWICK et al. [291]. These studies implysome possible link to a PM-NO2 complex, and some pos-sible role of hydrocarbons (as has been shown in min-ing). There is an AQG for NO2 to avoid chronic effects[61].

ETS. Passive smoking (ETS) has been found to be asso-ciated with COPD [159, 292]. ETS in the presence offormaldehyde has been shown to relate to increased preva-lence rates of childhood asthma and bronchial respon-siveness, whilst formaldehyde alone was also associatedwith increased prevalence rates of childhood chronic

bronchitis [160]. INFANTE-RIVARD [242] reported thatmonitored NO2 had a dose-response relationship withasthma in a case-control study; she also showed thatquestionnaire information on mothers' heavy smoking,bedroom humidifiers, home heating, a history of pneu-monia, a family history of asthma, and the absence ofbreast-feeding might be important. Other questionnairesurveys, with appropriate controls for these other vari-ables, have yielded conflicting relationships with passivesmoking [159]. Many other surveys have not had appro-priate controls, especially for family history, and havenot measured pertinant pollutants that might affect asth-ma.

Other pollutants. The effect of other chemical pollutantexposures on the incidence of asthma is not sufficientlyknown. However, it is known that aeroallergens are stron-gly associated [8, 249]. There are also some low mole-cular weight chemicals [171, 172, 293] and certain metals,such as chromium and nickel (WHO EHCs) which can,with significant exposures, produce asthma. Chemicalpollutants can also act as adjuvants with allergens in thedevelopment of asthma [8]. In addition, chronic expo-sure to high levels of volatile organic compounds (VOCS)and to NOx are related to chemical pneumonitis [25, 120].

Risk assessment. COPD appears to increase significantly(relative risk (RR) of 1.5–2.5) as annual TSP increasesabove 100 µg·m-3 and SO2 (concurrently). Chronic bronchi-tis appears to increase linearly with SO4: every 2 µg·m-3

above 5.8 µg·m-3 adds 1.24% to the prevalence rate [289].In urban areas, significantly more chronic COPD symp-toms may occur with SO4 above 9 µg·m-3 in the pres-ence of high SO2 and TSP, and 15+ without high TSP[10]. In a Californian study [236], asthma was also foundto increase significantly with SO4 by about 2.9 times per7 µg·m-3. The Cracow study found a 24% prevalencerate of chronic bronchitis in males (11.5% in women)[253, 254]. Many estimates have been made of excessAOD in parts of Europe, due to the excessive PM/SOxpollution in certain locales; they have been quite large(e.g. 2–7 million cases). A 24 h guideline of 180 µg·m-3

of NO2 was also established by the WHO [61] to avoidchronic effects of repeated exposures.

Lung function and particulates

Differences in lung function in children residing invarious areas have also been related to the many differ-ences in air pollution in those areas [4–7, 13]. Fur-thermore, TOYAMA [287] and WATANABE [294] showedimprovement in peak expiratory flow rates in childrenliving in more polluted communities when air pollutionconcentrations decreased. In France, the PAARC study[256] found differences in children but not in adult fe-males related to SO2. The sulphate and nitrate particu-late forms of SOx and NOx appear to have greater impacton lung function in normals than the gaseous form becausethey have greater airway penetration [4, 8, 25, 102].

Several studies of indoor pollution have shown rela-tionships between monitored NO2 and PM and reducedlung function [8, 11, 84, 85, 175, 199, 250]. Passivesmoking over long periods of time in susceptible chil-dren leads to significantly slower and reduced lung growth

[295], and in children in the general population to areduction of 0.1–3% in FEV1 [159].

Significant decrements (3–8%) appear to be related toambient annual TSP above 180 µg·m-3 (PM10 about 110µg·m-3) (also associated with SO2), or 100 µg·m-3 of SO4and SO2 in children. Significant differences (<3%) occurin children related to ETS (mostly PM2.5) differences of60–100 µg·m-3 or more. Decreases occur more frequentlyand are larger in those starting with low lung function,bronchial responsiveness, and/or a chronic respiratorydisease.

Bronchial responsiveness is related to various contami-nants. Increased bronchial responsiveness was found inchildren in relation to O3, possibly related to T-lym-phocyte changes but not to atopy or immunoglobulin E(IgE), in an area of high ozone levels in Austria [291].Increased BR has also been found in an urban-industrialarea in Latium, Italy, even though baseline lung func-tion and atopy were not different, and after controllingfor ETS exposure and other risk factors [296]. It has alsobeen found that the relationship of BR (indexed by diur-nal PEF) and PM2.5 occurred primarily in homes inde-pendent of ETS, although rates of BR were higher inhomes with more PM10 and ETS; the rates of BR in chil-dren were independently related to ETS [161]. Preval-ence rates of BR are independently associated withincreasing exposure to HCHO, and to NO2 [176]; thelatter association has also been found experimentally[109]. Several metals have also been associated withincreased bronchial responsiveness (nickel, chromium,vanadium, platinum salts) [10, 12, 25, 171]. As discussedpreviously, BR is longitudinally associated with reducedlung function (op cit.). Both BR and asthma in child-hood are associated with as much as a 25% decrement infunction at the onset of adulthood ([208]; S. Weiss, per-sonal communication).

