INQUINAMENTO E DISTURBI RESPIRATORI NEL BAMBINO E

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INQUINAMENTO E DISTURBI RESPIRATORI NEL BAMBINO
E. Baraldi, G.Bonetto
Dipartimento di Pediatria, Unità di Pneumologia e Allergologia,
Azienda Ospedaliera-Università di Padova
Negli ultimi 50 anni le patologie respiratorie di natura allergica sono nettamente aumentate
in diversi paesi con stili di vita “moderni”. Allo stesso tempo il traffico autoveicolare ed i
livelli di inquinamento ambientale hanno subito profonde modifiche.
Si distinguono abitualmente due principali tipi di inquinamento esterno: lo smog industriale
determinato principalmente dall’anidride solforosa (SO2) e dalle particelle corpuscolate
(TSP) e lo smog urbano legato al traffico autoveicolare, costituito essenzialmente da
ozono, ossidi di azoto, particolati respirabili e composti volatili.
Sono ormai classici gli studi condotti su una popolazione pediatrica agli inizi degli anni
Novanta nelle due città tedesche di Lipsia e Monaco, la prima (nella Germania dell’Est)
caratterizzata da alte concentrazioni di anidride solforosa, la seconda da biossido d’azoto
e particolati respirabili. La prevalenza di bronchite era maggiore a Lipsia, mentre a
Monaco si registrava una prevalenza maggiore di asma e malattie allergiche. (von Mutius)
Ci sono inoltre diversi studi che hanno messo in relazione l’abitare in prossimità di strade
ad alta percorrenza ad una aumentata prevalenza di manifestazioni respiratorie in età
pediatrica. (Venn, Ghering, Brunekreef)
Per quanto riguarda le malattie respiratorie di natura non allergica (bronchite ed infezioni
delle alte vie aeree) è evidenziata una relazione con il diossido di zolfo (SO2) e la
concentrazione di particelle corpuscolate totali (TSP). (Heinrich 2003) Un modello è offerto
ancora dagli studi epidemiologici condotti in diverse città della Germania dell’est, questa
volta dopo alcuni anni dalla riunificazione. Infatti la prevalenza di bronchite, infezioni delle
alte vie aeree e tosse persistente ha presentato un importante decremento in parallelo con
la riduzione e la modificazione del tipo di inquinamento. (Heinrich 2000)
Per quanto riguarda l’asma, la sua prevalenza è maggiore nei Paesi Industrializzati e
numerosi studi hanno dimostrato che taluni tipi di inquinanti ambientali sono trigger delle
riacutizzazioni asmatiche, tuttavia nessuno studio ha fornito risultati conclusivi relativi al
fatto che l’inquinamento sia causa dell’aumentata prevalenza dell’asma. (Brauer)
I dati epidemiologici riguardanti gli effetti sulla morbilità respiratoria delle particelle
particolate sono discordanti, anche se sembra dimostrato che le particelle di diametro
inferiore ai 10 micron (PM10, PM10-PM2,5 e PM2,5), alle concentrazioni che si incontrano
comunemente nelle città, producano una risposta infiammatoria e uno stress ossidativo a
livello delle vie aeree e possano determinare una riduzione dei parametri di funzionalità
polmonare come pure una riesacerbazione di una preesistente flogosi. Il loro effetto è più
evidente in soggetti suscettibili come per esempio chi è affetto da una pneumopatia di
base (asma, allergia, fibrosi cistica), chi ha un infezione polmonare in atto o chi è esposto
al fumo. I bambini sono più suscettibili degli adulti per le ridotte dimensioni delle vie aeree
e per la minor capacità di clearance dai tossici a livello polmonare. E’ ancora oggetto di
studio il peso relativo dei diversi componenti dei particolati nell’effetto proflogistico, anche
se particolare attenzione sta suscitando il monossido di carbonio (CO).
Un recentissimo studio ha evidenziato associazione tra particolati (del diametro inferiore a
2,5 micron), monossido di carbonio, biossido d’azoto e ozono con i sintomi bronchitici in
bambini asmatici. (McConnell)
L’esposizione al biossido di azoto (NO2) è stata messa in relazione con la comparsa di
sintomi respiratori sia nel bambino che nell’adulto. In particolare sembra che l’esposizione
all’NO 2 sia associata ad una maggiore gravità del broncospasmo in corso di infezione
virale, ed interferisca anche con la risposta immunitaria dell’ospite verso l’agente infettivo
(Curie). Uno studio longitudinale condotto in età scolare ha dimostrato che un’esposizione
protratta all’NO2 è in relazione con un incremento inferiore alle attese di alcuni parametri
spirometrici, che riflettono la funzionalità delle piccole vie aeree. (Gaudermann)
Le esalazioni dei motori diesel possono sia adsorbire gli allergeni ed aumentare la loro
deposizione a livello polmonare che evocare direttamente una risposta infiammatoria di
tipo T-helper2. (Sydbom) Studi epidemiologici hanno mostrato una maggior incidenza di
sintomi respiratori ed una riduzione dei parametri di funzionalità respiratoria nei bambini
che vivevano vicino a strade con transito di mezzi pesanti. (Van Vliet)
L’ozono può determinare riacutizzazioni asmatiche e ridurre i parametri di funzionalità
polmonare.(Ruth)
Un ulteriore problema è quello dei bambini che praticano attività sportiva all’aperto, in
particolare la corsa. In tale condizione vi è un aumento della ventilazione e quindi della
dose di inquinante che raggiunge il polmone. Alcuni studi hanno dimostrato che sia l’ozono
che l’NO2 possono aumentare i sintomi respiratori in queste condizioni. (McConnell)
All’inquinamento atmosferico contribuiscono sia gli inquinanti degli ambienti esterni che
quelli degli ambienti interni e poichè i residenti dei Paesi industrialiazzati trascorrono il 9095% del tempo in ambienti chiusi è fondamentale considerare tale tipo di inquinamento.
Studi recenti sembrano anzi indicare che, se l’inquinamento esterno è correlato ad
esacerbazioni asmatiche, quello interno potrebbe essere implicato anche nell’aumento
dell’incidenza della patologia.(Stone) In particolare per quanto riguarda l’esposizione al
fumo di sigaretta vi sono evidenze sufficienti per stabilire una relazione causale tra
l’esposizione ad esso e lo sviluppo di asma (Insitute of Medicine). Alcuni Autori hanno
messo in relazione il fumo materno, sia in gravidanza che nel primo anno di vita, con una
riduzione nei parametri di funzionalità respiratoria, come riflesso di modificazioni nel
calibro o nella geometria delle vie aeree. (Dezateux)
Gli altri principali inquinanti interni sono rappresentati dall’ossido nitrico, dagli ossidi di
azoto, dal monossido di carbonio, dall’anidride carbonica, dall’anidride solforosa, dalla
formaldeide, e da sostanze di natura biologica come le endotossine. Le principali fonti di
inquinamento che si trovano comunemente nelle case sono le cucine alimentate a gas
liquidi, il riscaldamento a metano e legna, gli arredi contenenti gommapiuma, colla, isolanti
termici.
In conclusione vi sono ampie evidenze che l’inquinamento ambientale possa essere alla
base di riacutizzazioni asmatiche, ma appare improbabile che possa giustificare il trend
secolare di aumento dell’asma. E’ importante non sottovalutare l’inquinamento interno, in
particolare l’esposizione dei bambini al fumo di sigaretta che è sicuramente altrettanto
dannoso e forse più facile da prevenire ed evitare.
Riferimenti bibliografici
-von Mutius E, Fritzsch C, Weiland SK, Roll G, Magnussen H. Prevalence of asthma and
allergic disorders among children in united Germany: a descriptive comparison. BMJ
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and the development of respiratory infections and asthmatic and allergic symptoms in
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between air pollution and lung function growth in southern california children.Am J Respir
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diesel exhaust emissions. Eur Respir J 2001; 17:733-746.
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and chronic respiratory symptoms in children living near freeways. Environ Res
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the air: Asthma and Indoor Air Exposures. Washington,DC: National Academy Press;2000
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association with premorbid airway function, wheezing, and maternal smoking. Thorax
2001;56:680-686
Airway Inflammation in Childhood Asthma
Angelo Barbato, Graziella Turato, Simonetta Baraldo, Erica Bazzan, Fiorella Calabrese, Maria Tura, Renzo Zuin,
Bianca Beghé, Piero Maestrelli, Leonardo M. Fabbri, and Marina Saetta
Department of Pediatrics; Department of Clinical and Experimental Medicine, Section of Respiratory Diseases; Department of Respiratory
Diseases and Radiology, University of Modena and Reggio Emilia; Institute of Pathology; and Department of Environmental Medicine and
Public Health, University of Padua, Padua, Italy
Airway pathology has been extensively investigated in adulthood
asthma, whereas only few studies examined bronchial biopsies in
childhood asthma. To evaluate the airway pathology in children
with asthma, we analyzed bronchial biopsies obtained from 23 children undergoing bronchoscopy for clinical indications other than
asthma. Nine had mild/moderate asthma. Six had atopy without
asthma, and eight had no atopy or asthma. We measured basement
membrane thickness and quantified the number of eosinophils, mast
cells, neutrophils, macrophages, T lymphocytes, and positive cells
for transforming growth factor-␤1 (TGF-␤1) and its receptors I and
II (TGF␤-RI and TGF␤-RII) in subepithelium. Children with asthma
had an increase in basement membrane thickness and in the number of eosinophils compared with control subjects, but not compared with children with atopy. They also had a decreased expression of TGF␤-RII compared with both those with atopy and control
subjects. In children with asthma, the number of eosinophils correlated negatively with TGF␤-RII and positively with symptom duration. In conclusion, airway eosinophilia and basement membrane
thickening, which are the pathologic features that are characteristic
of adulthood asthma, are already present in children with mild
asthma, and even in children with atopy without asthma. Moreover,
in children with asthma but not in children with atopy without
asthma, there is a downregulation of TGF␤-RII.
Keywords: inflammation; remodeling; pediatric asthma; cytokines
Airway inflammation and remodeling play an important role in
the pathophysiology of asthma. Although the airway pathology
has been extensively investigated in adulthood asthma, only a
few studies examined bronchial biopsies obtained from children
with asthma (1). Investigating the airway pathology in childhood
asthma may be of interest to clarify whether the pathologic
features seen in adults begin early in the course of the disease
and whether remodeling occurs in parallel with inflammation or
sequential to it. Previous studies (2, 3) have described the presence of both inflammation and thickening of the basement membrane in children with asthma. However, in those studies, only
a qualitative analysis was performed, and a control group of
children without asthma was not included. More recently, Payne
and coworkers (4), in a quantitative well-conducted study, demonstrated that children with difficult asthma had a thickened
basement membrane as compared with pediatric control subjects
and that this thickening was similar to that seen in adulthood
asthma. However, as stated by the authors, the children examined in that study are not typical of the majority of children with
(Received in original form May 14, 2003; accepted in final form July 26, 2003)
Supported by the Ministry of University and Research.
Correspondence and requests for reprints should be addressed to Marina Saetta,
M.D., Divisione di Pneumologia, Dipartimento di Medicina Clinica e Sperimentale,
Università degli Studi di Padova, via Giustiniani 3, 35128 Padua, Italy. E-mail:
[email protected]
Am J Respir Crit Care Med Vol 168. pp 798–803, 2003
Originally Published in Press as DOI: 10.1164/rccm.200305-650OC on July 31, 2003
Internet address: www.atsjournals.org
asthma but represent those with the most severe disease, with
persistent symptoms despite maximal steroid therapy. Furthermore, that study did not include a control group of children
with atopy without asthma. Therefore, it is yet to be elucidated
whether inflammation and remodeling can be already observed
in children when the disease is mild or even when only atopy is
present.
There is accumulating evidence to suggest that transforming
growth factor-␤1 (TGF-␤1) may be involved in orchestrating both
inflammatory and remodeling processes in asthma. TGF-␤1 is a
pleiotropic cytokine that through binding to its type I and type
II receptors (TGF␤-RI and TGF␤-RII) can exert a number of
biological effects, including profibrotic and antiinflammatory activities (5, 6). Although some studies in human asthma have shown
an increased expression of TGF-␤1 (7–9), underlining its profibrotic role, other studies have demonstrated an antiinflammatory
activity of this cytokine (10, 11). It could be of interest to investigate the expression of TGF-␤1 and its receptors in childhood
asthma, when the onset of inflammation and remodeling processes
is probably occurring.
As far as we know, no study has addressed the issue to quantify the airway inflammatory and structural changes in children
with mild/moderate asthma and to compare them with the appropriate pediatric control subjects, in particular with children with
atopy without asthma. We therefore decided to measure the
inflammatory cells and the basement membrane thickness in
bronchial biopsies of children with mild/moderate asthma, of
children with atopy but without asthma, and of children with
no atopy or asthma. Moreover, to clarify the role of TGF-␤1 in
airway inflammation and remodeling, we examined the expression of TGF-␤1, TGF␤-RI, and TGF␤-RII in the three groups
of children. Some of the results of these studies have been previously reported in the form of an abstract at the 2003 Meeting
of the American Thoracic Society (Seattle, WA) (12).
METHODS
Subjects
We recruited to the study 23 children who had undergone fiberoptic
bronchoscopy for appropriate clinical indications other than asthma
(13, 14). The study population included the following three groups:
nine children with asthma (age of 4–12 years), six children with atopy
without asthma (age of 3–13 years), and eight control children without
asthma or atopy (age of 4–12 years). Children with asthma underwent
bronchoscopy for persistent atelectasis (n ⫽ 3) or for recurrent pneumonia (n ⫽ 6). Children with atopy without asthma underwent bronchoscopy for stridor (n ⫽ 1), persistent atelectasis (n ⫽ 1), or recurrent
pneumonia (n ⫽ 4). Children who were control subjects underwent
bronchoscopy for stridor (n ⫽ 2), persistent atelectasis (n ⫽ 1), recurrent
pneumonia (n ⫽ 3), or chronic cough (n ⫽ 2).
Asthma was diagnosed when the child had episodic cough, breathlessness, and a wheeze responsive to bronchodilators (15). The presence
of atopy was defined by an increase in total (paper-radio-immunosorbent-test) or specific (radio-allergo-sorbent-test) IgE. All children
Barbato, Turato, Baraldo, et al.: Pathology of Asthma in Children
of the three groups underwent paper-radio-immuno-sorbent-test, radioallergo-sorbent-test, and routine blood tests, whereas spirometry was
performed only in children who were able to cooperate with the test.
FEV1 was measured using a 10-L bell spirometer (Biomedin, Padua,
Italy), and the best of three maneuvers was expressed as a percentage
of predicted values (16).
Performance of endobronchial biopsy for studying airway pathology
was approved by local ethics committees. Informed consent was obtained from the children’s parents. The study was performed according
to the Declaration of Helsinki. Bronchoscopy was performed as previously described (17), except that the fiberoptic bronchoscope was
inserted orally using a mouth Olympus MA-651 (K). One bronchial
biopsy specimen was taken from the main carina using a bronchial
forceps (Olympus FB 15 C-1) inserted through the service channel of
the bronchoscope.
Sample Processing and Analysis
Biopsies were processed as previously described (18). Reticular basement membrane thickness was assessed on sections stained with hematoxylin and eosin by making measurements at 50-␮m intervals along
all the basement membrane, using a computer-aided image analysis
(Casti Imaging, Venice, Italy). The infiltration of eosinophils, neutrophils, mast cells, macrophages, and CD4 T lymphocytes was assessed
in the subepithelium by immunohistochemistry as previously described
(19). The expression of TGF-␤1, TGF␤-RI, and TGF␤-RII was assessed
in the subepithelium using immunohistochemical methods. Briefly, all
biopsy sections were subjected to antigen retrieval by heating in a
microwave oven on high power for 8 minutes in 0.01 mol/L citrate
buffer (pH 6.0) and then incubated with a mouse monoclonal antibody
anti–TGF-␤1 (150 ␮g/ml, dilution 1:20; Genzyme Diagnostics, Cambridge, MA) with a polyclonal antibody anti–TGF-␤1 receptor type I
(200 ␮g/ml, dilution 1:200; Santa Cruz Biotechnology Inc., Santa Cruz,
CA) or with a polyclonal antibody anti–TGF␤-RII (200 ␮g/ml, dilution
1:200; Santa Cruz Biotechnology Inc.). Before incubation with primary
antibody, the sections were treated with a biotin blocking kit (Vector
Laboratories, Peterborough, UK) to inhibit endogenous biotin. The
detection system was performed using the Vectastain ABC kit (Vector
Laboratories) with 3-amino-9-ethylcarbazole as the chromogenic substrate. Sections were counterstained with Mayer’s hematoxylin. The
surface epithelial layer was not included in the count because of the
frequent erosion or loss by technical misprocessing.
To avoid observer bias, the cases were coded, and the measurements
were made without knowledge of clinical data. Differences between
groups were analyzed using the analysis of variance for clinical data
and the Kruskall-Wallis test for histologic data. The Mann-Whitney
U test was performed after Kruskall-Wallis test when appropriate.
Correlation coefficients were calculated using Spearman’s rank method.
Probability values of 0.05 or less were accepted as significant. Group
data were expressed as means and SEM or as medians and range when
appropriate.
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with asthma, four of six children with atopy, and five of eight
control subjects. Children with asthma had a FEV1 value (percentage of predicted) that was significantly lower than control
children (p ⫽ 0.008). The three groups of children were similar
with regard to age and sex. Six out of nine children with asthma
were atopic. The bronchoscopy procedure was well tolerated by
all children.
Seven of nine children with asthma had mild asthma and
were treated with only inhaled salbutamol when needed. The
remaining two children had moderate asthma and were treated
regularly with combined salmeterol/fluticasone (50/100 twice a
day in one child and 50/250 twice a day in the other child). All
children with recurrent pneumonia (n ⫽ 13) were in treatment
with antibiotics.
To confirm further the absence of asthma in children with
atopy without asthma, we performed exercise challenge in those
children who were able to cooperate with the test (three out of
six). None of them had a fall in FEV1 that was 15% or more
after exercise.
Biopsy Findings
Quantification of inflammatory cells was satisfactory in all children except in one of the group with asthma and in one of the
control group in whom we could quantify only eosinophils and
basement membrane thickness because of the limited amount
of biopsy tissue. For the same reason, we were not able to
quantify TGF-␤1 and its receptors in one child in the group with
atopy.
Children with asthma had an increased reticular basement
membrane thickness as compared with children who were control
subjects (6.0, 4.5–9.5 vs. 4.2, 3.3–4.9; p ⫽ 0.001) (Figures 1 and
2). Even if to a lesser extent, also children with atopy showed
an increased basement membrane thickness as compared with
children who were control subjects (4.9, 4.2–6.6 vs. 4.2, 3.3–4.9;
p ⫽ 0.052) (Figure 1). In addition, both children with atopy
without asthma and children with asthma had an increased number of eosinophils in the subepithelium as compared with children who were control subjects (p ⫽ 0.033 and p ⫽ 0.038, respectively) (Figures 3 and 4 and Table 2). No significant difference
was observed between children with atopy and with asthma in
the reticular basement membrane thickness or in the eosinophilic
infiltration. Of the two children taking inhaled steroids, one had
a value of tissue eosinophils in the range of control subjects (48
RESULTS
Clinical Findings
The characteristic of the children studied are shown in Table 1.
Spirometry was successfully performed in six of nine children
TABLE 1. CLINICAL CHARACTERISTICS OF CHILDREN
WITH ASTHMA, CHILDREN WITH ATOPY, AND
CONTROL CHILDREN
Characteristics
Number, male/female
Age, yr
Age range, yr
Atopy
Duration of asthma, yr
FEV1, % predicted
Children with
Asthma
Children with
Atopy
Control
Children
5/4
8⫾1
4–12
6/9
5.7 ⫾ 1.2
79 ⫾ 5*
3/3
7⫾1
4–12
6/6
—
90 ⫾ 2
3/5
7⫾1
3–13
0/8
—
102 ⫾ 4
Values are expressed as absolute numbers or as means ⫾ SEM.
