Associa ion o en i onmen al noise exposu e wi h co isol le els in child en
om eigh Eu opean bi h coho s
Ane A egi
a,b,*
, Oli e Robinson
c,d
, Gunn Ma i Aas ang
e
, Sand a And usai y e
,
Aud ius Dedele
, Jo unn E and
e
, Gonzalo Ga cia-Baque o
a,b,g
, No un Hje age K og
e
,
M`
onica Guxens
h,i,j,k,u
, Vincen W.V. Jaddoe
l,m
, Ma ianna Ka achaliou
g,n
,
Ai ana Le xundi
b,j,o
, Ka e ina Ma ge aki
n
, Rosema y McEachan
p
, Ma k Nieuwenhuijsen
g,h,j
,
Clai e Philippa
q
, Osca J. Pozo
, Remy Slama
q
, Mikel Subiza-P´
e ez
a,b,j,p
,
Elisabe h F.C. an Rossum
s,
, Ma ine V ijheid
g,h,j
, John W igh
p
, Ti any C. Yang
p
,
Osca Vegas
a,b
, Ne ea Le xundi
a,b,j
a
Facul y o Psychology, Uni e si y o he Basque Coun y (UPV/EHU), San Sebas ian, Spain
b
En i onmen al Epidemiology and Child De elopmen G oup, Biogipuzkoa Heal h Resea ch Ins i u e, San Sebas ian, Spain
c
Medical Resea ch Council Cen e o En i onmen and Heal h, School o Public Heal h, Impe ial College London, London, Uni ed Kingdom
d
Mohn Cen e o Child en’s Heal h and Well-being, School o Public Heal h, Impe ial College London, London, Uni ed Kingdom
e
Depa men o Ai Quali y and Noise, No wegian Ins i u e o Public Heal h, Oslo, No way
Depa men o En i onmen al Sciences, Facul y o Na u al Sciences, Vy au as Magnus Uni e si y, Kaunas, Li huania
g
Facul y o Biology, Uni e si y o Salamanca, Campus Miguel de Unamuno, Salamanca, Spain
h
ISGlobal, Ba celona, Spain
i
Uni e si a Pompeu Fab a (UPF), Ba celona, Spain
j
Spanish Conso ium o Resea ch on Epidemiology and Public Heal h (CIBERESP), Ins i u o de Salud Ca los III, Mad id, Spain
k
Depa men o Child and Adolescen Psychia y/Psychology, E asmusMC, Uni e si y Medical Cen e , Ro e dam, he Ne he lands
l
Depa men o Pedia ics, E asmusMC, Uni e si y Medical Cen e , Ro e dam, he Ne he lands
m
The Gene a ionR S udy G oup, E asmus MC Uni e si y Medical Cen e , Ro e dam, he Ne he lands
n
Clinic o P e en i e and Social Medicine, Medical School, Uni e si y o C e e, C e e, G eece
o
Facul y o Medicine, Uni e si y o he Basque Coun y (UPV/EHU), San Sebas ian, Spain
p
B ad o d Ins i u e o o Heal h Resea ch, B ad o d Teaching Hospi als NHS Founda ion T us , B ad o d, Uni ed Kingdom
q
Uni e si y G enoble Alpes, Inse m U 1209, CNRS UMR 5309, Team o En i onmen al Epidemiology Applied o he De elopmen and Respi a o y Heal h, Ins i u e o
Ad anced Biosciences, 38000, G enoble, F ance
Applied Me abolomics Resea ch G oup, Hospi al del Ma Resea ch Ins i u e, 08003, Ba celona, Spain
s
Depa men o In e nal Medicine, Di ision o Endoc inology, E asmus MC, Uni e si y Medical Cen e Ro e dam, Ro e dam, he Ne he lands
Obesi y Cen e CGG, E asmus MC, Uni e si y Medical Cen e Ro e dam, Ro e dam, he Ne he lands
u
ICREA, Ba celona, Spain
ARTICLE INFO
Keywo ds:
En i onmen al noise
Child en
Hai co isol concen a ion
U ine co isol concen a ion
ATHLETE p ojec
ABSTRACT
En i onmen al noise is a majo en i onmen al isk ac o o public heal h. Acco ding o he noise eac ion model
he elease o s ess ho mones like co isol in esponse o noise exposu e, plays a key ole in he de elopmen o
noise-induced heal h e ec s. We aimed o s udy he associa ion be ween en i onmen al noise wi h bo h acu e
(UCC) and cumula i e (HCC) co isol le els in child en 5–12 yea s o age. To do so, we analysed da a om he
HELIX coho –wi h spo UCC da a- and om he Gene a ion R and INMA coho s (Gipuzkoa and Sabadell) –wi h
HCC da a. The analy ical sample in ol ed: 750 HELIX child en (mean age =7.75), 1326 Gene a ion R child en
(mean age =6.06), 111 INMA-Sabadell child en (mean age =8.75) and 288 INMA-Gipuzkoa child en (mean age
=7.85). Day-e ening-nigh equi alen (L
den)
en i onmen al noise exposu e du ing he yea o he ollow-up was
Abb e ia ions: BM, Body Mass Index; CBCL, Child Beha iou Checklis ; DAG, Di ec ed acyclic g aph; HCC, hai co isol concen a ion; HPA, hypo halamic-pi-
ui a y-ad enal; LC-MS/MS, liquid ch oma og aphy- andem mass spec ome y; L
den
, day-e ening-nigh noise indica o ; NDVI, No malized Di e ence Vege a ion
Index; RIA, adioimmunoassay; UCC, u ine co isol concen a ion.
* Co esponding au ho . Facul y o Psychology, Uni e si y o he Basque Coun y (UPV/EHU), San Sebas ian, Spain.
E-mail add ess: [email p o ec ed] (A. A egi).
Con en s lis s a ailable a ScienceDi ec
En i onmen al Resea ch
jou nal homepage: www.else ie .com/loca e/en es
h ps://doi.o g/10.1016/j.en es.2025.121541
Recei ed 7 No embe 2024; Recei ed in e ised o m 18 Ma ch 2025; Accep ed 3 Ap il 2025
En i onmen al Resea ch 277 (2025) 121541
A ailable online 7 Ap il 2025
0013-9351/© 2025 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY-NC-ND license ( h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/ ).
es ima ed in he add esses o pa icipan s, using exis ing noise maps. Di ec ed acyclic g aphs (DAGs) we e used
o iden i y app op ia e co a ia es and educe he chance o biased es ima ion. We used mixed-e ec s modelling
and linea modelling o examine he associa ion be ween L
den
and co isol concen a ion using comple e case
analyses. None o he models eached he s a is ical signi icance. We obse ed no co ela ion be ween HCC and
UCC in INMA-Sabadell pa icipan s, o whom bo h u ina y and hai co isol da a we e a ailable. Fu u e esea ch
should p io i ize in es iga ing he e ec s o en i onmen al noise on HCC, as i may se e as a mo e eliable
indica o o assessing associa ions wi h ch onic exposu es. Addi ionally, u u e s udies on noise-induced heal h
e ec s in child en should inco po a e o he bioma ke s o s ess and ch onic in lamma ion o p o ide a mo e
comp ehensi e unde s anding o hese associa ions.
1. In oduc ion
En i onmen al noise is a ubiqui ous u ban exposu e and i is
conside ed a majo en i onmen al isk ac o o public heal h
(Eu opean En i onmen Agency, 2020), and con ibu es o a wide ange
o ad e se heal h e ec s such as noise annoyance, sleep dis u bances,
ca dio ascula and me abolic diseases, and cogni i e impai men as
shown in p e ious li e a u e (Cla k and Pauno ic, 2018; Guski e al.,
2017; Smi h e al., 2022; an Kempen e al., 2018; Vienneau e al.,
2019). The knowledge o he mechanis ic pa hway unde lying
noise-induced heal h e ec s has been conside ably s eng hened he las
decade (Sø ensen e al., 2024). Exposu e o noise igge s a p ima y
s ess eac ion: he ac i a ion o hypo halamic-pi ui a y-ad enal (HPA)
axis and he sympa he ic ne ous sys em (Daibe e al., 2019). The HPA
axis is one o he main biological sys ems ha manages he s ess
esponse, and i s ac i a ion causes he elease o s ess ho mones, such
as co isol. Hence, co isol has been equen ly used as a bioma ke o
s ess, as i pa icipa es in he esponse o acu e and ch onic bio-
psychosocial s esso s (Adam e al., 2017). In an acu e s ess eac ion,
he inc eased p oduc ion o co isol by he ad enal glands p o ides
immedia e ene gy o muscles, he b ain and o he i al o gans o
espond o he s esso ( an de Valk e al., 2018). These ele a ed
co isol le els also se e as a nega i e eedback mechanism, es o ing
basal le els o s ess ho mones (He man e al., 2016). Howe e , in cases
o ch onic s ess, dys unc ion in he HPA axis occu s, and bu e ing
mechanisms become insu icien o e u n o baseline condi ions. This
physiological phenomenon is known as allos a ic load and has been
associa ed wi h se e al de imen al heal h ou comes, such as inc eased
isk o ca dio ascula diseases and diabe es, cogni i e impai men and
men al heal h p oblems (Guidi e al., 2021; Mc Ewen, 1998). Se e al
ac o s may ac as a s esso ac i a ing HPA axis and simul aneous
in e ela ionship be ween mul iple a iables may a ec le els o s ess
ho mones: he physical en i onmen al su ounding such as noise
exposu e, g een spaces o ai pollu ion such as noise exposu e, g een
spaces o ai pollu ion, social and amilial ela ionships, ea ly li e
s ess ul condi ions and indi idual cha ac e is ics (A egi e al., 2024).