Chronic outcomes of acute changes

Do acute morbidity effects lead to chronic effects?Those with chronic obstructive airway disease have ahistory of significantly more frequent and severe ARIs[210, 279] and a significant history of childhood respira-tory problems [205, 210]. It is also known that childhoodARIs are longitudinally associated with a decrement oflung function [208]. A study of acute pulmonary func-tion changes in healthy children in a smelter town [19]indicated significant acute reversible changes. A furtherstudy of children in that town, another smelter townand a control town [228, 229], indicated that pulmonaryfunction values were lower overall in the smelter towns(even despite potential selective migration). Thus, thereare grounds for a possible relationship between acute andchronic pulmonary function changes. Furthermore, it issometimes difficult to separate the acute (peak) exposureeffects from the chronic exposure effects ([84, 102, 176,239]; M. Green, public comments at ERS, Firenze, 1993).

Discussion

The separate effects of gases and PM, though diffi-cult, have been investigated, both epidemiologically as


well as in controlled human exposure studies. PM andgases appear to have an interactive effect in clinical andepidemiological studies (e.g. formaldehyde particles, radonand particles, gases and particles in passive smoking,ambient ozone and/or NO2 and PM). It is still difficultto evaluate the impact of short-term exposures, includ-ing peak exposures, on chronic conditions (SO2 as in-termittent outdoor peaks, has also been associated withacute and chronic respiratory conditions [5]). The roleof "peak" exposures to gases (NO2, O3, SO2) has alsobeen related to bronchial responsiveness (as discussed).

Factors affecting responses. It has been mentioned thattemperature is usually even more important than air pol-lutants; humidity is also an important factor. For instance,heat and relative humidity (RH) may contribute to symp-toms and physiological impairment. A hot (31–40°C)and/or humid (85% RH) environment, combined withexercise, has been shown to reduce forced expiratoryvolume more than similar exposures (25°C, 50% RH)[297, 298]. Modification of the effects by heat or humi-dity stress may be attributed to increased ventilation as-sociated with elevated body temperature but there mayalso be an independent effect of elevated body tempera-ture on pulmonary function. Also, increased ventilationat altitude, as in exercise, increases doses of pollutantsin the lung (tracheobronchial and alveoli), as adequatelevels of ventilation are necessary to maintain sufficientO2 partial pressures in alveolar and arterial blood. Thus,all considerations of the effects of air pollutants musttake these factors into account.

Effect-modifiers and factors affecting confounding. Hostfactors are significant effect modifiers. Immunologicaland physiological status appear to be the most important[8, 11, 12, 16, 22, 55, 175, 179, 208, 293, 295]. (As dis-cussed above, prior ARIs and concurrent morbidity arealso of importance). These potential links require furtherstudy.

Not all potential confounders are important per se [6].Follow-up studies on a cohort started by DOUGLAS et al.[186] did not confirm original social class differences tobe significant in accounting for health findings later inlife. MANFREDA et al. [285] did not find "urban" charac-teristics to be relevant in explaining results. Thus, oneshould not overemphasize the relative importance ofpotential confounding or covariant factors when thesehave not been specifically ruled out as alternative expla-nations for specific results [6].

Conclusions

The most important aspects of this issue need to beaddressed [4–9, 17, 18, 22, 60, 299, 300]: 1) pollutionexposure is a cause, albeit with others (and not the mostpotent) of chronic respiratory disease; 2) it is a majorcause of exacerbations of asthma and COPD. (both aspectsare responsible for major disability, cost, and reductionin the quality of life); 3) it influences (and is part of) theaetiological and natural history chain of chronic respira-tory disease, which includes increased ARIs, increasedinflammation and bronchial reactivity, and reduced lungfunction. The first two would also imply that at least

some pollutants alter immunological function in morethan one way, as found in animal studies [301], and pos-sibly in human studies [302, 303]. Thus, further studiesof the epidemiology of air pollution and its control arenecessary [8, 10, 304–306].

With regard to asthma and chronic obstructive pul-monary disease, we consider the following to be the futureepidemiological perspectives: methods of interventionand associated studies; methods of ascertaining patho-physiological and immunological changes, including bio-markers of noncarcinogenic and of acute changes; furtherstudies of irritation and reactive airways dysfunction syn-drome (RADS) (with respect to asthma and chronicobstructive pulmonary disease), the study of the role ofacute effects in the aetiology and natural history of chro-nic disease; and methods and studies to ascertain quan-titative exposure dose-response relationships for individualair pollutants and complex mixes.

Acknowledgements: The authors wish to acknowledgeI. Hewitt, administrative assistant, without whom this workcould not have been accomplished.

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