* p ⬍ 0.01 as compared with control children.
Figure 1. Individual values for reticular basement membrane thickness
in bronchial biopsies of children with asthma, children with atopy, and
children who were control subjects. Horizontal bars represent median
values. The asterisk indicates children with asthma who were not atopic;
S indicates children with asthma who were treated with inhaled steroids.
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 168 2003
Figure 2. Microphotograph
showing bronchial biopsies
from a child with asthma (A )
and a control child (B ), demonstrating an increased basement membrane thickness in
the child with asthma. The tissue sections are stained with
hematoxylin and eosin. Original magnification, ⫻630.
cells/mm2), whereas the other had a prominent tissue eosinophilia
(338 cells/mm2). No significant differences were observed among
the three groups of subjects in the number of neutrophils, mast
cells, CD4⫹ T lymphocytes, and macrophages (Table 2). The expression of TGF-␤1 and TGF␤-RI was not significantly different
in the three groups of children examined (Table 2). However,
children with asthma had a decreased expression of TGF␤-RII
in the subepithelium as compared with both children with atopy
and children who were control subjects (p ⫽ 0.004 and p ⫽ 0.047,
respectively; Figure 5).
When only the group of children with asthma was considered,
the number of eosinophils in the airway wall showed a negative
correlation with TGF␤-RII expression (p ⫽ 0.035, r ⫽ ⫺0.86)
and a positive correlation with the duration of asthma symptoms
(p ⫽ 0.020, r ⫽ 0.79). No other significant correlations were
observed between cellular counts and functional data or between
reticular basement membrane thickness and cellular counts or
functional data.
DISCUSSION
This study shows that the pathologic features characteristic of
adulthood asthma, that is, airway eosinophilia and basement
membrane thickening, are already present in children with mild/
Figure 3. Individual counts for eosinophils in bronchial biopsies of children with asthma, children with atopy, and control children. The results
are expressed as number of cells per mm2 of tissue examined. Horizontal
bars represent median values. The asterisk indicates children with asthma
who were not atopic; S indicates children with asthma who were treated
with inhaled steroids.
moderate asthma. Moreover, in children with asthma, these pathologic features are paralleled by a decreased expression of
TGF␤-RII. Children with atopy without asthma also exhibit an
increase in number of eosinophils and, even if to a lesser extent,
in basement membrane thickness.
By showing that basement membrane thickening is already
present in childhood asthma, this study confirms the qualitative
observations of previous reports (2, 3). The only study that
provided quantitative measurements of basement membrane
thickness in childhood asthma has been performed in children
with difficult asthma, that is, in children with persistent symptoms
despite maximal conventional therapy (4). Moreover, a group
of children with atopy without asthma, which, according to the
authors, would be the most appropriate control group, was not
included in that report. Therefore, to the best of our knowledge,
this is the first study to provide a quantification of basement
membrane thickening in children with mild/moderate asthma
and to compare the results with those of two appropriate pediatric control groups, that is, a group of children with atopy but
without asthma and a group of children with no atopy or asthma.
Our observation of an increased number of eosinophils in
bronchial biopsies of children with asthma may appear to be
in disagreement with previous studies (3, 20). Cokugras and
coworkers (3) showed that eosinophilic inflammation was present only in 1 of 10 children with moderate asthma, and Payne
and coworkers (20) found that the number of eosinophils in
children with difficult asthma was not different from that of
children without asthma. However, children examined in those
studies had been treated with high doses of inhaled (3) or oral
steroids (20), which may have reduced the number of eosinophils. In our study, only two children with asthma were treated
with inhaled steroids; thus in the majority of children, we obtained objective measurements of inflammatory cells without
the influence of antiinflammatory drugs. The eosinophilic inflammation observed in our study is in keeping with the pioneer
observation of Cutz and coworkers, who described a prominent
eosinophilia in two endobronchial biopsies and two autopsy samples of children with asthma (2). Moreover, previous studies
performed in bronchoalveolar lavage and induced sputum of
children with asthma reported an increased number of eosinophils,
which was related to the degree of bronchial hyperresponsiveness
(21, 22). More recently, analysis of exhaled breath condensate
confirmed the presence of an airway inflammatory process in
childhood asthma (15, 23).
In this report, airway eosinophilia and, even if to a lesser extent,
also basement membrane thickening were already present in
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Fi gu re 4. Microphotograph showing
bronchial biopsies from a child with
asthma (A ) and a control child (B ), demonstrating an increased number of eosinophils infiltrating the subepithelium in the
child with asthma. Immunostaining with
monoclonal antibody anti–EG-2 (positive
cells are stained in red). Original magnification, ⫻630.
children with atopy without asthma. The relationship between
these pathologic changes, atopy, and asthma symptoms is difficult to establish, especially in children. Indeed, early allergic
sensitization seems to play an important role in the development
of persistent asthma in the first years of life (24). It can be
hypothesized that airway inflammation and remodeling are early
lesions that may occur even before the establishment of the
disordered lung function characteristic of the disease. On the
other hand, as not all children with atopy will eventually develop
asthma (25, 26), it is also plausible that these pathologic lesions
are not directly related to functional abnormalities. This hypothesis is consistent with the findings of previous studies that reported
that basement membrane thickening and airway eosinophilia are
present in adults with atopy without asthma (27–30).
One generally accepted hypothesis is that in asthma, airway
remodeling is dependent on the prior development of chronic
inflammation. Our observation of the presence of both thickening of basement membrane and airway eosinophilia in children
with mild asthma suggests that remodeling processes begin early
in the course of the disease and most likely occur in parallel
with the establishment of the chronic inflammation rather than
sequential to it.
To assess the role of TGF-␤1 in modulating the pathways
leading to airway remodeling and inflammation, we examined
the expression of this cytokine and its receptors in children with
asthma. TGF-␤1 is a pleiotropic cytokine that can exert both
profibrotic and antiinflammatory activities. The increased expression of TGF-␤1 observed in adults with asthma (7–9) has
been traditionally related to tissue repairing processes occurring
in the airways damaged by inflammatory cells. It has been hypothesized that the persistent activity of TGF-␤1, induced by
chronic inflammation, might have detrimental consequences
such as subepithelial fibrosis and airway remodeling (5). How-
ever, other studies have demonstrated that this cytokine may
have antiinflammatory activities as well (10, 11), probably
through the induction of apoptosis of inflammatory cells, particularly eosinophils (31). In our study, the expression of TGF-␤1
was similar in the three groups of children examined, whereas
the expression of TGF␤-RII was decreased in children with
asthma as compared with both children with atopy and children
who were control subjects. These findings suggest that TGF-␤1
signaling may be downregulated in childhood asthma and therefore may be unable to exert its antiinflammatory activity. This
hypothesis is supported by the negative correlation observed
between the number of TGF␤-RII⫹ cells and the number of
eosinophils in children with asthma. Conversely, neither TGF-␤1
nor its receptors were correlated with basement membrane thickness, suggesting that the profibrotic activity of this cytokine does
not contribute to airway remodeling in childhood asthma.
Interestingly, in our population of children, the downregulation of TGF␤-RII expression was the only pathologic feature
that was able to differentiate children with asthma from children
with atopy without asthma, despite the presence of a similar
eosinophilia and a similar basement membrane thickening in
the two groups of children. These findings suggest a possible role
for the impaired TGF-␤ signaling in the clinical manifestations of
asthma in childhood.
A potential weakness of this study is that all children underwent bronchoscopy for specific clinical indications other than
asthma (recurrent pneumonia, persistent atelectasis, chronic
cough, and stridor) (13, 14), and the presence of these pathologic
conditions, particularly pneumonia, could have influenced the
results. However, because these conditions were equally distributed in children with asthma, children with atopy, and children
who were control subjects, we feel rather confident that our
observation of the presence of pathologic lesions in children
TABLE 2. CELLULAR COUNTS IN THE SUBEPITHELIUM
Children with Asthma
Eosinophils
Neutrophils
Mast cells
CD4 T-lymphocytes
Macrophages
TGF␤1⫹ cells
TGF␤-RI⫹ cells
TGF␤-RII⫹ cells
48
87
23
89
175
182
623
179
(13–376)*
(16–244)
(0–132)
(42–535)
(56–344)
(66–354)
(291–1167)
(47–332)*†
Children with Atopy
81
98
93
259
138
172
550
543
(8–330)*
(19–225)
(0–213)
(97–357)
(68–225)
(78–372)
(308–1381)
(391–676)
Control Children
15 (0–72)
90 (38–268)
56 (0–157)
213 (11–316)
137 (11–244)
87 (9–470)
952 (196–1,092)
479 (71–948)
Definition of abbreviations: TGF-␤1 ⫽ transforming growth factor-␤1; TGF␤-RI ⫽ TGF-␤ receptor I; TGF␤-RII ⫽ TGF-␤ receptor II.
Values are expressed as cells/mm2.
Values are expressed as median (range).
* p ⬍ 0.05 as compared with control children.
§
p ⬍ 0.05 as compared with children with atopy.
802
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 168 2003
Acknowledgment : The authors thank Dr. Cristina Panizzolo for helping with the
clinical selection of patients and Mrs. Elisabetta Baliello and Giuseppa Castriciano
for assistance with staining the biopsies for TGF-␤.
References
Figure 5. Individual counts for TGF␤-RII⫹ cells in bronchial biopsies of
children with asthma, children with atopy, and control children. The
results are expressed as number of cells/mm2 of tissue examined. Horizontal bars represent median values.
with atopy and asthma but not in normal control subjects is valid.
Moreover, biopsies from children undergoing bronchoscopy for
clinical indications other than asthma are the only specimens
allowing direct examination of airway pathology in children with
mild asthma, which would be otherwise impossible for ethical
reasons (32).
Another limitation of our report is the low power of the study
because of the small number of subjects in each group. However,
this is a common problem in biopsy studies, especially in children,
in whom invasive maneuvers are more problematic. Even if only
multicenter studies collecting high numbers of biopsies could
overcome these difficulties, we believe that our study provides
preliminary data that could prove useful for the design of future
research in this field.
Finally, we should acknowledge that because our population
included very young children, we performed only one biopsy
per child, thus introducing a possible sample error. Despite all
of these limitations, we believe that studies on bronchial biopsies
provide a unique opportunity to investigate airway inflammation
and remodeling in childhood asthma.
In conclusion, this study shows that airway eosinophilia and
basement membrane thickening, which are the pathologic features characteristic of adulthood asthma, are already present in
children with mild asthma and even in children with atopy without asthma. Moreover, we found that in children with asthma,
but not in children with atopy without asthma, there is a downregulation of TGF␤-RII.
Conflict of Interest Statement : A.B. has no declared conflict of interest; G.T. has no
declared conflict of interest; S.B. has no declared conflict of interest; E.B. has no declared conflict of interest; F.C. has no declared conflict of interest; M.T. has no
declared conflict of interest; R.Z. has no declared conflict of interest; B.B. has no
declared conflict of interest; P.M. has no declared conflict of interest; L.M.F. has
been reimbursed by industries for attending several conferences, has participated
as a speaker in scientific meetings or courses organized and financed by various
pharmaceutical companies (AstraZeneca, Boehringer Ingelheim, Byk Gulden–
Altana, Ciesi Farmaceutici, GlaxoSmithKline, Menarini, Merck, Sharpe & Dohme,
Schering Plough), served as a consultant to AstraZeneca, Boehringer Ingelheim,
Byk Gulden–Altana, Ciesi Farmaceutici, GlaxoSmithKline, Miat, Roche, Schering
Plough and received honoraria for speaking at sponsored conferences and received
research grants for participating in multi-center clinical trials and his institution
has received educational and research grants from many pharmaceutical companies; M.S. has been reimbursed by various pharmaceutical companies (GlaxoSmithKline, AstraZeneca and Merck, Sharpe & Dohme) for attending several conferences and has participated as a speaker in scientific meetings or courses organized
and financed by GlaxoSmithKline, AstraZeneca and Merck, Sharpe & Dohme.
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Copyright # ERS Journals Ltd 2003
European Respiratory Journal
ISSN 0903-1936
Eur Respir J 2003; 21: 913–915
DOI: 10.1083/09031936.03.00014903
Printed in UK – all rights reserved
EDITORIAL
Asthma, rhinitis and air pollution: is traf c to blame?
B. Brunekreef* , J. Sunyer#
12
This issue of the European Respiratory Journal contains
two papers that contribute to a growing body of evidence
incriminating traf c fumes in respiratory disease. NICOLAI
et al. [1] report a cross-sectional study that nds signi cant
associations between traf c counts and exposure to traf crelated air pollution on the one hand and current asthma,
wheeze and cough on the other. In a sub-group of children
exposed to environmental tobacco smoke, traf c counts are
also related to allergic sensitisation. LEE et al. [2] report a
large questionnaire survey from Taiwan, in which a composite
measure of exposure to traf c-related air pollution is found
to be associated with physician-diagnosed allergic rhinitis.
A parallel analysis reported previously [3] found a similar
association between traf c-related air pollution and physiciandiagnosed as well as questionnaire-reported asthma.
How do these studies relate to earlier work on air pollution
and childhood respiratory illness? How do they relate to
earlier work on traf c-related pollution?
Large-scale, cross-sectional studies on air pollution and
respiratory outcomes in children have been reported from the
USA [4], Switzerland [5], Canada [6] and Austria [7]. The US
and Swiss studies found associations between some air
pollutants (especially ne particles) and cough and bronchitis
symptoms, the Canadian study found no relationships and
the Austrian study documented associations between nitrogen
dioxide (NO2; described as a marker for traf c-related air
pollution) and asthma, wheeze and cough. East/West comparisons have generally highlighted high bronchitis and cough
prevalence in the East, which were ascribed to "classical"
pollution, consisting of sulphur dioxide (SO2) and particles
[8], with higher rhinitis in the West. A recent study from
California, USA, found an association between wheeze
prevalence and the air pollution components, acid and NO2.
Taken together, these ndings suggest that society is witnessing a transition from classical pollution, dominated by SO2
and particles generated by coal and oil combustion, with the
effects primarily on cough and bronchitis, to pollution mixtures dominated by traf c exhausts represented by NO2, with
effects on wheeze and perhaps asthma prevalence.
It is important to look at what precisely is the de nition of
asthma in some of these studies. The paper by NICOLAI et al.
[1] de nes asthma as a report by parents that a doctor has
diagnosed asthma at least once or that a doctor has diagnosed
asthmatic, spastic or obstructive bronchitis more than once.
This de nition therefore includes, to some extent, symptoms
that may be bronchitic rather than asthmatic. "Current
asthma" is then de ned as a combination of asthma and
wheeze symptoms occurring in the past year. The study
*Institute for Risk Assessment Sciences, Utrecht University, the
Netherlands and #Institut Municipal d9Investigatio Medica, Barcelona,
Spain.
Correspondence: B. Brunekreef, Institute for Risk Assessment
Sciences, Utrecht University, PO Box 80176, 3508 TD, Utrecht,
the Netherlands. Fax: 31 302535077. E-mail: [email protected]
performed by GUO et al. [3] in Taiwan used two de nitions:
the rst was the parental report of a doctor9s diagnosis of
asthma at any point throughout life; the second reported
dyspnoea and nocturnal dyspnoea associated with wheezing
and/or attacks of dyspnoea with wheezing and/or physiciandiagnosed asthma. Although both studies used the International Study of Asthma and Allergies in Childhood (ISAAC)
questionnaire to collect symptom and diagnosis data, the
construction of the asthma variables used in the analysis
was different, so that a direct comparison becomes dif cult.
The study by NICOLAI et al. [1] is one of the few in the
literature that has investigated bronchial hyperresponsiveness
in relation to air pollution, only to nd that there was no
association. Another ISAAC study, conducted in France,
found that "wheeze in the last 12 months" and "asthma ever"
were related to ozone but not SO2 and NO2 in a simple
regression analysis. However, all associations disappeared
after adjustment for a family history of asthma, early childhood respiratory disease and socioeconomical status [9].
Surely, the worldwide variation in the prevalence of asthma is
so large that it seems unlikely that traf c-related air pollution
is a major determinant of this variation [10]. Nevertheless,
it seems the respiratory arena is gradually seeing more data
suggesting that asthma prevalence may, to some extent, be
determined by air pollution, especially traf c-related air
pollution, and that it may not just be a factor triggering
attacks in patients with developed asthma. A recent longitudinal report suggesting that children exercising in a high
ozone area developed more asthma is another piece of
evidence that makes the respiratory eld more hesitant to
say that air pollution does not induce new asthma cases [11].
The new studies from Taiwan add further observations on
air pollution and allergic rhinitis to previous ndings.
Surprisingly few air pollution studies have addressed allergic
rhinitis as an endpoint. A report from Leipzig, Germany [12],
investigated upper respiratory symptoms, including runny
nose, cough and hoarseness and found these to be related to
high SO2 levels and intermediate particulate matter (PM) and
NOx (NOzNO2) levels. The French ISAAC study found no
relationship whatsoever between air pollution and allergic
rhinitis [9]. Other reports show that rhinoconjunctivitis symptoms are increased with higher concentrations of ozone and
NO2, and, to a lesser extent, PM10 [13], and that daily
consultations, with a general practitioner for allergic rhinitis,
increases with ozone and SO2 [14]. It is clear that more studies
are needed on air pollution and allergic rhinitis.
How could traf c-related air pollution in uence asthma
and allergic rhinitis? Experimental evidence obtained in
studies on human volunteers, animals and in vitro test systems,
suggest that diesel exhaust particles have the capability to: 1)
enhance immunological responses to allergens; and 2) elicit
in ammatory reactions in the airways at relatively low
concentrations and short exposure durations [15–22]. The
promoting role of NO2 in the allergen response has also been
reported, but only in a few studies on asthmatics [23]. It is
914
B. BRUNEKREEF, J. SUNYER
dif cult, in observational studies, to separate effects of
pollutants from different types of vehicles. Questionnaire
studies do suggest that perhaps heavy traf c powered by
diesel engines is more harmful when compared with light
traf c powered by gasoline engines [24–26]. Work undertaken
in the Netherlands that was able to use objective traf c counts
as exposure metrics suggested the same [27–29].
The use of geographical information systems to obtain
more accurate measures of exposure to traf c-related air
pollution, as in the study by NICOLAI et al. [1], has increased.
The power of such systems was well illustrated by two
subsequent analyses from Nottingham, UK. The rst found
no relationship between traf c activity and wheeze in school
children when analysing traf c activity in the living area in
tertiles [30]. When the same material was analysed for
children living within short distances of major roads, a clear
relationship with wheeze was observed [31]. Similarly, the use
of data on home location with respect to roads and traf c
density on those roads resulted in observations of signi cant
relationship with: 1) respiratory hospital admission rates in
Toronto, Canada [32]; 2) rates of childhood asthma hospitalisation in New York, USA [33]; and 3) childhood asthma
medical care visits in San Diego County, USA [34]. These and
other studies suggest that improvement of accuracy and
precision of exposure classi cation helps to detect associations between adverse respiratory outcomes in children and,
in a few studies, adults.
The Taiwan studies [2, 3] have used factor analysis to
develop one indicator variable to characterise traf c-related
air pollution. Not surprisingly, the primary pollutants, carbon
monoxide and NOx, contribute strongly and positively to this
factor. However, at the same time, ozone has a negative
loading, most likely related to the well-known fact that ozone
concentrations are low in areas where primary emission
concentrations are high. The interpretation then becomes
complicated. Surely the associations found should not be
interpreted as showing a protective effect of ozone but rather
as suggesting an important role for primary combustion
products from traf c. There are only a few other studies that
have used pollution factors, rather than single components, as
exposure variables. In one example, factor analysis was used
to estimate the contribution of various sources to ambient
PM2.5 concentrations [35]. PM2.5 from motor vehicles and
coal combustion, but not from crustal sources, was found to
be related to daily mortality in that particular case.