Al hough nume ous s udies poin ou he nega i e e ec ha psy-
chosocial s esso s ha e on he physical and men al heal h o child en
(Ca lsson e al., 2014), he scien i ic li e a u e on he e ec s o noise on
child en is sca ce. Co isol le els ha e been s udied as indica o o acu e
s ess esponses o en i onmen al noise. In ha ein, mos o he s udies
ha e measu ed co isol in sali a o u ine samples (Hellhamme e al.,
2009). Ne e heless, his app oach in o ms abou sho - e m co isol
le els, while hai co isol concen a ion (HCC) has been p oposed as a
alid me hod o assess ch onic s ess and HPA axis ac i i y (Ki schbaum
e al., 2009; S alde e al., 2017) and i is conside ed a iable ool o
s udying he ela ion be ween en i onmen al noise exposu e and cu-
mula i e s ess (Dopico e al., 2023; Michaud e al., 2022). To he bes o
ou knowledge, only wo s udies ha e ocused on he ela ion be ween
en i onmen al noise and HCC. One o hese, ound no associa ion be-
ween esiden ial exposu e o a ic noise and HCC in 14–15-yea -old
adolescen s (Ve heyen e al., 2021). The o he s udy wi h child en aged
11 yea s, highe exposu e o en i onmen al noise was associa ed wi h
lowe HCC. Mo eo e sex-s a i ica ion e ealed ha his ela ion was
only ound in boys (A egi e al., 2024).
Rega ding sho - e m co isol le els, many s udies ha e ound
en i onmen al noise o impac on co isol le els, measu ed in u ine o
sali a. Some s udies wi h adul s showed ele a ed sali a y co isol le els
in hose li ing nea ai po s (Baudin e al., 2019; Le `
e e e al., 2017;
Selande e al., 2009). None heless, a sleep labo a o y s udy ound no
signi ican in luence o ai c a noise on u ina y co isol (Maass and
Basne , 2006). In addi ion, a sys ema ic e iew concluded ha oad
a ic noise was ela ed o highe u ina y o sali a y co isol le els
(Hohmann e al., 2013). S udies ega ding he e ec o en i onmen al
noise on acu e co isol le els in child en, howe e , showed inconsis en
esul s. Some o hem showed highe co isol le els in child en li ing in
noisie a eas (E ans e al., 2001; Ising and Ising, 2002; Ising, 2003)
while o he s obse ed no associa ion (Bloemsma e al., 2021; E ans
e al., 1998; Haines e al., 2001; Wallas e al., 2018).
Gi en he disc epancies in p e ious li e a u e on he associa ion o
en i onmen al noise exposu e and co isol le els in child en, he main
objec i e was o s udy he associa ion be ween en i onmen al noise
exposu e and s ess esponse in child en, as indica ed by bo h sho - e m
(u ina y co isol concen a ion, UCC) as well as cumula i e (HCC)
co isol. We hypo hesized ha noise exposu e as an en i onmen al
s esso may inc ease bo h acu e and ch onic co isol le els in child en.
2. Me hods
2.1. Pa icipan s
This s udy is based on he Ad ancing Tools o human Ea ly Li e-
cou se Exposome Resea ch and T ansla ion (ATHLETE) p ojec (V ijheid
e al., 2021). Speci ically, we included da a om hose coho s wi h
a ailable co isol concen a ion da a du ing childhood. We used da a
om he Gene a ion R coho (Jaddoe e al., 2006), he Gipuzkoa and
Sabadell IN ancia y Medio Ambien e coho (Guxens e al., 2012)
(INMA), Bo n in B ad o d (McEachan e al., 2024) (BiB), ´
E ude des
D´
e e minan s p ´
e e pos na als p ´
ecoces du d´
e eloppemen e de la san ´
e
de l’EN an (Heude e al., 2016) (EDEN) he Kaunas bi h coho
(G azule iciene e al., 2015) (KANC) The No wegian Mo he , Fa he and
Child Coho S udy (Magnus e al., 2016) (MoBa) and he Rhea
mo he -child coho (Cha zi e al., 2017). The la e six coho s
(INMA-Sabadell, BiB, EDEN, KANC, MoBa and Rhea) a e pa icipan s
om he Human Ea ly-Li e Exposome (HELIX) subcoho . The HELIX
subcoho is based on six bi h coho s udies h oughou Eu ope and
implemen ed a common ollow-up isi when child en we e 6–11 yea s
old. Fu he de ails ega ding he selec ion and cha ac e is ics o he
HELIX subcoho can be ound in Mai e e al. (2018).
We eques ed da a om he HELIX subcoho ollow-up, he 5-yea -
old ollow-up om he Gene a ion R s udy, and he 8-yea -old ollow-up
om he INMA-Gipuzkoa s udy. Fo he analyses p esen ed in his
manusc ip , we included only pa icipan s wi h comple e da a o he
s udy a iables (see Fig. 1). App o al was ob ained om he e hics
commi ees in e e y si e and all pa icipa ing mo he s p o ided
in o med w i en consen .
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
2
2.2. En i onmen al noise exposu e
The noise exposu e assessmen was based on exis ing noise maps
de eloped unde he amewo k o he Eu opean Noise Di ec i e, END
(Di ec i e 2002/49/EC, 2002) in cases he e we e a ailable. Ou doo
annual a ic noise le el noise maps we e a ailable o all cases bu
INMA-Gipuzkoa, and Rhea. Fo he es o he coho s (Gene a ion R,
INMA-Sabadell, BiB, EDEN, KANC and MoBa), exis ing maps we e u i-
lized. A new noise map o Rhea was de eloped by ISGlobal, ollowing
same me hodology speci ied in he END and using da a om a a ic
moni o ing campaign conduc ed as pa o he EXPOsOMICS p ojec (de
Cas o e al., 2021). En i onmen al noise exposu e o hese coho s was
calcula ed a each pa icipan ’s geocoded add ess du ing he yea p io
o he ollow-up. The noise le els we e de e mined based on he ype o
a ailable noise map. I noise laye ype was “line”, he closes s ee was
used o assess noise alues, like he app oach aken o INMA Sabadell
and Rhea coho s. In he o he cases, whe e he laye ype was polygon
o as e , an in e sec ion be ween noise maps and geocodes was pe -
o med o es ima e noise le els a each pa icipan ’s esiden ial add ess
a he ime o he ollow-up (Esse s e al., 2022; P´
e ez-C espo e al.,
2024; Robinson e al., 2018).
In he case o INMA-Gipuzkoa, he s udy a ea is less u banized,
consis ing o small owns wi h popula ions below 15,000 inhabi an s.
Howe e , in he Basque Coun y, he egion whe e he INMA-Gipuzkoa
coho is se , egional egula ions equi e ha all local councils wi h a
popula ion exceeding 10,000 mus c ea e a noise map (Dec ee
213/2012, 2012). Mo eo e , as pa o he INMA p ojec , noise maps o
municipali ies wi h be ween 6000 and 10,000 inhabi an s we e
compiled using he same me hodology. Da a om 2019 was used o
ob ain he o al en i onmen al noise exposu e, whe e a ic noise,
ailway noise and indus y was conside ed. These maps illus a e he
le els o sound immissions on building açades: calcula ion poin s a e
posi ioned a a heigh o 4 m. The p ocedu e in ol es calcula ing he
noise le el ha eaches a speci ic ecep o om noise sou ces men ioned
abo e. Geocoded esiden ial add esses we e u ilized o es ima e he
en i onmen al noise exposu e o each pa icipan .