The two studies published in this issue of the European
Respiratory Journal not only contribute to the present
knowledge of the effects of traf c-related pollution, but also
show new direction for exposure assessment methods that
may help to improve traf c studies in the future.
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Inquinamento atmosferico: quante vittime?
Air pollution: how many victims?
Paolo Crosignani, Istituto Nazionale per lo Studio e la Cura dei Tumori. Via Venezian, 1 – 20133
Milano. E-mail: [email protected] (1)
Ennio Cadum, Area di Epidemiologia Ambientale ARPA Piemonte
Dario Mirabelli, Unità di Epidemiologia dei Tumori, Ospedale San Giovanni Battista di Torino e
Centro di riferimento per la Prevenzione Oncologica CPO Piemonte
Alessandro Borgini, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano
Emma Porro, Dipartimento di Varese, ARPA Lombardia
(1) a cui inviare la corrispondenza
Una precedente versione del presente contributo è stata pubblicata su New Directions / Atmospheric
Environment 36 (2002) 4705–4706
Riassunto: Effetti sulla salute dell’inquinamento atmosferico sulla mortalità sono stati osservati sia
a breve sia a lungo termine. I primi non costuiscono una semplice anticipazione di eventi destinati
comunque a manifestarsi ma rappresentano il riflesso di un generale peggioramento delle condizioni
di salute della popolazione che patisce effetti molto più importanti a lungo termine. L’articolo
propone una visione unificante dei due fenomeni ed un metodo per calcolarne l’entità.
Parole chiave: inquinamento atmosferico, impatto sulla salute, mortalità naturale
Abstract: Air pollution is associated with short- and long-term effects on “natural” mortality. Both
can be viewed as the worsening of population health, more pronounced for long-term effects. A
method for estimating this burden is proposed
Key words: air pollution, health impact, natural mortality
L’inquinamento atmosferico è un importante determinante della salute pubblica. Studi sugli effetti a
breve termine (“serie temporali”) hanno mostrato una sistematica associazione dei livelli di
inquinamento atmosferico con la mortalità generale (“naturale”) e altri effetti negativi 1 sulla salute.
Nonostante l’inquinamento atmosferico comprenda svariati composti, il PM 10, la concentrazione di
particolato con dimensione inferiore a 10 µm, rappresenta una delle misure più utili tenuto conto
della sua ben stabilita associazione con effetti negativi sulla salute e della plausibilità biologica 2,3
dei meccanismi d’azione. Il particolato è infatti in grado di provocare infiammazione delle parti
profonde del polmone, alterare la coagulabilità del sangue 4, sino a penetrare nel torrente
circolatorio 5.
E’ stato spe sso sostenuto che nel breve termine l’inquinamento atmosferico anticipi solamente
delle morti che non sarebbero ad ogni modo evitabili. Schwartz 3 e Zanobetti et al. 6 hanno però
evidenziato che ciò non è del tutto vero, e che invece quando l’inquinamento atmosferico aumenta
vi sono sì eccessi di mortalità causati dalle morti anticipate di particolari soggetti malati (questo
effetto è chiamato in inglese “harvesting” cioè “mietitura”) ma questi eccessi non sono poi seguiti
compensati da alcun successivo deficit di mortalità. Questo significa che l’inquinamento
atmosferico non solo uccide persone tra la categoria ad alto rischio, ma fa pure affluire nuovi
individui in questa categoria. Quindi le serie temporali danno una stima delle morti “extra” che
avvengono in pochi giorni ma che sono anticipate da mesi a anni 3 rispetto a quanto si sarebbe visto
in assenza di inquinamento.
Ostro 7 ha illustrato come questo numero di decessi può essere stimato in modo semplice
moltiplicando la differenza tra il livello medio annuale di PM10 e un livello “desiderabile” più basso
di PM10 per l’aumento del rischio di morte per ogni unità di PM10.
Per esempio, dati forniti dall’ARPA lombarda indicano per Milano un livello medio annuale di
PM10 di 59 µg/m3 mentre le morti da cause naturali sono in media 10.580 all’anno (dati 1990 -1997).
Studi di serie temporali a Milano 8 indicano uno 0,06 % di aumento nella mortalità “naturale” per
ogni aumento di PM10 di 1 µg/m3. Se il livello di PM10 fosse stato di 40, obiettivo programmato
dall’Unione Europea 9 per il 2005, invece che 59 vi sarebbero state (59-40)x 0,06=1,14% morti
“naturali” in meno, o in altre parole 148 morti sarebbero state posticipate. Tale proiezione è una
stima conservativa: le analisi di serie temporali 10 sottostimano il vero impatto dell’inquinamento
atmosferico; inoltre considerare il solo PM10 invece che l’intera gamma di inquinanti atmosferici
(CO, SO2, N0x, etc.) ha anch’esso un probabile effetto di sottostima del reale impatto negativo.
Gli studi serie temporali non rilevano gli effetti di esposizioni cumulative. Studi a lungo termine di
coorti 11,12 hanno evidenziato che livelli più alti di inquinamento atmosferico sono associati ad una
aumentata mortalità. Tali risultati non sono influenzati dal fumo di tabacco o da altri potenziali
confondenti e indicano una mortalità considerevolmente più alta degli studi a breve termine. Kunzli
et al. 13 hanno stimato che una differenza di esposizione di 10 µg/m3 di PM10 per un lungo periodo
(15 anni o più) è associata con un rischio relativo (RR) di morire (per cause naturali negli adulti
oltre i 30 anni) di 1,043. Ciò significa che il rischio di morte aumenta del 4,3% ogni 10 µg/m3 di
aumento del PM10. Secondo Kunzli possiamo calcolare il RR come:
RR=1+ (eccesso di inquinamento in incrementi di 10 µg/m3 × 0.043)
La frazione attribuibile sarà (RR-1)/RR, assumendo che tutti gli abitanti di una città siano esposti
agli stessi livelli. Per esempio il RR di morte per qualcuno che vivesse per lungo tempo a Milano
(59µg/m3) invece che in un area con un PM10 di 40µg/m3 è 1+(59-40)/10×0.043=1.08. La
corrispettiva frazione attribuibile è (1.08-1)/1.08=7.4%, corrispondente a 783 extra morti per anno
dovute a questo eccesso di inquinamento atmosferico.
I valori calcolati per il breve termine ed il lungo termine in realtà raccontano delle storie diverse. Le
stime a breve termine (nel nostro esempio 148 morti premature per anno) rappresentano la mortalità
che potrebbe essere evitata immediatamente se i livelli di inquinamento fossero abbassati al livello
di 40µg/m3. Gli effetti a lungo termine (783 morti risparmiate per anno) stimano ciò che accadrebbe
se l’inquinamento atmosferico rimanesse a livello del valore “desiderabile” per un numero
considerevole di anni.
Calcoli simili possono essere eseguiti dalle autorità sanitarie, o da membri della comunità, per
stimare gli eccessi di mortalità nelle loro aree e i guadagni potenzialmente raggiungibili con una
riduzione dell’inquinamento atmosferico. I dati di mortalità sono disponili presso le autorit à
sanitarie. Per molte città Europee vi sono i dati dei livelli di PM10 e, quando non vi fossero,
possono essere estrapolati partendo dal particolato totale sospeso (PTS). Per questo scopo dovrebbe
essere usato un coefficiente compreso tra 0,6 e 0,8. Valori di aumentato rischio a breve termine per
incrementi di PM10 sono disponibili per molte città 8,14,15. Per la stima degli effetti a lungo termine
potrebbe essere usato il coefficiente di Kunzli, anche se recenti risultati 16 indicano un effetto più
pronunciato.
Si potrebbero anche calcolare i benefici a lungo e breve termine che si potrebbero ottenere se il
livello di PM10 fosse di 20 µg/m3 (obiettivo per il 2010 dell’Unione Europea) o anche inferiore –
visto che un livello di soglia per gli effetti da inquinamento atmosferico non è stato ancora
identificato.
E’ improbabile che l’inquinamento atmosferico abbia un impatto solo su chi è già malato: la salute
di una parte consistente della popolazione esposta sembra invece messa a rischio. Ciò è evidenziato
dal forte impatto causato da esposizioni a lungo termine e dalla limitata importanza del fenomeno di
“harvesting”. Le implicazioni sono che invece di limitare i picchi di inquinamento (lo stop del
traffico cittadino quando una determinata soglia è superata) la sola via per ridurre l’impatto sulla
salute è ridurre la media di esposizione a PM10. In molti centri urbani il traffico è fonte di più del
70% del PM10 atmosferico 13. Il controllo delle emissioni tramite migliorie dei motori o l’uso di
carburanti alternativi non è un opzione immediata ma potrebbe esserlo nel futuro. L’opzione
corrente fondamentale per poter migliorare la salute pubblica nelle città sembra quindi quella di
adottare politiche che limitino il traffico stradale nelle nostre città e nelle aree limitrofe.
Bibliografia
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particulate matter on mortality in 12 European cities: results from time series data from the
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effects. Lancet 1995; 345: 176-178.
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4. HEI Perspectives. Understanding the health effects of components of particulate matter mix:
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circulation in humans. Circulation 2002; 150: 411-4
6. Zanobetti A, Schwartz J, Siamoli E, et al. The temporal pattern of mortality responses to air
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in United States. Environmental Research 1998; A76: 94-106
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air pollution. Epidemiol Prev 2001; 25 (2) suppl: 1-72.
9. Commission of the European Communities. Council Directive 1999/30/EC relating to limit
values for sulphur dioxide, oxides of nitrogen, particulate matter and lead in ambient air.
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multiple studies, with application to air pollution and daily death. Epidemiology 2000;11:666672.
11. Dockery DW, Pope CA III, Xu X, et al. An association between air pollution and mortality in
six US cities. N Engl J Med 1993, 329:1753-1759.
12. Pope CA 3rd, Thun MJ, Namboodiri MM, et al. Particulate air pollution as a predictor of
mortality in a prospective study of U.S. adults. Am J Respir Crit Care Med 1995; 151: 669–674.
13. Kunzli N, Kaiser R, Medina S, et al. Public health impact of outdoor and traffic-related air
pollution: a European assessment. Lancet 2000; 356(9232):795-801.
14. Samet JM, Dominici F, Curriero FC, et al. Fine particulate air pollution and mortality in 20
U.S. cities, 1987-1994. N Engl J Med 2000, 343:1742¯ 1749.
15. Katsouyanni K, Touloumi G, Samoli E, et al. Confounding and effect modification in the short
term effects of ambient particles on total mortality: Results from 29 European cities within the
APHEA2 project. Epidemiology 2001; 12: 521–531.
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Long-term Exposure to fine Particulate Air Pollution. JAMA 2002, 287:1132¯ 1141.
Roma, 29 Novembre 2002
1
Gli effetti dell’inquinamento atmosferico sulla salute
Francesco Forastiere
Dipartimento di Epidemiologia ASL Roma E, Roma
E-mail: [email protected]
Premessa
Gli effetti dell’inquinamento atmosferico sulla salute umana, in particolare gli effetti sulla mortalità
complessiva, sono ormai conosciuti da anni, specie per l’enorme impatto sanitario dei gravi episodi di
inquinamento degli anni ‘30-‘50. Gli studi epidemiologici condotti negli anni ‘90, tuttavia, hanno messo
in luce nuovi danni per la salute alle concentrazioni ambientali degli inquinanti normalmente presenti
nelle aree urbane dei Paesi sviluppati. Tali studi sono stati esaminati in dettaglio in revisioni recenti
(ATS, 1996; Pope, 1999a; Bates, 2000; Brunekreef, 2000) e i risultati delle indagini epidemiologiche
hanno avuto una importanza notevole nella revisione delle linee guida sulla qualità dell’aria negli Stati
Uniti (EPA, 1996) e in Europa (WHO, 1999). L’Unione Europea ha di recente approvato direttive che
stabiliscono i valori limite degli inquinanti dannosi per la salute; in particolare sono stati stabiliti nuovi
limiti per le particelle sospese, contaminante molto rilevante dal punto di vista sanitario (EC, 1999).
Nuove indicazioni sono comunque disponibili anche per il biossido di azoto e l’ozono. Molti dei
risultati delle indagini epidemiologiche sono stati accolti con iniziale scetticismo e critiche, anche per
gli enormi interessi industriali sui temi dell’inquinamento (Gamble, 1998). Vi sono tuttavia lavori
scientifici recenti, condotti anche nel contesto italiano, che hanno contribuito all’enorme crescita delle
conoscenze.
Sono di seguito brevemente riassunte le evidenze scientifiche circa gli effetti acuti e cronici degli
inquinanti, con particolare riguardo per le polveri sospese, sono discussi i possibili meccanismi
biologici, e vengono riportate le stime sull’impatto sanitario dell’inquinamento ambientale. Nel
considerare gli aspetti sopraelencati si è dato particolare valore alle ricerche condotte nell’ambito
nazionale.
Caratteristiche e proprietà delle polveri sottili ed ultrasottili
L’inquinamento da polveri sospese comprende una miscela di particelle allo stato solido o liquido che
varia in dimensione, origine e composizione. La distribuzione dimensionale del Particolato Totale
Sospeso (TSP) comprende la frazione più grossolana (“coarse”), le polveri sottili (“fine”), e la frazione
delle polveri ultrasottili (“ultrafine”). Le polveri più grandi (diametro aereodinamico > 2.5µm) sono
spesso di origine naturale (suolo); le polveri fini hanno origine dai processi di combustione (veicoli,
industrie, produzione energia elettrica) e possono essere di origine primaria (generate direttamente)
ovvero possono formarsi (solfati e nitrati) per trasformazione chimica dalle emissioni primarie di ossidi
di zolfo e di azoto. Le polveri ultrasottili (diametro <0.1 µm) hanno un tempo di residenza
nell’atmosfera molto ridotto perché tendono ad aggregarsi o a coagulare a formare particelle di
dimensioni più grandi. Si noti che a parità di peso (10 µg/m3), il numero di particelle di diametro uguale
a 2.5 µm (per cm3 di aria) è pari a 1.2 con una area di superficie (µm3 per cm3 di aria) di 24, mentre i
valori corrispondenti per particelle ultrasottili di diametro pari a 0.02 µm è pari a 2.4 milioni con una
area di superficie di 3016 (µm3 per cm3 di aria).
Varie considerazioni d’ordine fisiologico e tossicologico fanno ritenere che le polveri sottili ed
2
ultrasottili possano avere importanza dal punto sanitario e rappresentino l’inq uinante più rilevante da un
punto di vista biologico (Seaton, 1995). Grazie alla loro dimensione possono essere respirate e penetrare
nel polmone profondo; sono costituite da svariate sostanze con proprietà tossiche quali solfati, nitrati,
metalli e numerose sostanze chimiche adsorbite sulla superficie; hanno una elevata proprietà di
penetrare negli ambienti chiusi e vengono trasportate anche a lunga distanza. Rappresentano un
inquinante ubiquitario e diffuso in modo uniforme nelle realtà urbane.
Per quanto riguarda la misura della concentrazione di tali particelle nell'aria, in passato era
generalmente usata la quantità "Particolato Totale Sospeso" (TSP) (Total Suspended Particulates),
ovvero la quantità totale di polveri a prescindere dal loro diametro e quindi dalla capacità di essere
inalate. Per molti anni anche i "Fumi Neri" (Black Smoke) sono stati usati come indicatori
dell'inquinamento da polveri. La nuova legislazione prevede la misura delle particelle di diametro
inferiore a 10 micron (PM10) ed è in avvio anche in Italia l’introduzione della misura delle particelle di
diametro inferiore a 2.5 micron (PM2.5) come migliore indice della contaminazione ambientale che può
avere una relazione con la salute umana.
.
Gli effetti sulla salute
L’Americ an Thoracic Society ha recentemente definito in modo sistematico la serie degli effetti sulla
salute potenzialmente attribuibili all’effetto degli inquinanti ambientali (ATS, 2000). Gli effetti sono
acuti (aggravamento di sintomi respiratori e cardiaci in soggetti predisposti, infezioni respiratorie acute,
crisi di asma bronchiale, disturbi circolatori ed ischemici, morte) e si manifestano nella popolazione in
risposta alle variazioni di breve periodo (oraria o giornaliera) nella concentrazione degli inquinanti,
oppure sono di tipo cronico, si presentano cioè per effetto di una esposizione di lungo periodo (sintomi
respiratori cronici quale tosse e catarro, diminuzione della capacità polmonare, bronchite cronica,
tumore polmonare) e possono comportare una diminuzione della speranza di vita.
3
Effetti di esposizioni acute
Gli studi epidemiologici degli anni ’90 hanno impiegato nuove metodologie statistiche per la
valutazione delle serie temporali al fine di evidenziare gli effetti acuti degli inquinanti sulla mortalità
giornaliera o sul ricorso ai servizi sanitari (ricoveri ospedalieri, ricorso al pronto soccorso, visite
mediche). Sono stati, inoltre, seguite per brevi periodi coorti di soggetti (asmatici, bronchitici cronici) in
modo da poter analizzare l’ef fetto degli inquinanti sulla comparsa di sintomatologia o sul grado di
compromissione della funzione respiratoria. Poiché la misura standardizzata delle polveri (PM10 o
PM2.5) è relativamente recente (specie in Europa ed in Italia), molti studi hanno dovuto utilizzare metodi
alternativi per la stima della concentrazione delle polveri (TSP, Fumi Neri) e sono scarse le indagini con
disponibilità di osservazioni sul livello ambientale delle particelle fini (PM2.5) (Schwartz, 1996).
Mortalità giornaliera
Dopo i rilevanti eccessi di mortalità osservati a causa degli importanti episodi di inquinamento (Londra,
Donora), decine di studi condotti in tutto il mondo hanno evidenziato una associazione tra
concentrazione giornaliera di inquinanti (soprattutto PM10, ma anche SO2, NO2, ed ozono) e numero
di morti nello stesso giorno o nei giorni seguenti (Dockery e Pope, 1993; Schwartz, 1996; Anderson et
al, 1996; Katsouyanni et al, 1997; Zmirou et al, 1998; Katsoutyanni et al, 2001).Risultati simili sono
stati riscontrati in Italia in studi condotti a Roma (Michelozzi et al, 1998), a Milano (Rossi et al 1999) e
a Torino (Cadum, 1999) nel quadro della indagine APHEA - Air Pollution and Health Effects: a
European Approach – un progetto di ricerca multicentrico che coinvolge 34 città in Europa. I metodi
diversi di misura dell’inquinamento da polveri (e la difficoltà di stimare la componente sottile delle
stesse in assenza di misure oggettive) rendono complesso il paragone tra le stime di effetto delle varie
indagini. Tuttavia, è stato possibile stimare un incremento lineare di 0.5-1% nella mortalità per ogni
10µg/m3 di PM10 (ovvero 5-6 µg/m3 PM2.5). L’eccesso nei morti è risultato più elevato per esposizioni
che avvengono nello stesso giorno o nei giorni immediatamente precedenti (Schwartz, 2000a), è più
elevato per le cause cardiache e respiratorie, ed è essenzialmente ascrivibile alla frazione PM2.5 del
PM10 (Schwartz, 1996).
Un supplemento alla rivista “Epidemiologia e Prevenzione” ha riporta per esteso la metodologia e
risultati della “MISA Metanalisi Italiana degli studi sugli effetti a breve termine dell’inquinamento
atmosferico” (Biggeri et al, 2001). Lo studio è stato condotto nell’ambito di un progetto di ricerca
nazionale che ha visto la partecipazione di numerose istituzioni e ricercatori italiani. L’indagine è stata
condotta sulla popolazione di otto grandi città italiane (con circa 7 milioni di abitanti) valutando la
relazione tra livelli giornalieri degli inquinanti atmosferici (Polveri - PM10 -, biossido di azoto, anidride
solforosa, ossido di carbonio, ozono) ed eventi sanitari rilevanti quali la mortalità (totale, cause
cardiache, cause respiratorie) e i ricoveri ospedalieri (cause cardiache e respiratorie) nel periodo 19901999. Questi i principali risultati:
•
•
si è osservata una associazione statisticamente significativa fra ciascuno degli inquinanti studiati e
ciascuno degli indicatori sanitari considerati. Fa eccezione l’ozono, che è risultato associato con la
mortalità totale e cardiovascolare e con i ricoveri per cause respiratorie;
le stime di rischio sono più elevate per gli esiti (mortalità, ricoveri) respiratori rispetto a quelli
cardiaci;
4
•
•
•
•
•
•
prendendo il PM10 (polveri fini) come parametro ambientale di riferimento, per ogni aumento di 10
µg/m3 di questo inquinante, si è osservato nel periodo 1995-99 nel complesso delle città considerate
un incremento nel giorno stesso o nel giorno successivo del 1.3% nella mortalità totale, 1.4% nella
mortalità cardiovascolare, 2.1% nella mortalità respiratoria, 0.8% nei ricoveri per cause
cardiovascolari, 1.4% nei ricoveri per cause respiratorie;
l’effetto dell’inquinamento sulla salute è quindi anche precoce e si realizza nell’arco temporale di
qualche giorno;
gli effetti degli inquinanti sono più pronunciati nei mesi più caldi dell’anno, anche perché si realizza
una maggiore esposizione della popolazione che tende a stare di più all’aperto;
le stime di rischio sono più elevate per la popolazione più anziana;
l’entità dell’effetto ha un gradiente Nord –Sud.
Il rischio è maggiore negli anni più recenti
Si è già ricordato che come tali studi abbiano hanno generato controversie e due aspetti sono rimasti per
lungo tempo materia di discussione scientifica: 1. L’effetto è realmente lineare senza soglia per
concentrazioni al di sotto dei limiti di qualità dell’aria attualmente in vigore nei paesi sviluppati, ovvero
si tratta di effetti non lineari con la possibilità di stabilire una soglia al di sotto della quale non sono
evidenziabili danni? 2. L’eccesso di mor talità osservato si traduce in una reale e significativa
diminuzione della sopravvivenza della popolazione esposta, ovvero i decessi si verificano
essenzialmente tra le persone (specie gli anziani) con uno stato di salute già molto compromesso per le
quali la morte viene solo anticipata di qualche giorno (cd. Effetto “mietitura” o “harvesting”).
Sono molto recenti i risultati relativi all’analisi dell’associazione tra livelli di PM10 e mortalità nelle 20
più grandi città americane (Daniels et al., 2000) che hanno consolidato le conoscenze sulla forma della
relazione dose-risposta. I dati ambientali sono stati raccolti in modo uniforme e standardizzato e sono
relativi ad insediamenti urbani dove la media annuale di PM10 era compresa tra 23.8 e 46.0• g/m3.
L’analisi statistica ha controllato in modo molto accurato l’effetto delle diverse variabili di
confondimento di tipo temporale. E’ stato stimato un aumento di 0.54% per 10 • g/m3 di Pm10 (media
dello stesso giorno e del giorno precedente) per la mortalità totale, 0.69% per le cause
cardiorespiratorie, e 0.38% per tutte le altre cause. Gli autori hanno dimostrato che la relazione è di tipo
lineare e non vi sono gli elementi scientifici sufficienti per giustificare una qualsiasi soglia. In un lavoro
recente, Schwartz (2000b) ha del resto dimostrato che l’effetto del PM10 registrato in dieci grandi città
americane è stabile quando si considera l’effetto confondente di altri inquinanti (NO2, CO, ozono).
Con l’impiego di metodi statistici molto sofisticati si è potuto inoltre escludere che l’effetto delle
polveri sia un mero effetto “mietitura”. Zeger et al (1999) sulla serie temporale di mortalità in relazione
alle concentrazioni di polveri totali sospese a Filadelfia sul periodo 1974-88 e Schwartz (2000c) su
un’analoga serie di dati per Boston 1979 -86, utilizzando diverse ed indipendenti tecniche di analisi
statistica, sono giunti alla conclusione che l’associazione tra inquinamento da polveri e mortalità totale
e per cause cardiorespiratorie osservata negli studi epidemiologici riflette un’anticipazione della morte
di ordine superiore alle settimane.
Ricoveri ospedalieri e ricorso ai servizi sanitari
La associazione tra concentrazione di inquinanti e frequenza giornaliera nei ricoveri ospedalieri è stata
5
analizzata con i metodi delle serie temporali come per la mortalità. La gran parte degli studi ha
evidenziato una associazione tra inquinamento da polveri e ricoveri per cause respiratorie sia negli
adulti sia nei bambini (Schwartz, 1996; Anderson et al, 1997; Burnett et al, 1997; Spix et al, 1998;
Sheppard et al, 1999). Molte indagini hanno anche valutato i ricorsi al pronto soccorso per asma,
broncopneumopatia cronica ostruttiva e altri disordini respiratori (Sunyer et al, 1993; Lipsett et al.,
1997; Atkinson et al, 1999. Studi più recenti hanno osservato una associazione con le malattie
dell’apparato cardiovascolare (Poloniecki et al, 1997; Schwartz, 1999; Burnett et al., 1999).
A Roma è stata valutata l’associazione tra livelli giornalieri di inquinamen to e ricoveri ospedalieri per
cause cardiovascolari e respiratorie (Fusco et al, 1998; Fusco et al, 2000). Non è stato tuttavia possibile
disporre della misura di PM10 ed il TSP era l’indicatore grossolano della concentrazione di polveri.
L’indagine ha mes so in rilievo un incremento dei ricoveri per patologie cardiovascolari, in particolare
per malattie ischemiche del miocardio, nei giorni in cui è più elevata la concentrazione ambientale di
NO2 e di CO (incremento di circa il 4% per ogni incremento di 20 µg/m3 di NO2 o di 1.0 mg/m3 di CO).
E’ stata inoltre evidenziata una associazione tra la concentrazione ambientale di NO 2 e di CO ed i
ricoveri ospedalieri per cause respiratorie (incremento di circa il 2.5% per ogni incremento di 20 µg/m3
di NO2 o di 1.0 mg/m3 di CO), e per infezioni respiratorie acute ed asma. L’effetto più forte sui ricoveri
per cause respiratorie è stato osservato nella classe di età 0-14 anni (aumento di circa 7.0-10.0% per
ogni incremento di 20 µg/m3 di NO2 o di 1.0 mg/m3 di CO). Infine, i livelli di ozono durante i mesi
estivi sono risultati associati ad un aumento dei ricoveri giornalieri per malattie dell’apparato
respiratorio totali e per infezioni respiratorie acute nella classe di età 0-14 anni (aumento dei ricoveri
giornalieri del 5.5% e dell’8.2% rispettivamente).
Sintomi/Funzione polmonare
Sono molto numerosi gli studi epidemiologici (Braun-Fahrlander et al., 1992; Hoek et al., 1993, 1994,
1995, 1998; Peters et al., 1997; Roemer et al., 1998) che hanno valutato l’associazione tra variazione
giornaliera dei sintomi respiratori o della funzione polmonare e inquinamento atmosferico sia in
popolazioni di asmatici sia in gruppi di popolazione generale. Il grado di associazione osservato è
risultato maggiore per i sintomi di interessamento bronchiale specie nei soggetti asmatici. Per questi
ultimi si è registrato un aumento dell’uso dei broncodilatatori. Osservazioni negli Stati Uniti hanno
messo in evidenza un aumento delle giornate lavorative perse (Ostro, 1989, 1990) tra gli adulti o dei
giorni di scuola tra i bambini (Roemer et al., 1993) per effetto dell’inquinamento ambientale. Nelle
valutazioni dell’effetto sulla funzione polmonare, si è osservato una diminuzione dei valori spirometrici
con un tempo di latenza dalla esposizione fino a 7 giorni.
Effetti delle esposizioni croniche
Sopravvivenza
Gli studi prima descritti sull’effetto acuto dell’inquinamento sulla mortalità giornaliera hanno messo in
evidenza una associazione di natura causale ma nulla ci dicono su quanto l’esposi zione cronica agli
inquinanti possa ridurre la speranza di vita, ovvero comportare l’insorgenza di malattie croniche. Su
questo tema sono stati condotti primi tentativi negli anni ’80 valutando i differenziali di mortalità in
relazione ai livelli di inquinamento in aree geografiche diverse (Archer, 1990). Tali studi, tuttavia, non
potevano tenere conto in modo accurato di altri possibili ed importanti determinanti della mortalità. Ha
tuttavia generato un grande interesse scientifico uno studio condotto nella Repubblica Ceca che ha
riscontrato una forte associazione tra concentrazione ambientale di polveri e mortalità infantile (Bobak,
1992).
6
L’approccio più adeguato per studiare il problema è quello di seguire nel tempo coorti di popolazione
residenti in aree geografiche con livelli diversi di inquinamento disponendo di informazioni accurate sui
più importanti fattori individuali che regolano la speranza di vita (es. fumo, peso corporeo) e studiare
nel tempo la loro mortalità. Tre studi di coorte di questo tipo sono stati condotti negli Stati Uniti, mentre
ad oggi è disponibile solo una indagine nel contesto europeo (Hoek et al, 2002).
Dockery et al. (1993) hanno studiato la mortalità di 8111 adulti residenti in sei città degli Stati Uniti
durante il periodo 1974-91. Per ciascuna città erano disponibili dati di inquinamento atmosferico dal
1977 al 1988. A livello individuale, erano state raccolte informazioni su diversi potenziali confondenti
(sesso, età, abitudine al fumo, livello di istruzione ed esposizione professionale a polveri, fumi o gas). I
residenti nelle città con concentrazioni medie annuali più elevate di materiale particolato con diametro
≤2.5 µm (PM2.5) mostravano, rispetto ai residenti nelle città con livelli inferiori di inquinamento, eccessi
di mortalità per tutte le cause, per malattie cardiorespiratorie e per tumore del polmone. In uno studio
successivo, Pope et al. hanno analizzato la mortalità dei 552.000 partecipanti alla seconda indagine sulla
prevenzione dei tumori dell'American Cance
r Society, seguiti dal 1982 al 1989, in funzione delle
concentrazioni di solfati e di PM2.5 rilevate nel 1980 in numerose aree metropolitane degli Stati Uniti
(151 aree con dati sulla concentrazione di solfati e 50 aree con informazioni sulla concentrazione di
PM2.5). Si osservava un incremento nel rischio di mortalità generale (+15%) in relazione ad una
differenza di concentrazione media annuale di solfati pari a 19.9 µg/m3 tra le aree a più elevato
inquinamento rispetto alle aree meno inquinate. Anche in questo caso si è osservato un eccesso per
malattie cardiorespiratorie (+26%) e tumore del polmone (+36%). L'analisi controllava l'effetto di
confondimento dovuto a età, sesso, gruppo etnico, fumo di sigarette, sigari o pipa, esposizione a fumo
passivo e a cancerogeni professionali, indice di massa corporea, consumo di alcolici e livello di
istruzione. L’indagine più recente consiste in uno studio di coorte su 6338 adulti non fumatori residenti
in California, appartenenti alla comunità degli Avventisti del Settimo Giorno, seguiti dal 1977 al 1992
(Abbey et al., 1999). Veniva calcolato un indicatore di esposizione cumulativa individuale, ottenuto
moltiplicando le concentrazioni medie mensili di alcuni inquinanti atmosferici (PM10, anidride solforosa
[SO2], biossido di azoto [NO2] e ozono [O3]) rilevate nelle diverse aree urbane per il tempo trascorso da
ciascun individuo in una determinata area geografica (definita in base al codice postale), per ragioni
residenziali o professionali. E’ stata riscontrata una a ssociazione tra inquinanti derivanti dai prodotti di
combustione e mortalità generale, per cause respiratorie e per tumore polmonare tra i maschi. Nel 2002,
Pope e coll. hanno pubblicato i risultati della estensione del follow al 1998 della coorte della American
Cancer Society. Lo studio ha ricevuto un elevata risonanza per la dimensione della coorte, la varietà
delle esposizioni ambientali indagate, e l’accuratezza nel controllo dei fattori di confondimento Si è
osservato un aumento della mortalità per tutte le cause (4%), per malattie cardiopolmonari (6%), e
tumore polmonare (8%) per ogni incremento di 10 microg/m3 nella esposizione a polveri fini.
È interessante notare come studi moderni condotti a livello individuale confermino la prima
osservazione di tipo ecologico di Bobak (1992) sulla possibilità che l’effetto dell’inquinamento si
eserciti già sul neonato nel primo anno di vita. In uno studio condotto negli Stati Uniti (Woodruff et al,
1997) è stato possibile abbinare l’archivio delle nascite (qua ttro milioni di nati) e della mortalità nel
periodo postnatale (in questo caso, due mesi dopo la nascita) del periodo 1989-1991 con l’archivio dei
dati ambientali di PM10 per 86 aree metropolitane. L’analisi dei dati ha potuto controllare per l’effetto
di variabili importanti relative alla madre e alla famiglia (età, razza, stato socioeconomico, fumo). E’
stata riscontrata una forte associazione tra concentrazione di PM10 e mortalità totale e per cause
respiratorie, inclusa la morte improvvisa del neonato. La ricerca epidemiologica recente, dunque, si
interessa sempre di più degli effetti degli inquinanti sulla gravidanza e nel periodo neonatale
(Brunekreef, 1999)
7
L’insieme delle osservazioni descritte fa ritenere che l’esposizione cronica ad inquinanti ambientali
abbia degli effetti importanti per quanto riguarda la speranza di vita di chi abita nelle moderne
metropoli. Sulla base delle osservazioni degli studi di coorte è stato suggerito, che gli effetti osservati
negli studi sulla mortalità giornaliera rappresentino una sottostima dell’effetto complessivo (McMichael
et al., 1998) e che vivere in un comune in cui la concentrazione di polveri sospese è pari a quella che
attualmente si registra nelle grandi città italiane (40-50 µg/m3) corrisponde ad una perdita di 1-2 anni
nella speranza di vita (Brunekreef, 1997).
Incidenza e prevalenza di malattie
Molti studi hanno valutato l’associazione tra esposizione cronica ad inquinanti e malattie o sintomi
respiratori (Abbey et al., 1995; Dockery et al., 1989; Dockery et al., 1995; Forastiere et al., 1992; Peters
et al., 1999) o funzione polmonare (Forastiere et al., 1994; Ackermann-Liebrick et al., 1997; Raizenne
et al., 1996). Uno studio longitudinale recente ha riscontrato una diminuita crescita dei volumi
polmonari per l’effetto della esposizione cronica a polveri e a NO2 (Gauderman et al., 2000). Sono stati
associati in modo più frequente con l’inquinamento ambientale i segni di bronchite, come la tosse e il
catarro cronico, mentre più controversi sono i risultati per quanto riguarda l’asma bronchiale.
A livello italiano il progetto SIDRIA (Studi Italiani sui Disturbi Respiratori nell’Infanzia e l’Ambiente)
ha approfondito lo studio di diversi possibili fattori di rischio, con particolare attenzione al ruolo
dell’inquinamento dell’aria (sia outdoor, sia indoor) per la salute respiratoria dei bambini (Agabiti et
al., 1999; Ciccone et al., 1998). In particolare, è stato valutato il ruolo dell’inquinamento da traffico
veicolare, stimato attraverso una valutazione del volume e della tipologia del traffico vicino la residenza
dei soggetti, su diversi disturbi respiratori tipici dell’età pediatrica, cercando di distinguere i disturbi di
tipo asmatico da quelli di tipo bronchitico (Ciccone et al.1998). Lo studio è stato condotto in dieci aree
del Nord e Italia centrale ed ha incluso un campione rappresentativo di 39275 bambini in due classi di
età (6-7 e 13-14 anni; rispondenza = 94.4%). Attraverso un questionario standardizzato compilato dai
genitori (e dai ragazzi di 13-14 anni), sono state raccolte informazioni dettagliate sulle condizioni di
salute respiratoria e sull’esposizione a diversi fattori di rischio, incluse le caratteristiche del traffico
vicino casa. Nel sottogruppo di bambini residenti in aree metropolitane è stata osservata una chiara
associazione tra il passaggio frequente di veicoli pesanti vicino l’abitazione e diversi disturbi respiratori.
Classificando i sintomi recenti in gruppi mutuamente esclusivi, è stata documentata un’associazione più
forte per i soggetti che avevano riferito solo sintomi bronchitici, con un rischio relativo di 1.44
(intervallo di confidenza 95%=1.17-31.78), mentre il rischio relativo per quelli che avevano riferito solo
l’asma o sintomi asmatici era 1.10 (0.96 -1.26). Associazioni più deboli sono state osservate in
relazione a più generici indicatori di traffico e per i bambini residenti in aree non metropolitane. Si è
dunque formulata l’ipotesi di una maggiore pericolosità delle emissioni dei veicoli pesanti dotati di
motori diesel e della possibilità, che tra diversi possibili danni respiratori, le infezioni delle basse vie
aeree siano quelle più strettamente connesse con l’inquinamento atmosferico. I risultati di SIDRIA, in
accordo con quelli di altri studi condotti in paesi diversi e con varia metodologia, suggeriscono che
misure di prevenzione volte a ridurre l’esposizione a gas di scarico della popolazione residente in aree
molto urbanizzate, anche attraverso una limitazione del traffico pesante in zone residenziali e nelle
vicinanze di scuole e asili, potrebbero avere ricadute positive in termini di salute, sia a breve, sia a
lungo termine.
Una valutazione schematica degli effetti
Ovviamente rimangono molte incertezze scientifiche riguardo agli effetti biologici degli inquinanti. In
particolare occorre approfondire il ruolo della dimensione delle particelle, dei costituenti chimici (come
i metalli in transizione), delle proprietà di superficie, della sinergia con gli inquinanti gassosi, del
particolare livello di acidità. Occorre studiare meglio i meccanismi biologici e i particolari gruppi di
8
popolazione suscettibili. La mole dei dati, tuttavia, permette già di quantificare gli effetti per orientare
gli interventi di sanità pubblica. La tabella riassume le conseguenze sulla salute dell’inquinamento
dell’aria a breve e a lungo termine stimati per un aumento di 10 • g/m 3 della concentrazione
dell’indicatore per le polveri sottili, il PM 10. Le stime sono basate sulla letteratura epidemiologica
disponibile già illustrata e sono in accordo con il rapporto preparato sotto l’egida dell’OMS che ha
stimato l’impatto dell’in quinamento in tre nazioni europee (Francia, Svizzera, Austria) (Kunzli et al,
2000).
I meccanismi biologici.
Solo di recente, e per effetto dell’enorme stimolo fornito dai risultati degli studi epidemiologici, si sono
moltiplicate le indagini di tipo sperimentale o clinico per spiegare i complessi meccanismi biologici che
alla base dell’effetto lesivo degli inquinanti, in particolare le polveri. È semplice riconoscere che il
sistema respiratorio è la sede primaria del danno (con meccanismi di tipo ossidativo ed infiammatorio),
ma di recente l’interesse si è spostato sull’apparato cardiovascolare, in particolare sui meccanismi che
regolano il ritmo cardiaco ((Pope et al., 1999b; Peters et al., 1999; Liao et al., 1999; Pope et al., 1999c;
Gold et al., 2000) o la viscosità plasmatica (Peters et al., 1997). Seaton (1995) ha infatti ipotizzato che
le particelle ultrasottili possano provocare infiammazione polmonare con il rilascio di citochine tossiche
per l’apparato cardiovascolare e conseguente aumento della v iscosità plasmatica. Recentemente Stone e
Godleski (1999) hanno suggerito l’importanza di alterazioni nel controllo della frequenza e della
variabilità del battito cardiaco da parte del sistema nervoso autonomo – alterazioni associate
all’esposizione a par ticolato atmosferico – come meccanismo alla base dell’associazione tra esposizione
a particolato e mortalità per cause cardiache. In effetti, in uno studio condotto a Boston su pazienti con
un impianto cardiaco di un defibrillatore seguiti per tre anni per valutare la presenza di aritmie (Peters
et al., 2000), è stata osservata un aumentata incidenza di aritmie gravi nei giorni a più elevato
inquinamento atmosferico (NO2, CO e PM2.5).