In all he cases, we calcula ed he day-e ening-nigh noise indica o
(L
den
). L
den
ep esen s he A-weigh ed a e age sound le el o e a 24-h
pe iod, inco po a ing penal ies o he e ening (+5 dB) and nigh
(+10 dB) pe iods. This app oach, ecommended by he En i onmen al
Noise Di ec i e, aims o accoun o he heal h impac s ela ed o noise
exposu e du ing he e ening and nigh ime hou s. Noise exposu e was
calcula ed om L
den
55 dB and in 5 dB ca ego ies. E en i L
nigh
was also
a ailable, L
den
was only used in his s udy, as bo h a iables we e
s ongly associa ed in all cases, as indica ed by he Chi-squa e es s (p <
0.001, C am´
e ’s V =0.74–0.84)
2.3. Co isol
Among he eigh coho s wi h a ailable co isol concen a ion da a,
some measu ed co isol in u ine, while o he s collec ed i om hai
samples. Hai co isol concen a ion (HCC) was a ailable o Gene a ion
R and INMA coho s, bo h Gipuzkoa and Sabadell cen es. U ina y
co isol concen a ion (UCC) was a ailable in he case o he HELIX
coho s (BiB, EDEN, INMA Sabadell, KANC, MoBa, and Rhea). Bo h
samples we e collec ed du ing he ollow-up pe iod. I is no ewo hy
ha bo h se s o da a we e a ailable only o pa icipan s om INMA-
Sabadell.
2.3.1. Hai co isol concen a ion (HCC)
T ained s a collec ed hai samples om he pos e io e ex a ea o
he pa icipan s’ heads ollowing he guidelines o he Socie y o Hai
Tes ing (Coope e al., 2012), and hen s o ed a oom empe a u e un il
analysis. The ini ial 3 cm o hai g ow h was examined o co isol
concen a ion, which se es as an indica o o a e age HPA axis ac i i y
o e he pas weeks o mon hs (Colding-Jø gensen e al., 2023). Fo he
INMA-Gipuzkoa coho , analysis was conduc ed a he Clinical Chem-
is y Labo a o y o he Uni e si y o Link¨
oping in Sweden using a
compe i i e adioimmunoassay (RIA) on me hanol ex ac s. Fu he
explana ion on his me hodology can be ound elsewhe e (Ka l´
en e al.,
Fig. 1. Flowcha depic ing he coho s included in he s udy and co isol measu emen in each case.
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
3
2013). In he INMA-Sabadell coho hai co isol analysis we e pe -
o med a he Hospi al del Ma Resea ch Ins i u e using liquid
ch oma og aphy- andem mass spec ome y (LC-MS/MS) as explained
by Gomez-Gomez and Pozo (2020). LC-MS/MS was also used o hai
sample analysis in he Gene a ion R coho , as explained by Noppe e al.
(2015). I is wo h no ing ha RIA analysis p oduces 2–3 imes highe
co isol le els ha LC-MS/MS analysis, as explained by Russell e al.
(2015) in he in e labo a o y analysis.
2.3.2. U ina y co isol concen a ion (UCC)
Co isol and ela ed me aboli es we e measu ed in u ine samples.
One u ine sample was collec ed du ing he las oid be o e bed ime on
he nigh p eceding he clinical isi o minimise he in luence o diu nal
a ia ion. These samples we e analysed in he Hospi al del Ma Resea ch
Ins i u e ollowing he p o ocol desc ibed in Ma cos e al. (2014), by
liquid ch oma og aphy- andem mass spec ome y (LC-MS/MS)B ie ly,
a e addi ion o iso opic labelled in e nal s anda d, an enzyma ic hy-
d olysis was pe o med o elease he conjuga ed me aboli es. Released
s e oids we e hen ex ac ed by liquid-liquid ex ac ion and de e mined
by LC-MS/MS using a selec ed eac ion moni o ing me hod. Fu he -
mo e, he o e all co isol p oduc ion was assessed by adding se e al
co isol me aboli es, which we e no malized based on c ea inine alues
(di ided by he c ea inine alues wi hin each sample): Co isol,
20
α
-dihyd oco isol, 20β-dihyd oco isol, 5β-dihyd oco isol, 5
α
- e a-
hyd oco isol, 5β- e ahyd oco isol, 6β-hyd oxyco isol, 5
α
,20
α
-co ol,
5
α
,20β-co ol, 5β,20
α
–co ol and 5β,20β–co ol. The o e all co isol
concen a ion ep esen s he o al co isol p oduc ion and i is p e e ed
o use in analysis o e co isol alone (Le ine e al., 2007)
2.4. O he assessed a iables
Based on he li e a u e, a se o en i onmen al, social and indi idual
co a ia es we e selec ed because o hei po en ial ela ionships wi h
exposu e o noise and/o co isol concen a ions. Rega ding en i on-
men al ac o s, neighbou hood g eenness and ai pollu ion we e
included. Neighbou hood g eenness was assessed using No malized Di -
e ence Vege a ion Index (NDVI; Tucke , 1979) de i ed om he
Landsa 4–5 Thema ic Mappe (TM), Landsa 7 Enhanced Thema ic
Mappe Plus (ETM+), and Landsa 8 Ope a ional Land Image (OLI)/-
The mal In a ed Senso (TIRS) wi h 30 m ×30 m esolu ion a 30 m ×
30 m esolu ion. NDVI, an indica o o g eenness, measu es he di e -
ence be ween isible ( ed) and nea -in a ed ligh e lec ed by ege a-
ion. I s alues all wi hin he ange o −1 o 1, whe e highe alues
indica e inc eased g eenness. Su ounding g eenness was abs ac ed as
he a e age o NDVI in 300 m bu e a ound each geocoded esiden ial
add ess o e he las yea when he ollow-up phase was conduc ed. Two
o mo e images we e selec ed o each coho o co e he ime poin s o
in e es .
T a ic ela ed ai pollu ion was es ima ed by ni ogen dioxide (NO
2
)
exposu e. Indi idual NO
2
exposu e a each pa icipan ’s geocoded es-
iden ial add ess du ing he pas yea o he ollow-up phase was es i-
ma ed using a land use eg ession (LUR) models. In he case o HELIX
coho s, exposu e assessmen is based on LUR modelling app oach
de eloped in he Eu opean S udy o Coho s o Ai Pollu ion E ec s
(ESCAPE) amewo k (Beelen e al., 2013). In case o Gipuzkoa and
Gene a ion R, exposu e es ima ion a each pa icipan ’s geocoded esi-
den ial add ess was es ima ed wi hin he amewo k o he Li eCycle
p ojec (Jaddoe e al., 2020). B ie ly, o es ima e exposu e le els o he
ele an pe iod empo al adjus men was applied, by combining
LUR-based spa ial es ima es wi h a empo al adjus men ac o om
ou ine moni o ing s a ions, ollowing ESCAPE guidelines (Hoek e al.,
2008).
Rega ding social ac o s neighbou hood SES was desc ibed using
coun y speci ic dep i a ion indexes and ha monized ollowing Ly e-
cycle p o ocol (de Cas o e al., 2021). Speci ically, o he Gene a ion R
coho S a us sco es we e used, o INMA coho s U ban ulne abili y
index, o BiB we used he Index o Mul iple Dep i a ion, F ench Eu o-
pean dep i a ion index sco e o EDEN. In he case o KANC and Rhea
dep i a ion index was calcula ed based on educa ional le el and o
MoBa i was measu ed based on income. Be ween one and ou laye s
we e selec ed o each coun y o co e he en i e s udy pe iod and we e
assigned o co espond wi h he ollow-up pe iod. Finally i was ca e-
go ized hem in o e iles, whe e 1 means less dep i ed and 3 mo e
dep i ed.
Se e al indi idual ac o s we e also selec ed. Body Mass Index (BMI)
was de e mined by di iding child en’s weigh in kilog ams by he squa e
o hei heigh in me e s (kg/m
2
) a he ime o he ollow-up. In he
p esen s udy, z-sco es p oposed by he Wo ld Heal h O ganisa ion we e
used (WHO, 2006).