9
Tabella. L’impatto sanitario dell’inquinamento atmosferico. Incremento percentuale nella frequenza dei
fenomeni sanitari in una città all’aumentare di 10 • g/m 3 nella concentrazione delle polveri sottili, PM10.
Effetti a breve termine
Aumento della mortalità giornaliera (escluse le morti accidentali) totale
0.5-1%
- per cause respiratorie
3-4%
- per cause cardiocircolatorie
1-2%
Aumento dei ricoveri in ospedale per malattie respiratorie
1.5-2%
- per malattie cardiocircolatorie
0.5-1%
Aumento delle consultazioni mediche urgenti a causa dell’asma
2%
Aumento degli attacchi di asma negli asmatici
5%
Aumento dell’uso dei farmaci broncodilatatori neg li asmatici
5%
Aumento delle assenze dal lavoro e diminuzione delle attività a causa di malattia
10%
Effetti a lungo termine
Aumento complessivo della mortalità
3-8%
Aumento della incidenza di bronchite cronica negli adulti
25%
Aumento della tosse e della espettorazione negli adulti
13%
Aumento della bronchite e dei disturbi respiratori nei bambini
35%
Diminuzione della funzione polmonare negli adulti
3%
Gli effetti cancerogeni
Le evidenze relative agli effetti degli inquinanti nell’aumentare il rischio di tumore sono state
ampiamente documentate in una revisione recente (Lagorio et al., 2000). In breve si può sostenere che i
risultati dei più recenti studi di coorte sui residenti nelle aree metropolitane degli Stati Uniti (Dockery et
al., 1993; Pope et al., 1995; Abbey et al., 1999; Pope et al, 2002) hanno rafforzato l’ipotesi che
l’inquinamento atmosferico abbia un ruolo nell’eziologia del tumore polmonare, specialmente in
associazione con altri noti fattori di rischio quali il fumo di sigaretta e alcune esposizioni professionali.
La questione dell’eventuale cancerogenicità per l’uomo delle emissioni dei motori diesel e a benzina è
stata affrontata mediante studi epidemiologici su soggetti esposti per ragioni professionali. Questi studi
hanno suggerito in modo convincente che l’esposizione ai gas di scarico dei motori diesel influenza
l’incidenza di tumore polmonare nell’uomo. Gli studi su gruppi professionali esposti esclusivamente o
prevalentemente ai gas di scarico di motori a benzina sono invece poco numerosi e poco conclusivi.
Nonostante siano stati ripetutamente segnalati incrementi del rischio di tumore polmonare tra gli autisti
professionali, in particolare tra i tassisti (anche nella città di Roma) (Borgia et al., 1994), è difficile
separare il ruolo delle esposizioni ad emissioni di motori diesel e a benzina. Alcuni studi
epidemiologici, infine, hanno suggerito un’associazione tra leucemia infantile e inquinamento da
traffico. Se questa associazione dovesse essere confermata, l’esposizione a benzene potrebbe rilevarsi il
fattore più importante.
Ci sono molti motivi per ritenere che il rischio cancerogeno associato all’inquinamento atmosferico
prodotto dal traffico automobilistico sia un argomento di notevole rilevanza in sanità pubblica. Infatti,
10
benché le associazioni osservate siano di modesta entità, l'esposizione interessa larghi strati della
popolazione; di conseguenza, l'impatto complessivo di tale esposizione in termini di carico atteso di
neoplasie (in particolare tumori polmonari e leucemie) potrebbe non essere trascurabile. Attualmente,
tuttavia, a causa di limiti nelle evidenze epidemiologiche sinora disponibili, non è possibile quantificare
precisamente il rischio. E’ da sottolineare, infine, che l'eccesso stimato di tumori attribuibili
all'esposizione a gas di scaric
o di motori, in particolare diesel, assume ulteriore rilevanza se si restringe
l'attenzione agli esposti per ragioni professionali.
Le stime di impatto in Europa ed in Italia
Esperienze iniziali negli Stati Uniti hanno cercato di stimare l’impatto comples sivo in termini di salute
della esposizione all’inquinamento ambientale ed hanno associato a questo una stima del costo
economico che la società sostiene (ALA, 1998; Ostro, 1998). In Europa il primo studio di questo tipo è
stato condotto per tre nazioni (Austria, Francia, Svizzera) ed ha riscosso un enorme interesse a livello
internazionale (Kunsli et al, 2000). In sostanza, sulla base dei livelli di esposizione della popolazione
all’inquinamento da polveri, considerati i risultati degli studi epidemiologic i e i coefficienti delle
relazioni dose-risposta tra esposizione a PM10 ed effetto sanitario, noti i livelli di base di frequenza
della mortalità e delle patologie in questi paesi, si è potuto stimare che all’inquinamento attuale è
ascrivibile il 6% della mortalità generale ( più di 40.000 casi per anno), 290.000 episodi di bronchite nei
bambini, e una quota molto elevata di attacchi di asma e di giornate lavorative perse ogni anno nei tre
Paesi.
Con le stesse modalità dello studio delle tre nazioni Europee, il Centro Europeo Ambiente e Salute di
Roma dell’Organizzazione Mondiale della Sanità (WHO Regional Office for Europe, European Centre
for Environment and Health, Rome Division) nel giugno 2000 ha completato uno studio
sull’inquinamento atmosferico ne lle 8 maggiori città italiane (Galassi et al., 2000). Lo studio ha stimato
l’impatto dell’inquinamento atmosferico urbano sulla salute dei cittadini ed è stato condotto in
collaborazione con altri enti e istituti italiani. Sono stati raccolti ed analizzati parte dei dati disponibili
sulle concentrazioni di inquinanti nelle città di Torino, Genova, Milano, Bologna, Firenze, Roma,
Napoli e Palermo per un totale di 8.5 milioni di abitanti. La stima dell’impatto sulla salute si è avvalsa
delle concentrazioni di PM10. Lo studio ha considerato la mortalità a lungo termine ed altri effetti a
medio e breve termine osservati nel corso di un anno, come i ricoveri ospedalieri, i casi di bronchite
acuta e gli attacchi d’asma nei bambini. Le stime delle quota di mortalit à, morbosità e ricoveri, sono
attribuibili a concentrazioni in eccesso di valori di riferimento prescelti (30µg/m3). Nello studio sono
state calcolate le morti che potrebbero essere prevenute se si abbattesse l’inquinamento a tali valori.
Tutte le città presentano concentrazioni di PM10 superiori all’attuale obiettivo di qualità dell’aria pari,
dal 01.01.99, a 40 µg/m3. In particolare, per Bologna viene indicato un valore per la concentrazione
media annuale di PM10 pari a 51.2 µg/m3. L’impatto dell’inquinam ento da PM10 sulla salute dei
residenti è stato stimato nelle 8 maggiori città italiane nel 1998. In particolare sono state calcolate le
morti, i ricoveri ospedalieri ed i casi di malattia potenzialmente prevenibili abbattendo le concentrazioni
medie di PM10 a 30 µg/m3. Lo studio ha indicato che un sostanziale numero di decessi, ricoveri
ospedalieri e disturbi respiratori, specie nei bambini, sono attribuibili all’inquinamento atmosferico
urbano e che l’ordine di grandezza è delle migliaia o decine di migl iaia di casi per anno nelle otto
maggiori città italiane. In particolare ha stimato che:
1. per la mortalità per tutte le cause (escluse cause accidentali) fra la popolazione di oltre trenta
anni si stima che il 4.7% di tutti i decessi osservati nel 1998, pari a 3472 casi, sia attribuibile
al PM10 in eccesso di 30 µg/m3. Ovvero, riducendo il PM10 ad una media di 30µg/m3 si
potrebbero prevenire circa 3.500 morti all’anno nelle 8 città.
2. per gli altri effetti considerati si sono ottenute stime di migliaia di ricoveri per cause
respiratorie e cardiovascolari e decine di migliaia di casi di bronchite acuta e asma fra i
bambini al di sotto dei quindici anni che potrebbero essere evitati riducendo le
concentrazioni medie di PM10 a 30µg/m3.
11
In generale, i dati indicano che la cattiva qualità dell’aria è responsabile di una parte rilevante della
mortalità e morbosità. Sebbene i dati di concentrazione non possano essere direttamente utilizzati per
stimare con precisione le esposizioni individuali, data la variabilità delle attività giornaliere dei
cittadini, il numero complessivo stimato di casi attribuibili rappresenta un importante problema di sanità
pubblica. Interventi mirati al contenimento dell’inquinamento atmosferico avrebbero ricadute
importanti in termini di salute e di costi socio-economici (Galassi et al., 2000).
Conclusioni
Sulla base degli studi epidemiologici elencati, condotti in ambito internazionale ed italiano, si può
concludere che all’inquinamento atmosferico urbano è attribuibile oggi una quota ri levante di morbosità
acuta e cronica . La speranza di vita dei cittadini che vivono in città con livelli di inquinamento elevato
è diminuita. Gli effetti si verificano ai livelli attuali di inquinamento ambientale e non sembra esserci
una soglia al di sotto della quale non si osservano danni. I gruppi di popolazione più colpiti
dall’inquinamento ambientale sono soprattutto gli anziani e le persone in condizione di salute più
compromessa come i malati di patologie cardiache e respiratorie. Per queste persone, l’esposizione ad
inquinamento ambientale peggiora la prognosi e aumenta la probabilità di morte. E’ stato documentato
che i bambini tendono ad ammalarsi più frequentemente per cause respiratorie, in particolare bronchite
ed asma, e l’esposizione ad inqui nanti peggiora lo stato di malattia in bambini affetti da
compromissione cronica delle vie aeree. I neonati, infine, sembrano essere a particolare rischio di morte
per effetto dell’inquinamento ambientale.
Sulla base delle stime di impatto condotte dalla Organizzazione Mondiale della Sanità, l’inquinamento
ambientale costituisce un problema di sanità pubblica molto rilevante.
12
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Copyright # ERS Journals Ltd 2003
European Respiratory Journal
ISSN 0903-1936
Eur Respir J 2003; 21: 956–963
DOI: 10.1183/09031936.03.00041103
Printed in UK – all rights reserved
Urban traf c and pollutant exposure related to respiratory outcomes
and atopy in a large sample of children
T. Nicolai* , D. Carr* , S.K. Weiland# , H. Duhme} , O. von Ehrenstein* , C. Wagner* , E. von Mutius*
Urban traf c and pollutant exposure related to respiratory outcomes and atopy in a
large sample of children. T. Nicolai, D. Carr, S.K. Weiland, H. Duhme, O. von
Ehrenstein, C. Wagner, E. von Mutius. #ERS Journals Ltd 2003.
ABSTRACT: Con icting results have been reported for the relationship between traf c
exposure and inception of atopy. The effect of traf c on the prevalence of asthma and
atopy at school age was investigated in a representative population.
Random samples of schoolchildren (n=7,509, response rate 83.7%) were studied using
the International Study of Asthma and Allergies in Childhood phase-II protocol with
skin-prick tests, measurements of speci c immunoglobulin E and lung function. Traf c
exposure was assessed via traf c counts and by an emission model which predicted soot,
benzene and nitrogen dioxide (NO2).
Traf c counts were associated with current asthma, wheeze and cough. In children
with tobacco-smoke exposure, traf c volume was additionally associated with a positive
skin-prick test. Cough was associated with soot, benzene and NO2, current asthma with
soot and benzene, and current wheeze with benzene and NO2. No pollutant was
associated with allergic sensitisation.
High vehicle traf c was associated with asthma, cough and wheeze, and in children
additionally exposed to environmental tobacco smoke, with allergic sensitisation.
However, effects of socioeconomic factors associated with living close to busy roads
cannot be ruled out.
Eur Respir J 2003; 21: 956–963.
During the last 50 yrs, respiratory allergic diseases have
increased in children in many countries with modern living
conditions. At the same time, car traf c and air-pollution
levels have undergone large changes. At suf ciently high
concentrations, pollutants such as particulate matter, sulphur
dioxide (SO2), car exhaust and ozone are known to be associated with respiratory symptoms. While it is well accepted
that air pollution can trigger symptoms in children with
established asthma [1], its in uence on the inception of
asthma and allergies is not known. It would be of major
concern if the increasing prevalence was, at least in part, due
to traf c-related air pollution.
In cities, car traf c accounts for almost all benzene and
most of the nitrogen dioxide (NO2) and carbon monoxide,
but only for a small fraction of SO2 [2]. Fine dust [2], latex
particles and black smoke are other emissions related to
motor vehicles. Animal and in vitro human experiments
[3–5] point towards an effect of diesel exhaust on allergic
sensitisation. Traf c-related pollutants have been suggested to
alter the antigenicity of pollen and might thereby cause
increased allergic sensitisation or precipitate symptoms in
allergic subjects [6–8].
Most, but not all, paediatric epidemiological studies found
a consistent but small effect of long-term exposure to car
traf c or its emissions on respiratory symptoms and lung
function [2, 9–14]. A large cross-sectional study using pollutant
exposure measured on a 1-km2 grid in Dresden, Germany,
found increased cough, bronchitis and nonatopic asthma,
but no effect on atopic asthma and allergies [2]. However, due
to the German reuni cation process, pollutant exposure has
For editorial comments see page 913.
*University Children9s Hospital, Munich,
#
Dept of Epidemiology, University of Ulm,
Ulm, }Institute of Epidemiology and Social
Medicine, University of Münster, Münster,
Germany.
Correspondence: T. Nicolai
University Children9s Hospital
Munich
Germany
Fax: 49 8951604409
E-mail: [email protected]
Keywords: Asthma
atopy
children
pollutants
respiratory
traf c
Received: May 17 2002
Accepted after revision: January 6 2003
changed greatly during the lifetime of these children. More
doctor-diagnosed asthma was reported in children living
within 100 m of a freeway compared with those living farther
away [15].
The relationship between allergy and traf c exposure is less
consistent. A recent study in Switzerland found increased
allergic sensitisation (but no relation to symptoms) in a
subgroup of adults living for >10 yrs on a busy road [16].
However, a number of paediatric studies found no increase in
allergy with measured traf c exposure [2, 9, 12, 13].
The con icting results of the epidemiological studies are at
least partly attributable to small sample sizes in some studies,
the dif culty of separating socioeconomic variables from
traf c exposure, and reporting bias for self-reported traf c
exposure and symptoms. As the reported effect size is mostly
rather small, the sample must be suf ciently large to detect or
exclude a possible association. Also, exposure assessment is
dif cult but critical in such studies.
The purpose of this study was to determine the relationship
between vehicle-traf c counts and estimated pollutant levels
at the place of residence and reported respiratory symptoms,
doctor diagnoses and measured allergic sensitisation and respiratory function in a large random sample of children.
Methods
Study population and study design
An International Study of Asthma and Allergies in Childhood (ISAAC) phase-II cross-sectional survey was performed
TRAFFIC EXPOSURE, RESPIRATORY OUTCOMES AND ATOPY
in Munich, Germany, with ~1.3 million inhabitants [17].
Random samples of school classes were selected in two age
groups: school beginners aged 5–7 yrs and schoolchildren
of the fourth grade aged 9–11 yrs. Questionnaires were given
to parents, and children underwent skin-prick tests, blood
sampling, lung function testing and bronchial challenge if
written informed consent had been obtained from the parents.
The local ethics committee had approved the study.
Questionnaires
The questionnaires included the ISAAC core questions on
symptoms of asthma, allergic rhinitis and atopic eczema,
which have been reported in detail elsewhere [18, 19], and
were administered between September 1995–December 1996.
Current wheeze was de ned as wheezing in the last 12
months. Children were de ned as having asthma if their
parents reported that asthma had been diagnosed at least
once or that a doctor had diagnosed asthmatic, or spastic or
obstructive bronchitis more than once. Asthma with symptoms in the last 12 months was de ned as current asthma.
Hay fever and atopic dermatitis were de ned by a reported
diagnosis from a doctor. The questionnaire included detailed
questions about the child9s nationality, the family history of
atopic diseases, the number of siblings, and several other
potential confounding factors, such as environmental tobacco
smoke (ETS) exposure and parental education as a marker of
socioeconomic status (SES). SES was de ned as highest
parental school education; high SES being >12 yrs of school
education or university. ETS was de ned as any current
exposure to cigarettes, pipes or cigars in the home.
Skin-prick tests
All children in the 9–11 yrs age group were invited to
participate in skin-prick testing, whereas in the younger age
group only a random subsample (n=1,875) was selected. The
sensitivity to six common aeroallergens (Dermatophagoides
pteronyssinus, D. farinae, tree pollen, grass pollen, Alternaria
tenuis and cat dander) was assessed using standardised
extracts (ALK, Hørsholm, Denmark) and ALK lancets. A
positive (histamine 10 mg?mL-1) and negative control were
added. The weal size after 15 min was de ned as the mean of
the longest diameter and the length of its perpendicular
diameter. Children with a weal reaction " 3 mm after subtraction of the reaction to the negative control, to one or more
of the allergens tested, were considered to be atopic.
Blood sampling and laboratory analyses
As with skin-prick testing, all children in the 9–11 yrs age
group were asked to provide a blood sample, whereas in the
younger age group only a random subsample (n=1,875 in
Munich) was selected. Serum was separated by centrifugation,
frozen and stored at -70°C before analysis. A screening test
(SX1 test; Pharmacia, Uppsala, Sweden) was used to detect
speci c serum immunoglobulin (Ig)E antibodies to a wide
array of aeroallergens (D. pteronyssinus, mixed grass pollen,
birch pollen, mugwort pollen, cat dander, dog dander and
Cladosporium herbarum) in one central laboratory at the
University of Berlin. Atopic sensitisation was assumed to be
present if a level of " 0.7 kU?L-1 of speci c serum IgE was
measured.
957
Pulmonary function testing and bronchial challenge
Because of the long duration of the bronchial challenge
protocol, only a random subsample of the children aged
9–11 yrs was invited to participate (n=2,019). Lung function
was measured with a spirometer (MasterScope; Jäger, Würzburg,
Germany). The criteria for completion of reproducible and
satisfactory spirograms as set by the American Thoracic
Society [20] were followed. Airway responsiveness was assessed
using a 4.5% hyperosmolar saline challenge [17, 21]. Each
subject, whose baseline forced expiratory volume in one
second (FEV1) was >75% predicted [22], inhaled the saline
solution for periods of increasing duration (0.5, 1, 2, 4, and
8 min). The challenge was stopped after the FEV1 had fallen
by " 15% (bronchial hyperresponsiveness positive) or if the
total inhalation period of 15.5 min had been completed.
Traf c exposure assessment
Average daily traf c counts were performed by the city
administration for all streets with an a priori estimated vehicle
count of >4,000?day-1. This resulted in counts being available
for 1,840 street segments (of a total of 19,000). In addition,
measurements of yearly average concentrations of traf cassociated pollutants (benzene, soot and NO2) at 18 heavy
traf c sites in the city, and from 16 low-to-medium traf c sites
were performed [23]. Traf c counts were measured in 1995;
air pollution data from December 1996–February 1998.
The street segments with traf c counts and the address of
each child were entered into a computer-based geographical
information system (GIS). By setting a distance limit of 50 m
around each child9s home, the program identi ed all street
segments with traf c counts within this distance, and the sum
of their daily traf c counts was used to characterise traf c
exposure for this child. This distance limit was used according
to published data showing that the effect of car traf c
decreases greatly approximately beyond this distance [24].
In a second step, the traf c-count categories of 0–50 m and
>50–300 m and other available traf c characteristics (traf cjam percentage) were used to validate a model predicting
average yearly pollutant levels as measured at these 34 monitors.
The details of this modelling approach are described in
another paper [23]. In short, a model using car-traf c counts
and a weighting function, to account for the distance between
measurement point and street, together with street characteristics (mainly per cent of time with stop-and-go conditions in
the segment), was used to derive pollutant estimates. The
parameters of this model were optimised to give the best t
for the available actual pollutant-measurement data at the
monitoring sites. The monitoring sites had been selected in a
way to include both areas of high and low exposure. This
model gave a very good estimate of the measured pollutants
at low/medium and high exposure locations (benzene R2=0.80,
soot 0.80, NO2 0.77). This model was then used to calculate
predicted pollution levels at each child9s home address as
exposure estimate.
Statistical analyses
As the expected effect of traf c was rather small, a highexposure group was de ned for comparison with less-exposed
children. For traf c counts, the children with one or more
traf c counts at å 50 m from their home (16.3% of all children)
were considered at high exposure. This high-exposure group
was then divided into tertiles to assess a possible dose/
response relationship, and was compared with the rest of the
958
T. NICOLAI ET AL.
Table 1. – Participation rates
All Munich children
Parental questionnaire
Skin-prick test
Serum sample
Bronchial challenge
6244/7509
3422/5705
2569/5705
1140/2019
German children with test#
German children
(83.2)
(60.0)
(45.0)
(56.5)
4777/6198
2577/3710
1895/3710
904/1381
(77.1)
(69.5)
(51.1)
(65.5)
3953/6198
2233/3710
1656/3710
771/1318
(63.8)
(60.2)
(44.6)
(55.8)
Data are presented as n/total n (%). #: plus geographically referenced address, stored in the geographical information system.
study sample (83.7%). The threshold distance was later
changed to 100 and 300 m for sensitivity analyses to assess
consistency of results across various cut-offs. The children
with no traf c count å 300 m were considered at very low
exposure (22.7% of all children).
For the pollutant levels, as derived from the validated
model, the same proportion of children (i.e. 16.3%) at the
upper end of the exposure distribution as in the 50 m limit
analysis of the traf c counts was regarded as highly exposed,
and this group was again divided into tertiles for the
assessment of dose/response effects.
Multiple logistic regression analyses including known relevant confounding variables (age, sex, ETS exposure, SES,
family history of asthma, hay fever or eczema) were used to
calculate odds ratios for the in uence of traf c exposure on
the outcome variables. The rationale to stratify for ETS came
from another paper published recently by the present group
[25], which showed a strong interaction between ETS and low
a1-antitrypsin serum levels resulting in low lung function
among children with both exposures. The authors therefore
reasoned that ETS might make the airways more susceptible
to other potentially damaging factors, such as pollutant
exposure.
Results
The questionnaire was distributed to 7,509 children in
Munich (table 1). The proportion of children without German
nationality was 23.1% (n=1,431) in Munich. As reported
elsewhere, reporting behaviour and socioeconomic variables
were profoundly different with regard to ethnic background
[26]. Therefore, the analysis presented here was restricted to
children with German nationality. Of the eligible German
children for whom the questionnaire was returned, skin-prick
tests were obtained in 2,577 (69.5%, table 1). Table 2 shows
the prevalence of health outcomes for all German children.
Table 3. – Outcomes and exposures in children participating
and nonparticipating in skin-prick testing (SPT)
With SPT
Current asthma#
Current wheeze#
Morning cough#
Hay fever#
No traf c count <50 m
Low traf c counts}
Medium traf c countsz
High traf c counts§
(3.7–5.4)
(7.1–9.4)
(17.3–20.6)
(11.8–14.6)
(81.8–84.9)
(4.5–6.3)
(4.8–6.7)
(4.7–6.6)
6.1
9.6
18.7
9.7
84.1
5.4
5.4
5.2
(5.0–7.3)
(8.3–11.1)
(16.9–20.6)
(8.4–11.2)
(82.3–85.8)
(4.4–6.6)
(4.4–6.5)
(4.2–6.3)
Data are presented as % (95% con dence interval). #: with respective
symptoms during last 12 months; }: 2600–15000 vehicles?day-1; z :
15001–30000 vehicles?day-1; §: >30000 vehicles?day-1, in street segment
<50 m away from home.
Substantial participation bias is unlikely since the prevalence
of outcomes (except for a slightly higher prevalence of hay
fever) and the proportion of car-traf c counts were not
statistically different in children participating in skin-prick
testing compared with those not participating (table 3). When
additional socioeconomic information about individual city
areas provided by the administration (percentage unemployed,
percentage unemployed youth, percentage immigrants, average family size) were used for cluster analysis, no local effects
on outcomes were seen (data not shown).
Traf c counts
Traf c counts in street segments varied from 2,600–
148,000 vehicles?day-1. Figure 1 shows the places of residence
in relation to street segments. SES and ETS exposure were
5345
Table 2. – Prevalences of health outcomes
5340
203/3946
342/3889
734/3908
453/3892
436/2233
317/2224
256/2233
(5.1)
(8.8)
(18.8)
(11.6)
(19.5)
(14.3)
(11.5)
Latitude km
Current asthma#
Current wheeze#
Morning cough#
Hay fever#
Any skin-test reactivity " 3 mm
Skin-test reactivity pollen " 3 mm
Skin-test reactivity against indoor
allergens " 3 mm
Speci c IgE against aeroallergens
" 0.7 kU?mL-1
Speci c IgE against food allergens
" 0.7 kU?mL-1
Bronchial hyperreactivity
4.4
8.2
18.9
13.1
83.4
5.3
5.7
5.6
Without SPT
5335
5330
592/1656 (35.8)
181/679 (26.7)
159/771 (20.6)
Data are presented as n/total n (%). Ig: immunoglobulin.
respective symptoms during the last 12 months.
#
: with
5325
4450
4455
4460
4465
4470
Longitude km
4475
4480
Fig. 1. – Places of residence of children and street segments in
Munich.
959
Table 4. – Respiratory and atopic outcomes in relation to traf c counts in the area of residence
Outcome
Crude reference
prevalence %
(raw numbers)
Exposure tertile
Asthma
10.4 (318/3071)
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Current asthma#
5.0 (157/3124)
Current wheeze#
8.6 (266/3085)
Cough}
18.0 (559/3097)
Hay fever
11.7 (360/3082)
Skin-prick test
" 3 mm
19.4 (341/1762)
Pollen
13.9 (243/1754)
Speci c IgE
aeroallergens
" 0.7 kU?mL-1
36.3 (476/1311)
Crude prevalence %
(raw numbers)
9.4
9.6
12.2
3.1
5.7
8.6
7.3
8.5
13.5
18.7
22.3
26.8
10.9
12.4
13.3
17.9
18.2
23.4
14.2
14.2
18.9
28.8
34.7
39.5
(18/192)
(20/208)
(24/197)
(6/196)
(12/211)
(17/197)
(14/192)
(18/211)
(26/193)
(36/193)
(47/211)
(52/194)
(21/192)
(26/209)
(26/196)
(20/112)
(22/121)
(26/111)
(16/113)
(17/120)
(21/111)
(23/80)
(34/98)
(32/81)
Adjusted OR
(95% CI)
0.902
0.931
1.194
0.607
1.177
1.790
0.848
1.008
1.663
1.049
1.323
1.622
0.940
1.061
1.171
0.846
0.971
1.373
0.961
1.067
1.567
0.682
0.933
1.213
(0.545–1.493)
(0.576–1.506)
(0.762–1.871)
(0.264–1.396)
(0.639–2.171)
(1.051–3.048) §
(0.483–1.488)
(0.609–1.669)
(1.073–2.578) §
(0.720–1.528)
(0.942–1.858)
(1.162–2.266) ƒ
(0.585–1.510)
(0.688–1.638)
(0.756–1.814)
(0.509–1.405)
(0.595–1.584)
(0.857–2.200)
(0.551–1.677)
(0.619–1.840)
(0.940–2.613)z
(0.411–1.130)
(0.600–1.453)
(0.755–1.947)
OR: odds ratio; CI: con dence interval; Ig: immunoglobulin; low: 2600–15000 vehicles?day-1; medium: 15001–30000 vehicles?day-1; high: >30000
vehicles?day-1 in street segment <50 m away from home. #: with respective symptoms during the last 12 months; }: morning cough during the last
12 months. ORs adjusted for age, sex, socioeconomic status, and family history of asthma, hay fever, or eczema. Traf c categories analysed versus
rest of population (reference). z : p=0.05–å 0.10; §: p=0.01–å 0.05; ƒ : på 0.01.
linked with traf c exposure. Children living close (å 50 m) to
a busy street (>30,000 cars?day-1) were more often of lower
SES (59.3%) compared with the total sample (48.8%)
and those (44.3%) with no traf c count å 300 m (p<0.0001;
Cochran Armitage trend test). When the effect of traf c
counts on outcomes was strati ed for SES, no effect
modi cation was seen. The same relationship was found for
ETS exposure: 51.9% of those living close to a busy street
were exposed compared with 40.0% in the total sample and
35.1% in the low traf c areas (p<0.0001).
When traf c counts at å 50 m distance were used as an
exposure variable and the outcomes were contrasted against
the rest of the population (table 4), a signi cant association
was found between total traf c count and cough, current
asthma and wheeze, and a dose/response effect was suggested.
When stratifying the population into children exposed and
not exposed to ETS, an effect modi cation for ETS was seen.
Among children with ETS exposure (table 5), traf c volume
was signi cantly associated with current asthma, a positive
skin-prick test and positive skin-prick tests to pollen. A dose/
response effect was again observed in this stratum. No
signi cant effects of traf c on lung function and bronchial
hyperreactivity were observed. In children without ETS exposure, the effect of traf c was statistically signi cant only for
cough (data not shown).
When children were strati ed by skin-prick test positivity,
the associations between traf c and outcomes remained signi cant only for atopic children. This was, however, probably
due to the small proportion of children with asthma and
asthma symptoms in the nonatopic group leading to very
small sample sizes for the highly exposed nonatopic children.
When the distance limit for roads de ning high traf c
exposure was increased from 50 m up to 100 m, the association of traf c counts with current asthma (in children with
ETS exposure with asthma, skin-prick test and sensitisation
to pollen) remained signi cant. For a distance limit of 300 m,
the association became less clear but was still signi cant with
cough.
In addition to car-traf c volume, truck-traf c counts
(~10% of total counts) were also available. When the latter
were used in the analysis, approximately the same associations as with total traf c counts were found with the outcome
variables (data not shown).
If the children living in areas with no available traf c count
at å 300 m distance were analysed separately, a tendency for
relatively high prevalences of atopic diseases were found,
although NS: 6.3% current asthma (versus 4.8% in the rest of
the population), 11.9% current hay fever (versus 11.7%) and
22.6% had a positive skin-prick test (versus 18.7%).
Pollutant concentrations
Estimated exposure to traf c-related pollutants, as calculated from the above-described model for the home of the
children, was used as exposure variables in a multivariate
logistic regression model. Results for the highest tertiles of
high exposure versus low exposure are shown in table 6, while
the same is presented for children additionally exposed to
ETS in table 7.
Cough was associated with soot, benzene and NO2, current
asthma with soot and benzene, and current wheeze with
benzene and NO2, each without a clear dose/response gradient.
No effect modi cation was found for exposure to ETS. No
signi cant associations with lung function and bronchial
hyperresponsiveness were detectable for any pollutant (data
not shown).
960
T. NICOLAI ET AL.
Table 5. – Respiratory and atopic outcomes in relation to traf c counts in the area of residence for children additionally exposed
to environmental tobacco smoke
Outcome
Crude reference prevalence
% (raw numbers)
Exposure
tertile
Asthma
10.8 (126/1169)
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Low
Medium
High
Current asthma#
5.2 (62/1193)
Current wheeze#
9.1 (107/1178)
Cough}
19.1 (226/1186)
Hay fever
10.4 (123/1179)
Skin-prick test " 3 mm
15.8 (110/695)
Pollen
11.8 (82/694)
Speci c IgE aeroallergens
" 0.7 kU?mL-1
33.1 (164/496)
Crude prevalence %
(raw numbers)
4.8
11.0
13.6
1.2
5.9
9.7
4.8
9.9
14.0
20.7
25.7
26.7
6.1
16.8
15.7
13.7
23.8
28.8
11.5
19.4
25.0
25.7
33.3
45.0
(4/83)
(11/100)
(14/103)
(1/83)
(6/101)
(10/103)
(4/83)
(10/101)
(14/100)
(17/82)
(26/101)
(27/101)
(5/82)
(17/101)
(16/102)
(7/51)
(15/63)
(15/52)
(6/52)
(12/62)
(13/52)
(9/35)
(16/48)
(18/40)
Adjusted OR
(95% CI)
0.438
1.009
1.343
0.232
1.130
2.047
0.523
1.095
1.697
1.177
1.487
1.543
0.578
1.678
1.739
0.785
1.539
2.670
0.915
1.662
3.255
0.655
1.003
1.761
(0.157–1.222)
(0.521–1.957)
(0.736–2.452)
(0.032–1.700)
(0.472–2.706)
(1.005–4.171) §
(0.187–1.461)
(0.550–2.179)
(0.927–3.106)z
(0.674–2.054)
(0.927–2.385)z
(0.967–2.462)z
(0.227–1.472)
(0.944–2.981)z
(0.967–3.126)z
(0.339–1.817)
(0.812–2.918)
(1.353–5.268) ƒ
(0.372–2.247)
(0.829–3.331)
(1.581–6.699) ƒ
(0.296–1.451)
(0.524–1.920)
(0.897–3.458)z
OR: odds ratio; CI: con dence interval; Ig: immunoglobulin; Low: 2600–15000 vehicles?day-1; Medium: 15001–30000 vehicles?day-1; High: >30000
vehicles?day-1 in street segment<50 m away from home. #: with respective symptoms during the last 12 months. }: morning cough during the last 12
months. ORs adjusted for age, sex, socioeconomic status, and family history of asthma, hay fever, or eczema. Traf c categories analysed versus rest
of population (reference). z : p=0.05–å 0.10; §: p=0.01–å 0.05; ƒ : på 0.01.
Table 6. – Respiratory and atopic outcomes in relation to estimated pollutant levels at residence
Outcome
Soot
Asthma
Current asthma
Current wheeze
Cough
Hay fever
Skin-prick test
Pollen
Benzene
Asthma
Current asthma
Current wheeze
Cough
Hay fever
Skin-prick test
Pollen
NO2
Asthma
Current asthma
Current wheeze
Cough
Hay fever
Skin-prick test
Pollen
Crude reference prevalence
% (raw numbers)
Crude prevalence %
(raw numbers)
Adjusted OR
(95% CI)
10.1
5.0
8.6
17.9
11.9
20.5
15.2
36.8
(301/2982)
(152/3031)
(259/2996)
(537/3008)
(357/2993)
(344/1682)
(255/1675)
(463/1258)
13.2
8.0
11.2
24.1
12.8
16.0
12.3
37.9
(26/197)
(16/201)
(22/197)
(48/199)
(25/196)
(21/131)
(16/130)
(36/95)
1.423
1.763
1.409
1.483
1.103
0.864
0.904
1.124
(0.920–2.201)
(1.021–3.044) }
(0.883–2.248)
(1.055–2.086) }
(0.708–1.721)
(0.528–1.417)
(0.520–1.573)
(0.723–1.747)
10.1
5.1
8.8
17.7
11.8
20.4
15.0
37.4
(302/2979)
(153/3029)
(263/2992)
(533/3005)
(353/2988)
(343/1684)
(251/1678)
(469/1255)
12.4
9.3
13.0
23.4
10.9
14.6
9.8
34.8
(25/201)
(19/204)
(26/200)
(47/201)
(22/201)
(18/123)
(12/123)
(31/89)
1.269
2.045
1.646
1.423
0.900
0.768
0.688
0.983
(0.816–1.975)
(1.227–3.407)z
(1.062–2.552) }
(1.010–2.005) }
(0.565–1.434)
(0.453–1.300)
(0.369–1.283)
(0.619–1.563)
10.2
5.1
8.8
17.9
11.8
20.5
15.2
37.1
(304/2980)
(154/3029)
(263/2992)
(538/3007)
(352/2990)
(344/1676)
(254/1669)
(464/1251)
12.1
7.4
12.1
25.5
12.2
15.4
10.9
38.1
(24/199)
(15/202)
(24/198)
(51/200)
(24/197)
(20/130)
(14/129)
(37/97)
1.282
1.655
1.579
1.599
1.038
0.818
0.777
1.141
(0.817–2.010)
(0.944–2.901) #
(1.005–2.482) }
(1.144–2.234)z
(0.661–1.630)
(0.495–1.354)
(0.433–1.394)
(0.736–1.767)
OR: odds ratio; CI: con dence interval; Ig: immunoglobulin; NO2: nitrogen dioxide. ORs adjusted for age, sex, socioeconomic status, and family
history of asthma, hay fever, or eczema. High exposure tertiles analysed versus rest of population. Soot (mg?m-3): 8.07–9.24, >9.24–10.73,>10.73;
Benzene (mg?m-3): 4.74–5.31, >5.31–7.27, >7.27; NO2 (mg?m-3): 42.87–47.15,>47.15–57.44, >57.44. For brevity, ORs (95% CI) and prevalences are
only shown for highest traf c exposure tertile for each outcome variable. #: p=0.05–å 0.10; }: p=0.01–å 0.05; z : på 0.01.
961
Table 7. – Respiratory and atopic outcomes in relation to estimated pollutant levels at residence for children additionally exposed
to environmental tobacco smoke
Outcome
Crude reference
prevalence %
(raw number)
Soot
Asthma
Current asthma
Current wheeze
Cough
Hay fever
Skin-prick test
Pollen
Benzene
Asthma
Current asthma
Current wheeze
Cough
Hay fever
Skin-prick test
Pollen
NO2
Asthma
Current asthma
Current wheeze
Cough
Hay fever
Skin-prick test
Pollen
Crude prevalence %
(raw number)
Adjusted OR
(95% CI)
10.3
5.2
8.9
18.9
10.5
17.3
13.3
33.4
(117/1136)
(60/1156)
(102/1144)
(218/1151)
(120/1143)
(113/655)
(87/654)
(156/467)
16.7
10.1
13.5
27.6
16.3
19.7
16.7
34.0
(16/96)
(10/99)
(13/96)
(27/98)
(16/98)
(13/66)
(11/66)
(16/47)
1.746
2.070
1.582
1.668
1.549
1.223
1.363
0.980
(0.978–3.115) #
(1.013–4.231) }
(0.848–2.950)
(1.042–2.670) }
(0.862–2.784)
(0.629–2.379)
(0.669–2.777)
(0.512–1.874)
10.4
5.2
9.3
18.6
10.5
16.9
12.9
34.3
(118/1130)
(60/1150)
(106/1137)
(213/1145)
(119/1137)
(110/651)
(84/651)
(158/461)
14.6
11.4
13.7
24.3
15.4
19.4
13.4
30.6
(15/103)
(12/105)
(14/102)
(25/103)
(16/104)
(13/67)
(9/67)
(15/49)
1.437
2.407
1.593
1.407
1.432
1.274
1.109
0.860
(0.797–2.588)
(1.235–4.692)z
(0.871–2.915)
(0.873–2.269)
(0.799–2.565)
(0.655–2.479)
(0.517–2.377)
(0.448–1.653)
10.3
5.2
9.0
18.9
10.3
17.3
13.3
34.0
(117/1131)
(60/1151)
(103/1139)
(217/1147)
(117/1138)
(112/649)
(86/648)
(157/462)
15.5
9.1
13.5
28.6
16.3
21.7
17.4
35.8
(15/97)
(9/99)
(13/96)
(28/98)
(16/98)
(15/69)
(12/69)
(19/53)
1.563
1.837
1.607
1.722
1.538
1.442
1.487
1.093
(0.865–2.826)
(0.873–3.867)
(0.861–2.999)
(1.081–2.744) }
(0.855–2.766)
(0.765–2.718)
(0.747–2.963)
(0.595–2.007)
OR: odds ratio; CI: con dence interval; Ig: immunoglobulin; NO2: nitrogen dioxide. ORs adjusted for age, sex, socioeconomic status, and family
history of asthma, hay fever, or eczema. High exposure tertiles analysed versus rest of population. Soot (mg?m-3): 8.07–9.24, >9.24–10.73,>10.73;
Benzene (mg?m-3): 4.74–5.31, >5.31–7.27, >7.27; NO2 (mg?m-3): 42.87–47.15,>47.15–57.44, >57.44. For brevity, ORs (95% CI) and prevalences are
only shown for highest traf c exposure tertile for each outcome variable. #: p=0.05–å 0.10; }: p=0.01–å 0.05; z : på 0.01.