Ex e nalizing p oblems and sleep dis u bances we e e alua ed using he
Child Beha iou Checklis (CBCL (Achenbach and Resco la, 2001). The
CBCL is a widely alida ed and eliable ins umen o assessing
emo ional and beha iou al p oblems (Achenbach and Ru le, 2000). A
he ime o he ollow up, he p ima y ca egi e a ed on a h ee-poin
scale (No T ue, Somewha T ue, Ve y/O en T ue) 113 i ems o assess
beha iou al p oblems in child en du ing he las wo mon hs. This o al
sco e can be subdi ided in o se e al subscales: we used ex e nalizing
beha iou sco e, which is he combina ion o he ule-b eaking beha -
iou and agg essi e beha iou scales. To al aw sco e in hese scales was
used, highe sco es indica ing mo e ex e nalizing p oblems (lowes
sco e: 0, highes sco e: 38). Fu he , we also employed he i ems om
he CBCL e e ing o sleep p oblems: 47, nigh ma es; 54, o e i ed
wi hou good eason; 76, sleeps less han mos kids; 77, sleeps mo e han
mos kids du ing day and/o nigh ; 92, alks o walks in sleep; 100,
ouble sleeping and 108, we s he bed. These i ems we e added o
ob ain o al sleeping p oblems wi h highe sco es indica ing g ea e
sleep p oblems ( ange 0–8). P e ious s udies employed hese i ems o
es ima e sleeping p oblems in child en (Gonz´
alez-Sa on e al., 2023;
G ego y e al., 2008) hey showed ema kable con e gen alidi y, as
hei sco es highly co ela ed wi h exis ing sleep scales (Mancini and
Pea cy, 2021) and objec i e measu emen s (G ego y e al., 2011).
Finally, pa en - epo ed in o ma ion on physical ac i i y was ga h-
e ed h ough a ques ionnai e illed ou by he main ca egi e . Fo HELIX
and INMA-Gipuzkoa pa icipan s a alida ed ques ionnai e designed o
assess physical ac i i y in child en aged 6–12 yea s was u ilized
(P ie o-Bo ella e al., 2022). In his ques ionnai e, pa en s speci ied hei
child en’s ype o physical ac i i y and he du a ion du ing he week.
Speci ically, hey we e asked abou he ac i i ies ha hei child
engaged in bo h a school and ou side o school hou s du ing a ypical
week in he pas yea . These ac i i ies we e classi ied as ligh (playing,
si ing on swings, going o he hea e, e c.), mode a e (walking, cycling,
olle blading, ska ing, e c.), o igo ous (swimming, baseball, oo ball,
baske ball, e c.), based on me abolic equi alen o ask alue assigned o
e e y ac i i y. Fo Gene a ion R pa icipan s, pa en s comple ed an
ad-hoc ques ionnai e on hei child en’s physical ac i i y. The ques-
ionnai e included equency and du a ion o physical educa ion on
school, ou doo play, swimming and in o he spo s ( ennis, hockey,
dancing, baske ball, a hle ics, e c). Following p e ious s udies, he ime
spen on each ac i i y was calcula ed as hou s pe day x days pe week
and o al physical ac i i y by adding hou s in each ac i i y
(Rod iguez-Ayllon e al., 2020, 2023). In bo h cases we ocused on he
o al minu es pe day o mode a e o igo ous physical ac i i y, calcu-
la ed by combining he du a ion o mode a e and igo ous ac i i ies.
2.5. Da a analysis
Da a we e analysed using R so wa e .4.0.3 (R Co e Team, 2022).
A e compu ing desc ip i e s a is ics, we ollowed a h ee-s ep p ocess
o de e mine he co a ia es o inclusion in he eg ession models. All
he analyses we e independen ly applied o UCC and HCC analyses. In
he la e case, we also sepa a ed he analysis o HCC measu ed by RIA
and LC-MS/MS. Fi s , we p oposed a Di ec Acyclic G aph (DAG)
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
4
adap ed om a p e ious s udy based on he hai co isol de e minan s in
child en (A egi e al., 2024) (see Fig. 2). Second, he alidi y o he DAG
was assessed ollowing he p ocedu e desc ibed elsewhe e (Ankan e al.,
2021; Subiza-P´
e ez e al., 2023): we used R package dagi y (Tex o ,
2020; Tex o e al., 2016) and la aan (Rosseel, 2012). Tes able impli-
ca ions e e o he pai wise ma ginal and condi ional independencies
in e ed om a DAG. Condi ional independencies we e assessed using
he mos app op ia e s a is ical es o each speci ic case. When he
p- alues o he independence es s we e lowe han 0.05, and he
-sco es we e la ge han 0.20, es able implica ions we e conside ed
unme , he eby sugges ing missing ela ionships ha we e subsequen ly
included in he DAG. A e alida ing he DAG, we p oceeded wi h he
las s ep: he iden i ica ion o he minimum and su icien se o a i-
ables o es ima e he e ec s o he exposu e a iable on he ou comes o
in e es (Pe ko i´
c e al., 2015; Van De Zande e al., 2014). Co a ia e
adjus men se s we e ob ained using he unc ion adjus men Se s () o
he R package dagi y.
All he analyses we e pe o med wi h he comple e cases (analy ical
sample om now on). The e we e subs an ial missing a iables in he
en i onmen al a iables, so we conduc ed a se ies o chi-squa e es s
and Welch’s - es o de e mine i he analy ical sample di e ed om he
ini ial sample (desc ibed in Supplemen a y Tables S1–S2). S a is ically
signi ican di e ences we e obse ed be ween he ini ial sample and he
analy ical sample a e ages o he ollowing a iables: physical ac i i y,
neighbou hood g eenness and ai pollu ion. Howe e , we concluded he
analy ical sample was ep esen a i e o he ini ial sample as mean di -
e ences be ween he inal and ini ial samples we e no subs an ial.
Finally, we es ima ed he o al and di ec e ec s o L
den
on ou comes
(in his case, UCC and HCC). Fo his pu pose, L
den
was ea ed as a
con inuous a iable o ob ain mo e in e p e able esul s. Fo HCC
measu ed by LC-MS/MS analysis and we applied mixed-e ec s model-
ling wi h he unc ion lme () o he R package nlme (Pinhei o e al.,
2022) wi h <coho >as a andom ac o and he iden i ied se s o
co a ia es as adjus men se s. Fo he sample wi h HCC measu ed by RIA
(INMA-Gipuzkoa coho ), linea modelling was applied.
3. Resul s
3.1. Sample desc ip ion and DAG alida ion
Table 1 con ains desc ip i e s a is ics o he s udy a iables in he
analy ical sample wi h hai co isol concen a ion (HCC), sepa a ed by
coho . The INMA-Gipuzkoa analy ical sample consis ed o 288 child en:
53.8 % we e emale and age a e age was 7.87 yea s (SD =0.11).
Rega ding he analy ical sample wi h HCC measu ed by LC-MS/MS, i
included 1326 child en om Gene a ion R (49.2 % Female, mean age =
6.06, SD =0.51) and 111 child en om INMA Sabadell (51.4 % Female,
mean age =8.75, SD =0.53).
In he INMA-Gipuzkoa coho , 61.1 % o he child en we e exposed
o noise le els exceeding 55 dB L
den
. Wi hin he analy ical sample whe e
HCC was measu ed using LC-MS/MS, 44.7 % o he pa icipan s we e
exposed o noise le els abo e 55 dB a hei esiden ial add ess. No
signi ican di e ences we e obse ed in sleep dis u bances [F (5, 282) =
0.223, p =0.952] o o al sco es on ex e nalizing p oblems [F (5, 282)
=0.322, p =0.9] ac oss di e en en i onmen al noise exposu e g oups.
Pa icipan s om he INMA-Sabadell coho we e exposed o highe
noise le els compa ed o child en in he Gene a ion R s udy. Simila o
he INMA-Gipuzkoa sample, he e we e no signi ican di e ences in
sleep dis u bances [F (5, 1431) =0.613, p =0.69] o o al sco es on
ex e nalizing p oblems [F (5, 1431) =0.435, p =0.824] among child en
in di e en en i onmen al noise exposu e g oups.
HCC le els we e highe when measu ed by RIA (median =8.75 pg/
mg) compa ed o LC-MS/MS (median =1.55 pg/mg). No di e ences in
HCC we e obse ed be ween gi ls and boys, ei he in he INMA-
Gipuzkoa subsample ( emale median: 8.20 pg/mg, male median: 8.23
pg/mg) o in he subsample analysed using LC-MS/MS ( emale median:
1.46 pg/mg, male median: 1.62 pg/mg).
All desc ip i e s a is ics o he s udied a iables in he analy ical
sample wi h u ine co isol concen a ion (UCC) a e p esen ed in Table 2,
s a i ied by coho . This analy ical sample was comp ised o 125 BiB
child en (42.4 % Female, mean age =6.60, SD =0.24), 27 EDEN
Figu e 2. DAG explaining he ela ionship be ween exposu e o en i onmen al noise and co isol. All he ela ionships we e de ined based on p e ious li e a u e.
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
5
child en (33.3 % Female, mean age =10.73, SD =0.52), 160 KANC
child en (45.0 % Female, mean age =6.45, SD =0.48), 57 Rhea child en
(47.4 % Female, mean age =6.55, SD =0.30) 198 MoBa child en (46.5
% Female, mean age =8.50, SD =0.49) and 183 INMA-Sabadell chil-
d en (42.6 % Female, mean age =8.78, SD =0.55).