Discussion
In this large population-based survey, high vehicle traf cdensity close to the home was related to respiratory complaints, such as cough, wheeze and current asthma in children.
The authors also found an association between exposure
to heavy road traf c and allergic sensitisation for a small
subgroup, additionally exposed to ETS. High traf c-related
air pollutant exposure was associated with asthma and cough,
but not with allergic sensitisation.
Several methodological limitations must be considered
before attempting to interpret these ndings. The city of
Munich provided traf c counts for all street segments with an
a priori estimate of>4,000 vehicles?day-1 only. In this city, most
street segments are small side streets and had no counts
available. This may have led to some misclassi cation of
traf c exposure. Also, pollutant exposure values at the homes,
derived from a validated model, were used to estimate
personal exposure rather than direct personal samplers.
This approach will only yield an approximation of real
exposure.
Children living close to streets with heavy traf c had
particular lifestyle characteristics, which make it dif cult to
differentiate a possible direct effect of car-traf c exposure
from these in uences. Their families were of a lower SES and
their children were more often exposed to ETS. When the
analyses were strati ed for high/low SES, however, no effect
modi cation for the traf c-related outcomes was seen. No
clustering of outcomes was observed with local socioeconomic characteristics of the city areas. Still, a residual
confounding effect of SES cannot be excluded, since
Munich has no areas with obvious social deprivation.
Children living in homes that were least exposed to traf c
were at the other end of the socioeconomic spectrum.
Atopic diseases have been found more often in af uent
families [27, 28]. The bene cial effect of low traf c exposure
might actually be obscured, as children from these families
can be expected to have higher prevalences of these diseases
due to lifestyle factors associated with high SES. Still, these
observations must be interpreted with care as the assessment
of SES rests on information on parental education and
misclassi cation may have occurred. Interestingly, the study
in children living close to a busy freeway in Holland showed
an effect on asthma only in children with low-to-medium SES
[15].
The advantages of this study are the large number of
subjects, the population-based design and the GIS-based
assessment of exposure using traf c counts or measurements
of air pollutants rather than self-reports. The use of pollution
exposure derived from a modelling approach, well validated
across high-to-low exposure measurement sites, allows assessment of the plausibility of direct pollutant effects versus other
traf c-related mechanisms.
Participation or reporting bias is a concern in studies
where only subsamples of children take part in some of the
measurements (such as skin-prick testing or serum sampling).
Participation rates for allergy tests were indeed lower than for
the questionnaire (table 1), but as outcomes and traf c
exposure categories showed only minor differences between
participating and nonparticipating children (table 3), it is
962
T. NICOLAI ET AL.
unlikely that bias introduced by this effect can explain these
results.
Two interesting observations can be derived from the data
presented here. Firstly, high traf c exposure was associated
with cough, asthma and wheeze in all children, and with
atopic sensitisation in children additionally exposed to ETS.
Similar associations with outcomes were seen for traf crelated air pollution levels. The ndings regarding asthma are
in accordance with those reported for Dutch children living
along busy freeways [10, 15]. A survey from Dresden found
pollutant effects for bronchitis, nonatopic asthma and cough
but not for atopic asthma, allergy and lung function [2].
However, exposure had changed over the lifetime of these
children and may have differed during the early years crucial
for allergy inception from the exposure measured later on.
A Swiss study reported traf c effects on pollen allergy for a
subsample of the adults studied (those living >10 yrs at the
same address) [16]. When effects are only found in subsamples
in epidemiological studies, the question of multiple comparisons resulting in spurious ndings must be considered.
Biological plausibility may argue in favour of both the results
in the Swiss study and the ndings of the study reported here.
Recently, ETS exposure was found to be associated with
diminished lung function in children with low a1-antitrypsin
levels [25] indicating that ETS exposure together with other
detrimental factors may result in overt respiratory damage.
Secondly, when streets >50 m from home were included in
the exposure assessment, the traf c effect was diluted. A large
study from Italy found effects only for reported lorry traf c at
the street of residence, but not in the zone of residence [11].
The same weakening of effects was apparent in this study
when mean yearly pollutant levels were used as the exposure
variable. No signi cant effect on allergic sensitisation was
seen for pollutant exposure. This could indicate that the
observed effects of traf c in streets <50 m from home on
atopy are not caused by emissions from vehicles but rather
due to residual confounding, e.g. socioeconomic characteristics
associated with such a place of residence. Although the
pollutant exposure assessment gave good results with ~80%
predictive power at the measurement stations, misclassi cation due to the limitations of the modelling approach cannot
be excluded. This would equally result in a diminished
association between estimated pollutants and outcomes.
A smaller study in 317 children from Düsseldorf, Germany,
found exposure to NO2 as estimated from measured outdoor
levels in front of the home (but not the personal sampler
derived individual exposure) to be related to skin-prick tests
positivity and speci c IgE [29]. This could indicate that
individual substances may not re ect the mechanism by which
the traf c-associated health effects are caused. Alternatively,
if traf c exposure at short distance were the cause for the
increased prevalence of sensitisation, it would have to be
mediated via an effect or substance that is less easily dispersed
in the surroundings than benzene, soot or NO2. Larger
particles may display such characteristics, and dust containing
latex or carbon has been implicated in health effects of traf c
[30]. However, a recent study found no increase in latex
sensitisation in children living close to busy streets [31].
The less clear association of pollutants compared with
traf c counts and lack of dose/response effect suggests that
the observed association with traf c may not be mediated
directly via the measured pollutants. Children living in areas
with particularly low traf c exposure also had relatively high
atopy prevalence, as well as a higher socioeconomic status.
It is also possible that increased outcome prevalences are
attributable to differences in lifestyle and/or living conditions
related to poverty and low socioeconomic status rather than
to traf c exposure itself.
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CHAPTER 1
Epidemiological studies of chronic
respiratory conditions in relation to
urban air pollution in adults
G. Viegi, S. Baldacci
Pulmonary Environmental Epidemiology, CNR Institute of Clinical Physiology, Pisa, Italy.
Correspondence: G. Viegi, Pulmonary Environmental Epidemiology Group, CNR Institute of Clinical
Physiology, Via Trieste 41, 56126 Pisa, Italy.
In 1952, in London, UK, there was an episode of air pollution that caused a substantial
number of excess deaths (y4,000), part due to respiratory diseases, especially bronchitis
[1]. Subsequently, attention was drawn to the possibility that high concentrations of
outdoor air pollutants may cause severe health effects and deaths. Investigations into
the mechanisms by which air pollutants affect respiratory diseases and which diseases are
caused by air pollution were therefore implemented. The need to control air pollutants
and to lay the basis for directives and laws to regulate air pollutant levels has prompted
epidemiological research.
The 20th century has seen decreases in the major infections (pneumonia and
tuberculosis) and a dramatic increase in lung cancer (due mostly to cigarette smoking)
[2, 3]. During the last 20 yrs, the increase in asthma morbidity and mortality in many
countries prompted studies aimed at evaluating the contribution of environmental
factors to these events.
In the 1970s, the large French "Pollution atmosphérique et affections respiratoires
chroniques" study investigated the effects of air pollution on the health of adults [4, 5].
It showed that air pollution, defined as black smoke or sulphur dioxide (SO2), affected
the prevalence of chronic bronchitis and cough.
Increasing motor vehicle traffic in the 1980s and its effects on health, such as raising
asthma rates in children and adults, led to new epidemiological studies, based on new
methods, which were concerned with the effect of air pollutants on respiratory diseases.
This process was also prompted by revisions of the air pollutant regulations in the USA
and in Europe, and of air quality guidelines by the World Health Organisation (WHO).
Air pollution epidemiology has, thus, become an important tool for the reformulation
of air quality guidelines by the WHO and for the regulation of air pollutants in different
regions. Because of the need to regulate air pollution and to rely, for this purpose, on
studies on the effect of air pollutants on human health, research has tended to focus on the
effects of individual pollutants. Regulation generally concerns single air pollutants, whereas
the health effects are probably often caused by the inhalation of several pollutants.
In the past, two main patterns of air pollution were recognised: the reducing or
London type and the oxidising or Los Angeles type [6, 7]. The first type contained
sulphur oxides (SO2, sulphur trioxide), sulphuric acid, sulphate salts, and total suspended
particulates (TSP) from fossil fuels. It was associated with episodes in which excess
mortality or preventable deaths were reported in patients with chronic heart or lung
disease. It was also considered a factor in the development of chronic obstructive
pulmonary disease (COPD). The second type, whose primary source was automobile
Eur Respir Mon, 2002, 21, 1–16. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2002; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-24-3.
1
G. VIEGI, S. BALDACCI
exhausts, contained oxides of nitrogen and hydrocarbons. These were transformed by
sunlight into secondary components i.e. ozone (O3), aldehydes and ketones, and
peroxyacetyl nitrate that were considered responsible for initiating effects.
The real situation is, indeed, less simple and mixed patterns of air pollution characterise urban air quality. However, in newer studies health effects are associated with
individual pollutants.
In this chapter, an attempt will be made to look at different health outcomes
(excluding cancers) of outdoor pollution exposure, and summarise studies which have
shown effects for different pollutants in adult populations. This chapter follows the
pattern of one written recently by Ackermann-Liebrich [8] for another European
Respiratory Monograph. Mechanisms and effects on children will be fully dealt with in
other chapters of this monograph.
Assessment of exposure
Many papers have been published about air pollution exposure assessment [9, 10],
but the question as to which measurement best reflects a person’s exposure remains to
be answered.
A personal monitor might be the best measure of a person’s exposure to a particular
pollutant, over an observed time. However, such measurements can only cover a shortterm period for one specific pollutant. The effects of pollutants are also determined by
previous exposure (e.g. whether the subject lived in a rural or an urban area), by the
pollution mix and by the way of pollutant penetration into the lung.
Studies on air pollution epidemiology mostly use central measuring stations as proxies
for population exposure, although this cannot entirely correspond to the true exposure.
When comparing different populations the investigators take into account the average
exposure in the community. Criticisms about the use of central measuring stations
are also based on the fact that in industrialised societies people spend most of the time
indoors. Exposure to air pollution in the indoor environment might deviate from
outdoor exposure due to the presence of indoor sources, but recent studies [11–13] have
shown that most outdoor pollutants penetrate indoors and indoor air quality is largely
determined by outdoor pollutant concentrations.
Air pollution epidemiology has to deal with defining the exposure time with which a
health effect is related. Two main strategies have been devised to study exposure time:
short- and long-term domains. The short-term effects of air pollutants have been studied
by analysing day-to-day changes in air pollutant concentrations along with changes in
population health indicators, such as peak flow variability [14–16], hospital admissions
[17] or mortality (Air Pollution and Health: a European Approach; APHEA project)
[18–21].
Long-term means (e.g. annual means) of community air pollution have been related to
individual health outcomes, such as lung function [22, 23], methacholine responsiveness
[24], cough, bronchitis or bronchitic symptoms [25–27] (considering other individual
characteristics which may be confounders or effect modifiers). The study designs used
have been cross-sectional studies [21, 22, 26], longitudinal studies of populations [28, 29]
or panel studies which have made a link between short- and long-term effects in
respiratory diseases [30, 31].
In this chapter "short-term exposure" stands for exposure measurements of varying
duration between hours (as used for O3) and days (for the other pollutants), whilst
"long-term exposure" refers to yearly or monthly averages. These studies can use either
2
RESPIRATORY EFFECTS OF AIR POLLUTION
exposure data from monitoring stations or personal samplers, or models incorporating
both [9, 10].
Distribution of exposure
Estimates about the number of people exposed to levels exceeding air quality standards
are regularly presented by the WHO. Excess O3 has become a problem not only in
southern Europe but also in the northern part of the continent. Nitrogen dioxide (NO2)
is a problem in urban areas where short- and long-term air quality standards are
continuously violated, as depicted in figure 1 of Ackermann-Liebrich’s chapter [8]. SO2
is no longer a problem within most of Western European regions, whereas in the former
Eastern European countries it still represents a considerable problem, due to massive
coal burning, however, the problem is decreasing. Data on particulates (measured as
TSP, black smoke or particles with an aerodynamic diameter v10 mm (PM10)) are
patchy. Not all countries report data on particulates and not in a standardised way. But
as TSP and especially PM10 tends to be correlated to the levels of NO2, a map of NO2
concentrations gives a usable measure of the situation.
In the USA, it was shown that in the early 1990s, w80 million people lived in counties
in which mean pollutants levels exceeded the national air quality standards, although
antipollution laws have a longer tradition in the USA than elsewhere [32].
Respiratory effects related to air pollutants
In adults, three respiratory conditions are epidemiologically important: 1) asthma
rates which are on the increase worldwide; 2) the increasing rate of bronchitis in
smokers and neversmokers; and 3) an undefined proportion of lung cancer in
nonsmokers. Diseases and mortality have been related to air pollution in all age
groups. The evidence, however, is different for different diseases. Data on respiratory
diseases linked to air pollutants and related to different durations of exposure will be
reviewed. Table 1 shows the main outdoor air pollutants and their sources and health
effects.
In recent years, attention has focused on particulate matter. Very recent evidence
is leading to a more detailed characterisation of this pollutant [33]. Previously, it
was reported that fine particle mass (PM2.5, expressed in mg?m-3), which is primarily
from combustion sources, but not coarse particle mass, which is primarily from crustal
sources, was associated with daily mortality in six eastern USA cities [34]. In the new
study, Laden et al. [33] used the elemental composition of size-fractionated particles
to identify several distinct source-related fractions of fine particles, and examined the
association of these fractions with daily mortality in each of the six cities. Using specific
rotation factor analysis for each city, they identified a silicon factor classified as soil
and crustal material, a lead factor classified as motor vehicle exhaust, a selenium factor
representing coal combustion, and up to two additional factors. They extracted daily
counts of deaths from National Centre for Health Statistics records and estimated
city-specific associations of mortality with each source factor by Poisson regression,
adjusting for time trends, weather, and the other source factors. In the combined
analysis, a 10 mg?m-3 increase in PM2.5 from mobile sources accounted for a 3.4%
increase in daily mortality (95% confidence interval (CI): 1.7–5.2%), and the equivalent increase in fine particles from coal combustion sources accounted for a 1.1%
3
Table 1. – Type, sources and respiratory health effects of common outdoor pollutants
Type
Source
Main health effects
Ozone (O3)
Photochemical reactions
from autovehicle traffic
Nitrogen dioxide (NO2)
Gas combustion
Autovehicle traffic
Sulphur dioxide (SO2)
Fuel combustion, mainly
from industry
Autovehicle traffic
Respirable suspended
particulates (e.g.
PM10, PM2.5)
Autovehicle traffic
Industrial activity
Carbon monoxide (CO)
Fuel combustion
Lung function reduction
Bronchial hyperresponsiveness
Increased prevalence of respiratory symptoms
Increased hospitalisation rate for respiratory disease
Reduced exercise tolerance
Bronchial hyperresponsiveness
Increased respiratory symptoms
Increased prevalence of respiratory symptoms
Increased mortality from respiratory diseases
Increased number of emergency visits for
respiratory disorders
Increased prevalence of respiratory
symptoms/diseases
Increased mortality from cardiorespiratory diseases
Asthma exacerbations
PM10: particles with an aerodynamic diameterv10 mm; PM2.5: particles with an aerodynamic diameterv2.5 mm.
increase (0.3–2.0%). PM2.5 crustal particles were not associated with daily mortality. These
results indicate that combustion particles in the fine fraction from mobile and coal
combustion sources, but not fine crustal particles, are associated with increased mortality.
Long-term effects of air pollutants on respiratory health
The study carried out in the USA, in six large cities characterised by different levels of
air pollution, revealed a 26% higher risk from death for cardiorespiratory disease among
the inhabitants of the most polluted city, with respect to those who lived in the least
polluted city [28]. Confirmation of the effects on mortality of chronic exposure to air
pollutants has also been obtained in a large prospective study on a sample of more than
500,000 Americans [35] and in a Swedish case-control study [36].
In California, USA, chronic bronchitis and asthma symptoms have been associated
with suspended particulates [37], and in Italy it has been shown that living in an urban
area is associated with a higher risk of chronic respiratory symptoms with respect to
living in a rural area [38]. Air pollutants have been found to be related with respiratory
symptoms/diseases in France [4, 5], in Switzerland [27], in the UK [39], in Sweden [40], in
China [41], and in India [42].
The evidence of the effect of air pollution on asthmatic symptoms is contradictory;
Scarlett et al. [39] could not find such an effect in so far as phlegm, and neither
cough nor wheeze, was associated with black smoke. Other studies [26, 38, 43] showed an
increase in the prevalence of asthmatic symptoms/diagnosis or of allergic sensitisation
to pollens [44], and the incidence of asthma has been related to long-term exposure to
higher O3 concentrations [45]. However, a recent review underlines the lack of sound
evidence that asthma prevalence is related to the incidence of air pollution in different
surroundings [46].
Beside the increment of mortality, symptomatology, requests for specialistic care
and hospital admissions, air pollution is responsible for the reduction of lung function.
4
Air pollution effects on lung function have been demonstrated in France [4, 5], the USA
[29, 47, 48], Switzerland [22, 49], and China [50]. In particular, Tashkin et al. [29] in three
different zones of Los Angeles, CA, USA, demonstrated that, among the inhabitants
of the most polluted zone, the annual forced expiratory volume in one second (FEV1)
decline was 23.6 mL?yr-1 higher, with respect to that of the inhabitants of the least
polluted zone, whilst Schindler et al. [49] found that home outdoor measurements of
NO2 and personal measurements of NO2 were related to a lower forced vital capacity
(FVC; -0.59 and -0.74% per 10 mg?m-3, respectively) (table 2).
In addition to the studies listed in table 2, KÜNZLI et al. [51], in a study of data
from Austria, France and Switzerland, determined the cases attributable to air pollution
for mortality and morbidity: epidemiology-based, exposure/response functions for a
10 mg?m-3 increase in PM10 above the daily mean level were used. Air pollution caused
6% of total mortality or w40,000 attributable cases per year. Approximately one-half
of all mortality caused by air pollution was attributed to motorised traffic, which also
accounted for w25,000 new cases of chronic bronchitis (adults), w290,000 episodes of
bronchitis (children), w0.5 million asthma attacks, and w16 million days of restricted
activity.
In a case-crossover study carried out in Spain, Sunyer et al. [52] observed that for an
increment of 20 mg?m-3 in the daily mean concentration of black smoke, patients who
had been visited at the emergency department for COPD showed an 18% increased risk
of mortality for respiratory diseases. Tellez-Rojo et al. [53] reported that a 10 mg?m-3
increase above the daily mean level of PM10 in Mexico City, Mexico, was associated
with a 4.1% increase of daily mortality for COPD in inhabitants w64 yrs, after a 3-day
lag (nonhospitalised). With a cumulative exposure of 5 days, the rate reached 6.1%,
pinpointing a linear relationship in the range of pollution levels observed in the study,
which was also able to show rate differences between deaths occurring inside medical
units as opposed to those occurring elsewhere.
The mechanisms of action already ascertained or hypothesised regarding which air
pollution induces damages to the respiratory system, are numerous and complex. They
were reviewed by the American Thoracic Society in 1996 [32]. Evidence of the importance
of bronchial hyperresponsiveness in terms of susceptibility to the effects of air pollution
comes from a Dutch study [54]. Only hyperreactive subjects showed an increase of
prevalence of cough (23% for each 100 mg?m-3 rise in PM10) and of phlegm (22% for each
40 mg?m-3 rise in NO2).
D’Amato [55], in a recent review, commented on the association of respiratory allergic
diseases (rhinitis, rhinosinusitis, bronchial asthma and its equivalents) with air pollution.
Laboratory studies confirm the epidemiological evidence that inhalation of some
pollutants, either individually or in combination, adversely affect lung function in
asthmatics. While NO2 does not exert consistent effects on lung function, O3, respirable
particulate matter and allergens impair lung function and lead to increased airway
responsiveness and bronchial obstruction in predisposed subjects. However, besides
acting as irritants, airborne pollutants can modulate the allergenicity of antigens carried
by airborne particles. By attaching to the surface of pollen grains and of plant-derived
paucimicronic particles, pollutants can modify the morphology of these antigen-carrying
agents and alter their allergenic potential. In addition, by inducing airway inflammation, which increases airway epithelial permeability, pollutants overcome the mucosal barrier and so facilitate the allergen-induced inflammatory responses. Moreover,
air pollutants such as diesel exhaust emissions are thought to modulate the immune
response by increasing immunoglobulin E synthesis, thus, facilitating allergic sensitisation in atopic subjects and the subsequent development of clinical respiratory
symptoms.
5
6
Prospective study
Cohort studies
Cross-sectional studies
1982 [4, 5]
1997 [40]
1999 [27]
1999 [41]
NOx/NO2, SO2
SO2, NO2
NO2, SO2
PM10, NO2, SO2
TSP
Stockholm, Sweden: 1042 cases,
2364 controls
France
Sweden
Switzerland
China
France
Switzerland
Switzerland
New Haven, CT, USA
Chongqing, China
California, USA
California, USA
France
Switzerland
Delhi, India
SO2
Traffic counts at domicile
Conventional monitored
pollutants
SO2, NO2
PM10, NO2, SO2
NO2
O3
PM2.5, SO2
O3
Sulphates, PM10
O3
2000 [36]
Black smoke
TSP, SO2
1982 [4, 5]
1997 [22]
1998 [49]
1999 [47]
1999 [50]
1994 [29]
1998 [48]
1999 [45]
1999 [43]
2000 [44]
2001 [42]
1995 [39]
1999 [38]
1993 [28]
1995 [35]
1995 [37]
England: birth cohort, 23-yrs follow-up
Italy
8000 Americans, 6 cities, 15-yrs follow-up
California, USA
1993 [28]
1995 [35]
Reference
and year
PM10, PM2.5, sulphates
PM2.5
Sulphates
PM2.5
Sulphates
TSP, PM10, PM2.5
Pollutants
Population studied
PM10: particles with an aerodynamic diameter v10 mm; PM2.5: particles with an aerodynamic diameter v2.5 mm; TSP: total suspended particulate; SO2: sulphur dioxide;
NOx: nitrogen oxides; NO2: nitrogen dioxide; O3: ozone.
Asthma incidence
Respiratory symptoms
Cough, respiratory symptoms
Lower respiratory symptoms
Persistent rates of cough, phlegm
and wheeze
Asthma prevalence
Allergic sensitization to pollens
Chronic cough, chronic phlegm,
dyspnoea, lung function reduction
Lung function
Chronic bronchitis, asthma
symptoms
Phlegm
Repeated cross-sectional
studies
Case-control
Cohort studies
Cardiopulmonary mortality
Lung cancer mortality
Study type
Health outcome
Table 2. – Respiratory effects of air pollution on adults
Short-term effects of air pollutants on respiratory health
In 1994, Dockery and Pope [56] published a review of a large series of epidemiological
studies, and placed particular attention on the role of suspended particulates. It was
estimated that, for each increase of 10 mg?m-3 of PM10, there is an increment of mortality
of 3.4% for respiratory diseases and of 1.4% for cardiovascular diseases; even total
mortality is increased by 1%. More recently, the APHEA study carried out in 12 large
European cities has confirmed these results [20]. Furthermore, it has been documented
that, for each increase of 10 mg?m-3 of suspended particulate concentration, there is a
proportional increment of hospital admissions and emergency room visits for respiratory
disorders (increase of 1%). The increase is more marked when only asthmatic disorders
are considered (an increment of 2–3% of both emergency visits and symptom exacerbations) [56]. In another study, the increase in hospital admissions has been documented not
only for increased PM10 concentrations, but also for increased concentrations of O3 [57].
Panel studies
Several panel studies have reported the effects on lung function of previous day levels
of O3 [58–60], PM10 [30] and several other pollutants in exercising [61], asthmatic subjects
[62] and adults [63]. In particular, FEV1 was associated with the level of PM10 on the
day of testing in middle-to-moderate COPD patients tested twice, 10–90 days apart, in
Salt Lake City, UT, USA [30]. Subjects retested on cleaner days had better lung function
values than in the previous test. Asthmatic symptoms have been reported to increase
with high previous day pollutant levels in asthmatic subjects in the Netherlands [64, 65],
and in Switzerland [63]. An increase in night-time chest symptoms (relative risk (RR),
1.38; 95% CI: 1.07–1.78), associated with the interquartile range of PM10 of 35 mg?m-3,
was observed in a panel study of 55 COPD patients followed up for 3 months in
Christchurch, New Zealand [31] (table 3).
Time-series studies
In time-series studies looking at the effect of air pollutants, populations serve as their
own control. Since other factors do not change very fast, the effect is unlikely to be
influenced by behavioural or other confounders in the community. Associations with air
Table 3. – Short-term effects of air pollutants on respiratory health of adults: panel studies
Health outcome
Population studied
Pollutants
Reference and year
Lung function
USA: adults, jogging
USA: smokers
The Netherlands: cyclists
Canada: farmers, 10–69 yrs
USA: asthmatics
USA: hikers
New Zealand: COPD patients
The Netherlands: asthmatics
The Netherlands: 50–70 yrs adults
O3
PM10
O3
O3
NO2, SO2, BS
O3, PM2.5, acid aerosols
PM10
O3, PM10
PM10, BS, sulphate, SO2
1988 [58]
1993 [30]
1994 [59]
1996 [60]
1996 [62]
1998 [61]
1997 [31]
1998 [64]
2000 [65]
Night-time chest symptoms
Asthmatic symptoms
O3: ozone; PM10: particles with an aerodynamic diameter v10 mm; NO2: nitrogen dioxide; SO2: sulphur dioxide;
BS: black smoke; PM2.5: particles with an aerodynamic diameterv2.5 mm; COPD: chronic obstructive pulmonary
disease.
7
pollution have been observed in many cities for general [34] and especially respiratory
mortality [66, 67]. The APHEA project confirmed findings from earlier American
studies [18, 20, 68, 69]. The effects were related to different fractions of particulate
pollution, to SO2 and in Athens to O3. More recent studies have confirmed the association of respiratory mortality with air pollution in USA [70], London [71], New Zealand
[72], Canada [73], and Brazil [74]. COPD mortality [34, 75] was found to be more strongly
related to PM10 than the other causes of mortality.
The same studies also looked at respiratory hospital admissions; COPD [17, 68, 69,
76–78] and asthma [79–81] admissions were found to be related to particulates, and
also to SO2, NO2 and O3. SO2 and NO2, have also been related to visits to accident
and emergency departments in London for respiratory complaints [82]. Particles, O3,
NO2 and even carbon monoxide (CO) have been related to respiratory hospital
admissions in other recent studies in the UK [82], Australia [83], Italy [84], and in the
USA [85]. In addition, daily consultations for allergic rhinitis have been related to
increased concentrations of SO2 and O3 in London [86] (table 4).
Meteorological conditions and a high concentration of air pollutants have been
associated with increased respiratory morbidity. In Valencia, Spain [87], the possible
Table 4. – Short-term effects of air pollutants on respiratory health of adults: time-series studies
Health outcome
Population studied
Pollutants
Reference
and year
Respiratory mortality
Philadelphia, PA, USA
London, UK
Paris, France
Milan, Italy
Mexico city, Mexico
Coachella Valley, CA, USA
London, UK
Christchurch, New Zealand
Montreal, Canada
Sao Paulo, Brazil
6 cities, USA
Birmingham, UK
Paris, France
Milan, Italy
London, UK
5 European cities
Sydney, Australia
London, UK
Brisbane, Australia
Rome, Italy
Paris, France
6 European cities
10 USA cities
Atlanta, GA, USA: children
Helsinki, Finland: adults
Helsinki, Finland: children
4 European cities
London, UK
TSP
O3
PM13
TSP, SO2
TSP
PM10
PM10, BS, NO2, SO2, CO
PM10
PM10, PM2.5
Fine particulates, SO2
PM10, PM2.5, sulphates
PM10
BS, PM13, SO2
TSP, SO2
O3
O3
Particles, O3
PM10, SO2
O3, particulates, SO2
NO2, CO
SO2, NO2
SO2, BS, TSP, NO2, O3
PM10
O3, PM10
SO2, O3
1994 [66]
1996 [18]
1996 [68]
1996 [69]
1997 [67]
1999 [70]
1999 [71]
2000 [72]
2001 [73]
2001 [74]
1997 [34]
1997 [75]
1996 [68]
1996 [68]
1996 [76]
1998 [77]
1998 [78]
1999 [82]
2001 [83]
2001 [84]
1996 [69]
1997 [17]
2000 [85]
1994 [79]
1996 [80]
NO2, SO2
SO2, PM10, NO2
1997 [81]
1999 [82]
London, UK
SO2, O3
2001 [86]
COPD mortality
Respiratory hospital
admissions
COPD hospital admissions
Asthma admissions
Visits for respiratory
complaints to accident
and emergency departments
Allergic rhinitis daily consultations
TSP: total suspended particulate; O3: ozone; PM13: particles with an aerodynamic diameter v13 mm; SO2:
sulphur dioxide; PM10: particles with an aerodynamic diameterv10 mm; BS: black smoke; NO2: nitrogen dioxide;
CO: carbon monoxide; PM2.5: particles with an aerodynamic diameter v2.5 mm; COPD: chronic obstructive
pulmonary disease.
8
relationship of the concentration of black smoke and SO2 in the air, local weather
conditions and emergency room visits for asthma was investigated. The weekly total of
emergency room admissions for asthmatic adults during a 1-yr period was recorded
together with daily metereological conditions (average temperature, humidity, rainfall,
wind speed and barometric pressure) and average weekly levels of daily pollutant
concentrations (black smoke and SO2). The relationship was assessed by stepwise
regression linear models and analysis of variance. The analysis took into account season
and metereological variables. Both air pollutants correlated significantly with emergency
room admissions for asthma (SO2: regression coefficient (r)=0.32; black smoke: r=0.35).
However, multiple regression analysis showed that black smoke was the only significant
predictor of weekly visits. There were y3.5 admissions per week per sd of change
(34.6 mg?m-3). There were no significant correlations between weekly emergency room
visits and the weather variables. Analysis of the data stratified by season and weather
conditions demonstrated that the association of black smoke with asthma exacerbation was
more pronounced in autumn (r=0.67) or when temperatures were higher than average.
A meteorological index of air stagnation was found to be associated with daily visits
to the emergency department for asthma in two urban areas in North America [88].
Data on daily values of a stagnation persistence index and visits to the emergency
department for asthma were collected for y2 yrs in Spokane, and for 15 months in
Seattle, WA, USA. The stagnation persistence index represents the number of hours
during the 24-h day when surface wind speeds are less than the annual hourly median
value, an index readily available for most urban areas. Associations between the daily
stagnation persistence index and daily emergency department visits for asthma were
tested using a generalised additive Poisson regression model. A factor analysis of
particulate matter (PM2.5) composition was performed to identify the pollutants
associated with increased asthma visits. The relative rate of the association between a
visit to the emergency department for asthma and the stagnation persistence index
was 1.12 (95% CI: 1.05–1.19) in Spokane and 1.21 (1.09–1.35) in Seattle for an increase
of 11 and 10 h, respectively, of low wind speed in a given day. Increased air stagnation
was shown to be a surrogate for accumulation of the products of incomplete combustion,
including CO and fine particulate levels of organic and elemental carbon, and was more
strongly associated with asthma aggravation than any one of the measured pollutants.
Care is needed when interpreting time-series models, which should clearly report
how the confounding variables have been modelled. Indeed, Spanish investigators [89]
have examined different methods of controlling for asthma epidemics in the time-series
regression of the relationship between air pollution and asthma emergency room visits
in Barcelona. Such a relationship was modelled using autoregressive Poisson models. The
effect of using no control by epidemics, and modelling asthma epidemics was examined with
a single dummy variable, six dummy variables, and a dummy variable for each epidemic
day. Air pollution coefficients increased when controlling asthma epidemics with six dummy
variables instead of a single variable. They further increased when autocorrelation was
allowed for. Standard errors were relatively unaffected when either the epidemics or the
autocorrelation were included in the model. Black smoke, NO2 and O3 were significantly
associated to asthma emergency visits after using six dummy variables to control for asthma
epidemics. Thus, different models, including different confounding variables, may give
markedly different estimates of the effect of a pollutant on health.
Semi-experimental studies
Most evidence of health effects of air pollution comes from studies that have
evaluated, either cross-sectionally, retrospectively or prospectively, the associations of
9
increased levels of air pollutions with health outcomes. From these, speculations have
been drawn on the possibility of preventing mortality and morbidity by abating pollution
levels. Instead, few investigators have been able to study the effects of situations in which
reductions of pollution levels were accomplished due to some man-made interventions.
Pope [90] studied the effects of the closure of a steel mill (the only important source of
particulate in an area of the Utah Valley, USA), because of a long strike. A decrease
in particulate pollution and respiratory hospital admissions was found. Jaakkola et al.
[91] in South Karelia, Finland, assessed the health effects of emission reduction of
malodorous sulphur compounds in a prospective cohort study with a controlled natural
experiment. In the severely polluted community, the annual ambient air concentration
of total reduced sulphur compounds decreased from 11 mg?m-3 to 6 mg?m-3. Compared
with the nonpolluted community, the relative decrease in acute respiratory infections,
adjusted for a change in smoking habits, was 0.53 episodes per person per year (95% CI:
0.22–0.83) in the severely polluted community and 0.36 episodes per person per year
(0.06–0.66) in the moderately polluted community. In addition, the frequency of nasal
symptoms and cough decreased significantly. Another interesting example occurred
in Dublin, Eire [92] where the Government introduced a ban to marketing, sale and
distribution of "bituminous coal" that resulted in a 65% reduction in average smoke
levels for the three winters after the ban. For such a period, with respect to the three
winters before the ban, total and respiratory mortality were estimated to have decreased
by 1.6% and 13.1%, respectively. The analogous values for those w75 yrs of age were
5.8% and 15.7%, respectively.
A peculiar "controlled" situation occurred in Germany [93, 94] after reunification. The
important social and environmental variations were related to the data on respiratory
conditions, assessed by consecutive prevalence studies conducted with the same methodology. It was possible to compare data between the two areas and the time trend in
East Germany (where the variations occurred). This "natural experiment" has provided
important information about the natural history of asthma and allergy.
A particular situation of environmental-related asthma was described in Spain [95–98].
Asthma outbreaks due to the inhalation of soybean dust released from handling of
soybean in the city harbour occurred in Barcelona, Spain from 1981–1987. The
installation of bag filters in the faulty silo was followed by a substantial reduction of
airborne soybean dust released into the atmosphere and the disappearance of asthma
outbreaks. A study was undertaken to assess the relevant outcomes in asthma patients
affected by soybean epidemic asthma 8 yrs after this environmental intervention. A
repeat case-control study was performed in 1995 on a population of subjects with
epidemic and nonepidemic asthma previously assessed in 1989. The same protocol was
used in both surveys to collect data from patients via a questionnaire, and respiratory
function, skin and laboratory tests were performed under blinded conditions with regard
to epidemic and nonepidemic status. Environmental soybean allergen in pollution filters
was measured by means of a radioallergosorbent test inhibition technique. During 1995–
1996 the 24-h mean airborne levels of soybean allergen on a sample of 39 unloading days
(range: 31–269 mg?m-3) were systematically below the lowest level ever detected during an
epidemic day (1500 mg?m-3). Measurable levels of serum immunoglobulin E antibodies
against soybean were still present in 55% of patients with epidemic asthma compared
with 6.0% of those with nonepidemic asthma (pv0.05). These proportions were almost
identical to those observed in 1989. The proportion of patients with soybean asthma with
symptoms in 1989 who reported the absence of symptoms in 1995 was similar to the
control subjects, so most of the RRs of improvement were near to 1.0. The only
statistically significant differences observed between the two groups were that a smaller
proportion of patients with epidemic asthma showed improvement, in terms of being
woken up by attacks of coughing (RR improvement 0.47; 95% CI: 0.22–0.99), and the
10
need for treatment at the emergency room decreased (0.63; 0.41–0.96). Thus, 8 yrs after a
large reduction in the levels of airborne soybean allergen, one-half of the former soybean
epidemic asthma patients were still sensitised to soybean. These results indicate an initial
improvement in soybean epidemic asthma in the 2 yrs following the intervention with no
further improvement in subsequent years, i.e. a condition similar to occupational asthma.
Very recently, Friedman et al. [99] were able to assess the impact of city-wide
transportation changes on air quality and childhood asthma during the Summer Olympic
Games in Atlanta, GA, USA. This ecological study compared the 17 days of the
Olympic Games to a baseline period consisting of 4 weeks before and 4 weeks after the
Olympic Games. Peak weekday morning traffic counts and peak daily O3 concentrations
decreased 22.5% and 27.9% (from 81.3 to 58.6 parts per billion), respectively. In addition,
PM10 concentrations showed a 16.1% decrease (from 36.7 to 30.8 mg?m-3). The number
of acute care events decreased 41.6–44.1% in a health insurance database, 11.1% in a
pediatric emergency department and 19.1% in hospital discharges. These data provide
support for efforts to reduce air pollution and improve health via reductions in motor
vehicle traffic.
Conclusion
Respiratory mortality and hospital admissions due to respiratory disease are strongly
related to the previous days levels of air pollutants. This relationship has been confirmed
by many studies in many different locations and has recently been investigated in the
APHEA project in 17 European cities. Since the London smog episode in 1952, the
discussion is ongoing whether mortality occurring in episodes is additional to what
would occur anyway, i.e. whether pollution has an effect only on persons who would
have been dying otherwise on the next days or whether it influences the total mortality
over a longer period.
People living in places with higher pollution levels, beside higher prevalences of
respiratory symptoms/diseases, have a reduced life expectancy [28, 35, 100], a greater
effect than would be expected from the short-term, time-series analyses. Lung function
has been shown to be one of the best predictors of mortality in the Framingham study
[101], and the relationship of air pollution with lung function has been described in terms
of development of chronic lung disease from continuous exposure to different pollutants
[27, 29, 37, 102].
It should be pointed out that clinically "small" effects of air pollution on FVC may
have a large public health impact. KÜNZLI et al. [103] calculated, based on the data
provided by the cross-sectional "Study on air pollution and lung diseases in adults", that
for an increase of 10 mg?m-3 in the annual mean of PM10, the percentage of subjects with
an FVC v70% predicted would increase from 5% to 8%.
Respiratory physicians, as well as public health professionals, should advocate for a
cleaner environment through the dissemination of knowledge about the respiratory
effects of outdoor air pollution. This could help to protect susceptible individuals as well
as to develop strategies to abate the sources.
Summary
This review of air pollution epidemiology methods and findings has focused on aspects
of exposure definition and selection of study design. Evidence about the long-term
11
consequences of air pollution in terms of mortality and morbidity is described.
Regarding short-term effects, both time-series studies on routinely collected statistics
and panel studies on individuals are quoted. Also cited are some semi-experimental
studies that have demonstrated beneficial effects of air pollution reduction. Overall,
there is evidence that air pollution is one of the major environmental risk factors for
the occurrence and/or the exacerbation of chronic respiratory conditions. Respiratory
physicians, as well as public health professionals, should advocate for a cleaner
environment through the dissemination of knowledge about the respiratory effects of
outdoor air pollution. This can help to protect susceptible individuals as well as to
develop strategies to abate the sources.
Keywords: Asthma, chronic obstructive pulmonary disease, epidemiology, lung
function, outdoor air pollution, respiratory symptoms.
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16

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