52.1 % o he child en we e exposed o highe noise le els han 55 dB
L
den
, wi h s a is ically signi ican di e ences be ween coho s. The e
we e no signi ican di e ences in sleep dis u bances [F (5, 744) =0.565,
p =0.727] o o al sco es on ex e nalizing p oblems [F (5, 744) =1.797,
p =0.111] among child en in di e en en i onmen al noise exposu e
g oups.
A Pea son co ela ion analysis showed no signi ican ela ionship
be ween UCC and HCC (n =104), =0.04, p =0.707. The ANOVA
showed signi ican di e ences be ween coho s on UCC le els, [F (5,
744) =107, p =<0.01]. We did no obse e di e ences in UCC be ween
gi ls (mean =0.40
μ
g/
μ
mol c ea inine; SD =0.33) and boys (mean =
0.40
μ
g/
μ
mol c ea inine; SD =0.37). All he desc ip i e s a is ics o he
s udied a iables in he analy ical sample wi h hai co isol concen a-
ion (HCC), a e shown in Table 2, sepa a ed by coho .
In he case o he sample wi h HCC measu ed by RIA and he one wi h
UCC, none o he es able implica ions de i ed om he ini ial DAG
ob ained -coe icien s abo e 0.2 and p- alues below 0.05 (see Appendix
I). In he case o he sample wi h HCC measu ed by LC-MS/MS, he
es able implica ion “Ai Pol ⊥En Noi | NeiG e, SES” was no me ,
he eby sugges ing he exis ence o a ela ionship be ween a ic-
ela ed ai pollu ion and en i onmen al noise (once con olled o
neighbou hood g eenness and SES). We upda ed he DAG wi h his
ela ionship (see Supplemen a y Fig. 1) and iden i ied he minimum
adjus men se o co a ia es o es ima e he o al and e ec o en i on-
men al noise on co isol le els. Fo he o al e ec s, he adjus men se
included neighbou hood socioeconomic s a us and neighbou hood
g eenness. T a ic ela ed ai pollu ion was also included in he case o
he analysis wi h HCC measu ed by LC-MS/MS. Fo he di ec e ec s, he
h ee a iables men ioned abo e plus ex e nalizing p oblems, physical
ac i i y, sleep dis u bances and sex we e included.
3.2. E ec es ima ion
Table 3 shows esul s o he o al and di ec e ec s o L
den
on hai
co isol concen a ion (HCC). Rega ding he e ec on he co isol
measu ed by LC-MS, bo h he o al and di ec e ec we e non-signi ican
(β-es ima e =-0.002). In he case o he o al and di ec e ec o noise on
HCC measu ed by RIA, he β-es ima e o each 5 dB inc ease in L
den
was
abou 0.05, bu none o he models e ealed s a is ically signi ican e -
ec s. Hence, we did no obse e any s a is ically signi ican associa ion
be ween en i onmen al noise exposu e and HCC, no in he case o hai
co isol measu ed by RIA nei he in he case o LC-MS/MS analysis.
Resul s ega ding he o al and di ec e ec o L
den
on u ine co isol
concen a ion (UCC) a e also shown in Table 3. The β-es ima e o he
o al and di ec e ec o noise exposu e on UCC was - 0.025 in bo h
cases. None o he e ec s showed s a is ically signi ican associa ion.
4. Discussion
In his s udy, ou objec i e was o in es iga e he associa ion be-
ween en i onmen al noise exposu e and bo h acu e and cumula i e
co isol le els in child en om eigh Eu opean bi h coho s. The β-es-
ima es o he e ec o L
den
on hai co isol concen a ion (HCC)
measu ed by LC-MS/MS and RIA we e −0.002 and 0.05 espec i ely,
e en i none o he models eached s a is ical signi icance. Simila ly, no
signi ican associa ion was ound o u ine co isol concen a ion (UCC;
β-es ima e = − 0.025).
Rega ding ch onic co isol le els, as indica ed by hai co isol con-
cen a ion (HCC), as a as we know, only wo s udies ocused on HCC
Table 1
Desc ip i e s a is ics o he s udy a iables in he sample wi h HCC (analy ical sample). Mean (SD) is shown in he nume ic a iables and equency (%) in he ca -
ego ical ones.
Va iable name INMA-Gipuzkoa
N =288
Gene a ion R N =1326 INMA-Sabadell N =111
Mean (SD)/Feq (%) Mean (SD)/Feq (%) Mean (SD)/Feq (%)
Age 7.87 (0.11) 6.06 (0.51) 8.75 (0.53)
Sex Female 155 (53.8) 674 (50.8) 57 (51.4)
Male 133 (46.2) 652 (49.2) 54 (48.6)
A ea-le el SES Low dep i a ion 240 (83.3) 346 (26.1) 49 (44.1)
Medium dep i a ion 48 (16.7) 231 (17.4) 43 (38.7)
High dep i a ion 0 (0.0) 749 (56.5) 19 (17.1)
Ex e nalizing p oblems 5.69 (5.62) 7.02 (6.21) 6.33 (6.47)
Sleep Dis u bances 0.99 (1.19) 0.76 (1.2) 0.99 (1.44)
BMI 17.4 (2.3) 16.14 (0.17) 18.0 (3.0)
BMI (adjus ed o sex and age) 0.8 (1.05) 0.43 (0.97) 0.71 (1.14)
Physical Ac i i y (min pe day) 63.5 (46.34) 127.6 (71.04) 49.94 (35.19)
NDVI (300 m) 0.42 (0.09) 0.42 (0.1) 0.25 (0.07)
T a ic- ela ed Ai Pollu ion (NO2) 14.32 (1.69) 33.39 (6.65) 36.48 (10.82)
L
den
<55 dB 112 (38.9) 785 (59.2) 10 (9.0)
[55–60)dB 93 (32.3) 258 (19.5) 21 (18.9)
[60–65)dB 59 (20.5) 178 (13.4) 36 (32.4)
[65–70)dB 20 (6.9) 89 (6.7) 26 (23.4)
[70–75)dB 2 (0.7) 16 (1.2) 11 (9.9)
>75 dB 2 (0.7) 0 (0.0) 7 (6.3)
L
nigh
<50 dB 208 (72.2) 1018 (76.8) 28 (25.2)
[50–55)dB 54 (18.8) 184 (13.9) 38 (34.2)
[55–60)dB 22 (7.69 92 (6.9) 23 (20.7)
[60–65)dB 3 (1.0) 32 (2.4) 13 (11.7)
[65–70)dB 1 (0.3) 0 (0.0) 9 (8.1)
Hai Co isol (pg/mg) 11.10 (7.83) 4.85 (15.91) 1.65 (3.74)
U ine To al Co isol (
μ
g/
μ
mol c ea inine) – – 0.23 (0.14)
No e: No s a is ically signi ican di e ences in he a iables p esen in he model we e ound be ween he analy ical sample composed by only comple e cases and he
ini ial sample, excep o physical ac i i y (W =843163, p <0.001), neighbou hood g eenness ( -s uden (1501.9) =3.46, p <0.001) and ai pollu ion ( -s uden
(1591.3) = − 6.278, p <0.001). Howe e , mean di e ences be ween he analy ical and ini ial samples we e no subs an ial and he e o e, we de e mined he analy ical
sample composed by only comple e cases was a ep esen a i e sample o he ini ial da a. Desc ip i e s a is ics o he ini ial sample a e shown in Table S1.
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
6
when s udying he ela ion be ween en i onmen al noise exposu e and
ch onic co isol le els. Like ou esul s, Ve heyen and colleagues (2021)
epo ed ha esiden ial exposu e o a ic noise, as cha ac e ized by
day-e ening-nigh equi alen noise le els, we e no associa ed wi h HCC
measu ed using LC-MS/MS in boys no gi ls aged 14–15. Howe e , in
ano he s udy wi h 11-yea -old INMA-Gipuzkoa pa icipan s, highe
o al en i onmen al noise exposu e ( ail, oad and indus y) in he
pa icipan s building was ela ed o lowe hai co isol concen a ions in
boys (A egi e al., 2024) Impo an ly, his esul was no eplica ed in
he p esen s udy using da a om he INMA-Gipuzkoa 8-yea ollow-up,
despi e he ac ha mos pa icipan s we e simila ac oss bo h s udies.
To u he explo e hese indings, we examined he co ela ion be ween
HCC measu ed a 8 and 11 yea s, and ound no signi ican co ela ion
be ween co isol le els ac oss he di e en ollow-up pe iods. The e o e,
we sugges ha sex and age could be ele an ac o s when s udying he
ela ion be ween hese a iables and u u e s udies should conside
hem.
Mo e li e a u e is a ailable wi h ega ds o he associa ion wi h
u ina y co isol concen a ion (UCC). Some s udies showed highe UCC
in child en li ing unde highe a ic noise exposu e (E ans e al., 2001;
Table 2
Desc ip i e s a is ics o he s udy a iables in he sample wi h UCC (analy ical sample). Mean (SD) is shown in he nume ic a iables and equency (%) in he ca -
ego ical ones.
Va iable name BiB
N =125
EDEN
N =27
KANC N =160 Rhea
N =57
MoBa
N =198
INMA-Sabadell N =
183
Mean (SD)/Feq
(%)
Mean (SD)/Feq
(%)
Mean (SD)/Feq
(%)
Mean (SD)/Feq
(%)
Mean (SD)/Feq
(%)
Mean (SD)/Feq (%)
Age 6.60 (0.24) 10.73 (0.52) 6.45 (0.48) 6.55 (0.30) 8.50 (0.49) 8.78 (0.55)
Sex Female 53 (42.4) 9 (33.3) 72 (45.0) 27 (47.4) 92 (46.5) 78 (42.6)
Male 72 (57.6) 18 (66.7) 88 (55.0) 31 (52.6) 106 (53.5) 105 (57.4)
A ea-le el SES Low dep i a ion 16 (10.8) 12 (44.4) 47 (29.4) 34 (59.6) 81 (40.9) 83 (45.4)
Medium
dep i a ion
55 (44) 6 (22.2) 84 (52.5) 12 (21.1) 83 (41.9) 67 (36.6)
High dep i a ion 54 (43.2) 9 (33.3) 29 (18.1) 11 (19.3) 34 (17.2) 33 (18.0)
BMI 16.10 (2.2) 16.80 (2.6) 16.37 (2.2) 16.64 (2.4) 16.39 (1.94) 17.97 (3.04)
BMI (adjus ed o age and sex) 0.30 (1.17)
′
-0.25 (1.04) 0.47 (1.20) 0.61 (1.28) 0.14 (0.91) 0.75 (1.23)
Ex e nalizing Beha iou 5.5 (6.2) 8.74 (7.50) 8.61 (6.27) 8.58 (6.08) 3.14 (4.43) 7.01 (6.95)
Sleep
Dis u bances
1.13 (1.59) 1.19 (1.42) 1.54 (1.70) 0.93 (1.22) 0.89 (1.1) 1.09 (1.43)
Physical Ac i i y (min pe day) 57.76 (43.9) 27.01 (24.66) 66.00 (53.67) 26.42 (20.57) 69.71 (41.09) 48.65 (33.14)
NDVI (300 m) 0.46 (0.09) 0.53 (0.09) 0.51 (0.08) 0.29 (0.12) 0.60 (0.09) 0.27 (0.09)
T a ic- ela ed Ai Pollu ion (NO2) 31.59 (3.91) 13.59 (3.25) 14.17 (2.61) 12.45 (4.29) 27.35 (5.40) 34.52 (12.36)
L
den
<55 dB 69 (55.2) 20 (74.1) 118 (73.8) 0 (0.0) 129 (65.2) 23 (12.6)
[55–60)dB 37 (29.6) 3 (11.1) 30 (18.8) 4 (7.0) 38 (19.2) 39 (21.3)
[60–65)dB 14 (11.2) 2 (7.4) 9 (5.6) 41 (73.7) 21 (10.6) 61 (33.3)
[65–70)dB 5 (4.0) 1 (3.7) 3 (1.9) 9 (15.8) 8 (4.0) 35 (19.1)
[70–75)dB 0 (0.0) 1 (3.7) 0 (0.0) 2 (3.5) 0 (0.0) 16 (8.7)
>75 dB 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.0) 9 (4.9)
L
nigh
<50 dB 99 (79.2) 22 (9.2) – – 0 (0.0) 58 (31.7)
[50–55)dB 20 (16.0) 3 (11.2) – – 183 (92.4) 63 (34.4)
[55–60)dB 5 (4.0) 1 (3.7) – – 10 (5.1) 29 (15.8)
[60–65)dB 1 (0.8) 1 (3.7) – – 4 (2.0) 22 (12.0)
[65–70)dB 0 (0.0) 0 (0.0) – – 1 (0.5) 11 (6.0)
U ine To al Co isol (
μ
g/
μ
mol
c ea inine)
0.79 (0.35) 0.20 (0.14) 0.38 (0.29) 0.77 (0.55) 0.26 (0.15) 0.22 (0.12)
No e: No s a is ically signi ican di e ences in he a iables p esen in he model we e ound be ween he analy ical sample composed by only comple e cases and he
ini ial sample, excep o physical ac i i y (W =843163, p <0.001), neighbou hood g eenness ( -s uden (1501.9) =3.46, p <0.001) and ai pollu ion ( -s uden
(1591.3) = − 6.278, p <0.001). Howe e , mean di e ences be ween he analy ical and ini ial samples we e no subs an ial and he e o e, we de e mined he analy ical
sample composed by only comple e cases was a ep esen a i e sample o he ini ial da a. Desc ip i e s a is ics o he ini ial sample a e shown in Table S1.
Table 3
Resul s o he linea eg ession models showing o al and di ec e ec s o en i onmen al noise on co isol le els.
Exposu e Ou come Co isol
measu emen
me hod
N Model Co a ia e adjus men β-es ima es %95 CI - alue p-
alue
L
den
HCC LC-MS/MS 1437 To al
E ec
Neighbou hood g eenness, neighbou hood SES, a ic-
ela ed ai pollu ion
−0.002 (-0.06;
0.06)
−0.05 0.96
Di ec
e ec
Neighbou hood g eenness, neighbou hood SES, a ic-
ela ed ai pollu ion, emo ional and beha iou al p oblems,
physical ac i i y, ma e nal s ess, sex and sleep dis u bances
−0.002 (-0.06;
0.06)
−0.08 0.93
L
den
HCC RIA 288 To al
E ec
Neighbou hood g eenness, neighbou hood SES 0.048 (-0.03-
0.12)
1.29 0.20
Di ec
e ec
Neighbou hood g eenness, neighbou hood SES, a ic-
ela ed ai pollu ion, emo ional and beha iou al p oblems,
physical ac i i y, ma e nal s ess, sex and sleep dis u bances
0.046 (-0.03-
0.12)
1.25 0.21
L
den
UCC LC-MS/MS 750 To al
E ec
Neighbou hood g eenness, neighbou hood SES −0.026 (-0.07;
0.19)
−1.133 0.258
Di ec
e ec
Neighbou hood g eenness, neighbou hood SES, a ic-
ela ed ai pollu ion, emo ional and beha iou al p oblems,
physical ac i i y, ma e nal s ess, sex and sleep dis u bances
−0.024 (-0.07;
0.21)
−1.046 0.296
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
7
Ising and Ising, 2002). Howe e , E ans e al. (1998) ound no s a is i-
cally signi ican di e ences in UCC be ween child en li ing nea o an
ai po and child en esiding in nea by communi ies ou side he
noise-a ec ed a ea o he ai po . O he s udies also did no ind a
ela ion be ween sali a y co isol and a ic noise (Bloemsma e al.,
2021; Haines e al., 2001; Wallas e al., 2018) o ai c a noise (Haines
e al., 2001). The e o e, esul s ega ding acu e co isol le els in chil-
d en and en i onmen al noise exposu e a e no conclusi e and mo e
esea ch is needed.
P e ious s udies ega ding he associa ion be ween en i onmen al
noise and co isol le els ha e measu ed co isol in a single biological
ma ix, wi h he majo i y assessing co isol in u ine o sali a samples. As
a o emen ioned, bo h u ina y and hai co isol da a we e a ailable only
o INMA-Sabadell pa icipan s. We obse ed no co ela ion be ween
HCC and UCC. Ou esul s align wi h p e ious s udies epo ing low
co ela ion ( an Ockenbu g e al., 2016) o e en null co ela ions be-
ween hai and u ina y co isol (Chen e al., 2019; Sho e al., 2016).
Sho e al. (2016) de e mined ha ou o he s udied sho - e m co isol
measu es, HCC was mos s ongly associa ed wi h he p io 30-day in-
eg a ed co isol p oduc ion based on a e age sali a y co isol a ea
unde he cu e. I is likely ha co isol measu ed in di e en samples
p o ides di e en in o ma ion ega ding HPA axis p oduc i i y; UCC
p o ides a measu e o sho - e m co isol le els while HCC e lec s
long- e m le els. Mul iple u ina y co isol measu es may be necessa y o
in es iga e long- e m s ess esponses ( an Ockenbu g e al., 2016) and
he e o e, o e nigh UCC can be di icul o in e p e in ela ion o
ch onic en i onmen al noise exposu e. Because hai co isol concen-
a ion e lec s co isol le els o e se e al weeks (S au enbiel e al.,
2013) o mon hs i may be a be e indica o when examining associa-
ions wi h ch onic exposu es (Michaud e al., 2022). In he cu en
s udy, we did no obse e an associa ion be ween en i onmen al noise
and co isol le els, as measu ed in bo h u ine and hai samples. The o al
en i onmen al noise exposu e may ha e been misclassi ied by consid-
e ing only esiden ial noise, as noise exposu e was es ima ed solely a
he subjec ’s building açade. Consequen ly, noise exposu e a he pa -
icipan ’s esiden ial add ess may no encompass all ele an sou ces o
noise, pa icula ly exposu e in o he con ex s, such as a school.
Ne e heless, nume ous s udies ha e iden i ied associa ions be ween
ou doo esiden ial L
den
and L
nigh
and a ious heal h ou comes. In his
s udy, L
den
was ca ego ized in o 5 dB in e als, and in o ma ion on noise
le els below 55 dB was no a ailable. This limi a ion may ha e in lu-
enced ou esul s, as ea ing noise le els as a con inuous a iable could
p o ide mo e p ecise in o ma ion ega ding exposu e. Howe e , such
da a we e no a ailable o all coho s included in his s udy.
In addi ion, indi idual noise pe cep ion could also be an impo an
ac o in he associa ion be ween en i onmen al noise exposu e and
co isol le els, as subjec i e pe cep ions o noise may media e associa-
ion be ween noise exposu e and co isol le els (Subiza-P´
e ez e al.,
2024; Tao e al., 2020). P e ious s udies ha e also shown ha indi idual
noise sensi i i y and pe cep ion can in luence co isol le els e en mo e
han he le el o exposu e i sel . Wallas e al. (2018) ound ha noise
annoyance ended o inc ease sali a y co isol le els, while oad a ic
noise exposu e was no associa ed wi h co isol. Simila esul s we e
epo ed in ano he s udy, whe e hey obse ed ha indi idual noise
sensi i i y was ela ed o co isol measu ed in blood, while he associ-
a ion was non-signi ican in he case o L
den
(Kim e al., 2017). In his
s udy, no di e ences we e obse ed in indi idual ac o s, such as sleep
dis u bances o ex e nalizing p oblems, be ween en i onmen al noise
exposu e g oups in he bi a ia e analyses. Had such di e ences been
ound, hey could ha e suppo ed he no ion ha indi idual noise
sensi i i y plays a c ucial ole in s udying he ela ionship be ween noise
exposu e and co isol le els Ne e heless, u u e esea ch should include
noise pe cep ion as a mode a o a iable.
Hence, i is impo an o highligh he complexi y o he ela ionship
be ween noise exposu e and co isol le els, which may depend on
di e en si ua ions. Fac o s such as indi idual suscep ibili y –
p e iously discussed-as well as he du a ion and sou ce o noise expo-
su e, can in luence his associa ion. P e ious esea ch sugges s ha
noise cha ac e is ics—such as loudness, equency, and pa e n—may
in luence i s e ec s (Münzel e al., 2017), and consequen ly, he s ess
esponse may also be a ec ed by he noise sou ce. In ou s udy, oad
a ic noise was es ima ed in all cases excep o he INMA-Gipuzkoa
coho , whe e o al en i onmen al noise exposu e—including a ic,
ailway, and indus ial noise—was conside ed. Addi ionally, he du a-
ion o noise exposu e may also play a ole in he s ess esponse. As
p e iously men ioned, HCC may se e as a be e indica o o ch onic
noise exposu e, while UCC migh be mo e e lec i e o acu e exposu e.
This s udy makes a meaning ul con ibu ion o he ield o se e al
easons. Fi s , aking in o accoun he small numbe o s udies in chil-
d en, he inconclusi e esul s among hem and he ac ha his popu-
la ion is conside ed pa icula ly ulne able o he e ec s o
en i onmen al noise, i is o i al impo ance o add e idence ocusing
on his popula ion. Second, we used da a om eigh Eu opean p o-
spec i e bi h coho s, which p o ides us wi h ex ensi e in o ma ion on
se e al en i onmen al, social, and indi idual s esso s and a la ge
sample size. Thi d, we used a DAG and he d-sepa a ion c i e ion o
iden i y he se o adjus men a iables. E en i he use o DAGs is
becoming popula in epidemiological s udies in he las yea s, es able
implica ions a e a ely checked (Ankan e al., 2021). The e o e, we
educed he isk o bias by esidual con ounding on ou es ima es.
Ne e heless, he e a e some limi a ions ha mus be conside ed
when ex ac ing conclusions om ou s udy. Fi s , co isol was
measu ed in u ine samples in some coho s and in hai samples in o he
ones. Bo h ypes o samples we e only a ailable o INMA-Sabadell
pa icipan s. Ha ing co isol measu ed in bo h ma ices would p o ide
he oppo uni y o compa e he wo measu es and de e mine which is
mo e app op ia e o s udying he ela ionship be ween en i onmen al
noise exposu e and co isol le els. Ne e heless, we belie e ha u u e
esea ch should p io i ize in es iga ing he e ec s o en i onmen al
noise on HCC, as i may se e as a mo e eliable indica o o assessing
associa ions wi h ch onic exposu es. Fu he mo e, hai co isol was also
measu ed wi h di e en me hods: LC-MS/MS analysis in he INMA-
Sabadell and Gene a ion R, and RIA analysis in he case o INMA-
Gipuzkoa. As a o emen ioned RIA analysis p oduces highe co isol
le els han LC-MS/MS analysis (Russell e al., 2015) and he e o e, we
had o conduc sepa a e analysis, educing sample size and s a is ical
powe . The lack o s a is ical powe could be he eason o no de ec ing
a signi ican e ec .
Secondly, he assessmen o noise exposu e ocused on ou doo es-
iden ial noise, which was ca ego ized in o 5 dB in e als s a ing a 55
dB. This app oach may no accu a ely e lec ac ual noise exposu e. As
p e iously men ioned, ea ing noise le els as a con inuous a iable
could yield mo e accu a e in o ma ion ega ding exposu e. Addi ion-
ally, es ima ing noise exposu e solely a he building açade may no
encompass o e all exposu e, as noise le els in o he con ex s, such as
schools o ec ea ional a eas, we e no conside ed. The e o e, he lack o
signi ican indings may be a ibu ed o po en ial inaccu acies in es i-
ma ing en i onmen al noise exposu e. Fu u e s udies should inco po a e
addi ional con ex s o p o ide a mo e comp ehensi e assessmen .
Thi d, e en hough conside able e o has been made o cons uc a
comp ehensi e DAG ha a emp s o cap u e he complexi y o he
ela ionship be ween en i onmen al noise and co isol le els, he model
we ha e de eloped is in luenced by da a a ailabili y ac oss all coho s.
Fo ins ance, a s anda dized, alida ed ques ionnai e on sleep dis u -
bances was no a ailable o all coho s. Consequen ly, i ems om he
CBCL ela ed o sleep p oblems we e used as a p oxy o sleep dis u -
bances. Finally, da a on pe cei ed noise and noise sensi i i y –o
annoyance-was no a ailable, which seems o be an impo an ac o
when s udying he ela ion be ween en i onmen al noise and co isol
le els (Kim e al., 2017; Wallas e al., 2018). Hence, u u e s udies o he
issue should conside his a iable oo.
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
8
5. Conclusion
This s udy aimed o p o ide addi ional e idence ega ding he as-
socia ion be ween en i onmen al noise exposu e and co isol le els in
child en. Ou indings indica e no signi ican ela ionship be ween hese
a iables among child en om eigh Eu opean bi h coho s. Nega i e
esul s do no necessa ily indica e he absence o an associa ion be ween
he s udied a iables. Ins ead, he limi a ions o he s udy may accoun
o he lack o obse ed ela ionship be ween en i onmen al noise and
co isol le els. The e o e, u he esea ch is necessa y o explo e how
en i onmen al noise exposu e may in luence ch onic s ess bioma ke s
in child en, and we p opose ha HCC may se e as a alid ool o
in es iga ing he ela ionship be ween en i onmen al s esso s and cu-
mula i e co isol le els. Focusing on s ess bioma ke s could deepen ou
unde s anding o he mechanis ic pa hways unde lying heal h e ec s
associa ed wi h noise exposu e. In his ega d, u u e esea ch should
inco po a e addi ional bioma ke s o s ess and ch onic in lamma ion,
such as o he s ess ho mones o immune ma ke s. The use o a
comp ehensi e ch onic s ess indica o , such as he allos a ic load
sco e—which encompasses neu oendoc ine, immune, me abolic, and
ca dio ascula bioma ke s—could also p o ide aluable insigh s.
CRediT au ho ship con ibu ion s a emen
Ane A egi: W i ing – o iginal d a , Fo mal analysis, Concep uali-
za ion. Oli e Robinson: W i ing – e iew & edi ing, Supe ision,
Funding acquisi ion. Gunn Ma i Aas ang: W i ing – e iew & edi ing,
Concep ualiza ion. Sand a And usai y e: W i ing – e iew & edi ing,
P ojec adminis a ion. Aud ius Dedele: W i ing – e iew & edi ing.
Jo unn E and : W i ing – e iew & edi ing, Valida ion. Gonzalo
Ga cia-Baque o: Me hodology, Fo mal analysis, Concep ualiza ion.
No un Hje age K og: W i ing – e iew & edi ing. M`
onica Guxens:
W i ing – e iew & edi ing, P ojec adminis a ion, Funding acquisi ion,
Concep ualiza ion. Vincen W.V. Jaddoe: W i ing – e iew & edi ing,
P ojec adminis a ion, Funding acquisi ion. Ma ianna Ka achaliou:
W i ing – e iew & edi ing. Ai ana Le xundi: W i ing – e iew &
edi ing, Valida ion, Supe ision, Funding acquisi ion. Ka e ina Ma -
ge aki: W i ing – e iew & edi ing. Rosema y McEachan: W i ing –
e iew & edi ing, Funding acquisi ion. Ma k Nieuwenhuijsen: W i ing
– e iew & edi ing, Funding acquisi ion. Clai e Philippa : W i ing –
e iew & edi ing. Osca J. Pozo: W i ing – e iew & edi ing, Resou ces,
In es iga ion. Remy Slama: W i ing – e iew & edi ing. Mikel Subiza-
P´
e ez: W i ing – e iew & edi ing, Fo mal analysis, Concep ualiza ion.
Elisabe h F.C. an Rossum: W i ing – e iew & edi ing. Ma ine
V ijheid: W i ing – e iew & edi ing, P ojec adminis a ion, Funding
acquisi ion. John W igh : W i ing – e iew & edi ing. Ti any C. Yang:
W i ing – e iew & edi ing, Valida ion. Osca Vegas: W i ing – e iew &
edi ing, Valida ion, Supe ision, Concep ualiza ion. Ne ea Le xundi:
W i ing – e iew & edi ing, Valida ion, Supe ision, Concep ualiza ion.
Funding
The s udy was suppo ed by he Eu opean Communi y’s Se en h
F amewo k P og amme [FP7/2007–2013] unde g an ag eemen no.
308333 [ he HELIX p ojec ], and om he Eu opean Union’s Ho izon
2020 esea ch and inno a ion p og amme (LIFECYCLE, g an ag ee-
men No 733206, 2016; EUCAN-Connec g an ag eemen No 824989;
ATHLETE, g an ag eemen No 874583; LongITools, g an ag eemen
No 874739). Co isol and ela ed Glucoco icos e oids we e measu ed
wi hin he HELIX coho s as pa o he UK Resea ch and Inno a ion
METAGE p ojec (G an e : MR/S03532X/1).
We u he acknowledge unding om Ins i u o de Salud Ca los III
(FIS-PI06/0867, FIS-PI09/00090, FIS464,445PI13/02187, FIS-PI18/
01142 include FEDER unds, Red INMA G03/176; CB06/02/0041;
PI041436; PI081151 incl. FEDER unds; PI12/01890 incl. FEDER unds;
CP13/00054 incl. FEDER unds, CPII18/00018), CIBERESP, Depa men
o Heal h o he BasqueGo e nmen (2005111093, 2009111069,
2013111089 and 2015111065), and he P o incial Go e nmen o
Gipuzkoa (DFG06/002, DFG08/001, DFG15/221 and DFG89/17),
Gene ali a de Ca alunya-CIRIT 1999SGR 00241, Gene ali a de Ca a-
lunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundaci´
o La ma a ´
o de
TV3 (090430), Spanish Minis y o Economy and Compe i i eness
(SAF2012-32991 incl. FEDER unds), Agence Na ionale de Secu i e
Sani ai e de l’Alimen a ion de l’En i onnemen e du T a ail
(1262C0010), EU Commission (261357, 308333, 603794 and 634453).
We acknowledge suppo om he g an CEX2023-0001290-S unded by
MCIN/AEI/10.13039/501100011033, and suppo om he Gene ali a
de Ca alunya h ough he CERCA P og am.
The gene al design o he Gene a ion R S udy is made possible by
inancial suppo om he E asmus MC, Uni e si y Medical Cen e ,
Ro e dam, E asmus Uni e si y Ro e dam, Ne he lands O ganiza ion
o Heal h Resea ch and De elopmen (ZonMw), Ne he lands O gani-
sa ion o Scien i ic Resea ch (NWO), Minis y o Heal h, Wel a e and
Spo and Minis y o You h and Families. VJ ecei ed unding om a
Consolida o G an om he Eu opean Resea ch Council (ERC-2014-
CoG-648916). The s udy sponso s had no ole in he s udy design, da a
analysis, in e p e a ion o da a, o w i ing o his epo .
BiB ecei es unding om he UK Medical Resea ch Council (MRC)
and UK Economic and Social Science Resea ch Council (ESRC) (MR/
N024391/1); he B i ish Hea Founda ion (CS/16/4/32482); a Well-
come In as uc u e G an (WT101597MA); he Na ional Ins i u e o
Heal h Resea ch unde i s Applied Resea ch Collabo a ion o Yo kshi e
and Humbe (NIHR200166). The Na ional Ins i u e o Heal h Resea ch
Clinical Resea ch Ne wo k p o ided esea ch deli e y suppo o his
s udy. The iews exp essed in his publica ion a e hose o he au ho s
and no necessa ily hose o he Na ional Ins i u e o Heal h Resea ch o
he Depa men o Heal h and Social Ca e.
The EDEN s udy was suppo ed by Founda ion o medical esea ch
(FRM), Na ional Agency o Resea ch (ANR), Na ional Ins i u e o
Resea ch in Public heal h (IRESP: TGIR coho e san ´
e 2008 p og am),
F ench Minis y o Heal h (DRG), F ench Minis y o Resea ch, INSERM
Bone and Join Diseases Na ional Resea ch (PRO-A), and Human
Nu i ion Na ional Resea ch P og ams, Pa is-Sud Uni e si y, Nes l´
e,
F ench Na ional Ins i u e o Popula ion Heal h Su eillance (InVS),
F ench Na ional Ins i u e o Heal h Educa ion (INPES), he Eu opean
Union FP7 p og ammes (FP7/2007–2013, HELIX, ESCAPE, ENRIECO,
Medall p ojec s), Diabe es Na ional Resea ch P og am ( h ough a
collabo a ion wi h he F ench Associa ion o Diabe ic Pa ien s (AFD)),
F ench Agency o En i onmen al Heal h Sa e y (now ANSES), Mu uelle
G´
en´
e ale de l’Educa ion Na ionale a complemen a y heal h insu ance
(MGEN), F ench na ional agency o ood secu i y, F ench-speaking
associa ion o he s udy o diabe es and me abolism (ALFEDIAM).
The “Rhea” p ojec was inancially suppo ed by Eu opean p ojec s
(EU FP6–2003-Food-3-NewGene is, EU FP6. STREP Hiwa e, EU FP7
ENV.2007.1.2.2.2. P ojec No 211250 Escape, EU FP7–2008-ENV-
1.2.1.4 En i ogenoma ke s, EU FP7-HEALTH-2009-single s age
CHICOS, EU FP7 ENV.2008.1.2.1.6. P oposal No 226285 ENRIECO, EU-
FP7-HEALTH-2012 P oposal No 308333 HELIX, ATHLETE) and he
G eek Minis y o Heal h (P og am o P e en ion o obesi y and neu-
ode elopmen al diso de s in p eschool child en, in He aklion dis ic ,
C e e, G eece: 2011–2014; “Rhea Plus”: P ima y P e en ion P og am o
En i onmen al Risk Fac o s o Rep oduc i e Heal h, and Child Heal h:
2012–2015). The unding bodies ha e no a ec ed in any way he s udy
and he p esen ed esul s.
KANC was unded by he g an o he Li huanian Agency o Science
Inno a ion and Technology (6-04-2014_31V-66). The No wegian
Mo he , Fa he and Child Coho S udy is suppo ed by he No wegian
Minis y o Heal h and Ca e Se ices and he Minis y o Educa ion and
Resea ch.
A. A egi e al.
En i onmen al Resea ch 277 (2025) 121541
9
