Els reptes mediambientals per la salut -...
70
Els reptes mediambientals per la salut Jordi Sunyer Juliol 2015
Transcript of Els reptes mediambientals per la salut -...
Els reptes mediambientals per la salut
Jordi Sunyer Juliol 2015
Index
bull Climate change in context
bull Air pollution as the major threat
bull Developmental origins of Health and Diseases (DOHAD) brain development
bull The case of autism
From 1800 to 2000 (Nakicenovik 2005)
bull Population increased by 6
bull Food production by 10
bull GdP by 20
bull Energy expenditure by 35
bull CO2 by 20
bull Urbanrural by 20
Climate change is potentially the biggest global health threat in the 21st century
(Lancet 20093731693ndash733)
bull Health effects will not be off-set if temperature rises above 2ordmC on average
IPCC Special Report on Emissions Scenarios (SRES)
Floods
Malaria
Diarrhoea
Malnutrition
020406080100120 0 2 4 6 8 10
Deaths (thousands) DALYs (millions)
2000 2030
Estimated deaths and DALYs attributable to climate change Selected conditions in developing countries
WHO 2004
Now (2000)
Future (2030)
Impact of the environment on health by country Pruumlss-Uumlstuumln A et al Env Health 2008
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Index
bull Climate change in context
bull Air pollution as the major threat
bull Developmental origins of Health and Diseases (DOHAD) brain development
bull The case of autism
From 1800 to 2000 (Nakicenovik 2005)
bull Population increased by 6
bull Food production by 10
bull GdP by 20
bull Energy expenditure by 35
bull CO2 by 20
bull Urbanrural by 20
Climate change is potentially the biggest global health threat in the 21st century
(Lancet 20093731693ndash733)
bull Health effects will not be off-set if temperature rises above 2ordmC on average
IPCC Special Report on Emissions Scenarios (SRES)
Floods
Malaria
Diarrhoea
Malnutrition
020406080100120 0 2 4 6 8 10
Deaths (thousands) DALYs (millions)
2000 2030
Estimated deaths and DALYs attributable to climate change Selected conditions in developing countries
WHO 2004
Now (2000)
Future (2030)
Impact of the environment on health by country Pruumlss-Uumlstuumln A et al Env Health 2008
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
From 1800 to 2000 (Nakicenovik 2005)
bull Population increased by 6
bull Food production by 10
bull GdP by 20
bull Energy expenditure by 35
bull CO2 by 20
bull Urbanrural by 20
Climate change is potentially the biggest global health threat in the 21st century
(Lancet 20093731693ndash733)
bull Health effects will not be off-set if temperature rises above 2ordmC on average
IPCC Special Report on Emissions Scenarios (SRES)
Floods
Malaria
Diarrhoea
Malnutrition
020406080100120 0 2 4 6 8 10
Deaths (thousands) DALYs (millions)
2000 2030
Estimated deaths and DALYs attributable to climate change Selected conditions in developing countries
WHO 2004
Now (2000)
Future (2030)
Impact of the environment on health by country Pruumlss-Uumlstuumln A et al Env Health 2008
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Climate change is potentially the biggest global health threat in the 21st century
(Lancet 20093731693ndash733)
bull Health effects will not be off-set if temperature rises above 2ordmC on average
IPCC Special Report on Emissions Scenarios (SRES)
Floods
Malaria
Diarrhoea
Malnutrition
020406080100120 0 2 4 6 8 10
Deaths (thousands) DALYs (millions)
2000 2030
Estimated deaths and DALYs attributable to climate change Selected conditions in developing countries
WHO 2004
Now (2000)
Future (2030)
Impact of the environment on health by country Pruumlss-Uumlstuumln A et al Env Health 2008
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
IPCC Special Report on Emissions Scenarios (SRES)
Floods
Malaria
Diarrhoea
Malnutrition
020406080100120 0 2 4 6 8 10
Deaths (thousands) DALYs (millions)
2000 2030
Estimated deaths and DALYs attributable to climate change Selected conditions in developing countries
WHO 2004
Now (2000)
Future (2030)
Impact of the environment on health by country Pruumlss-Uumlstuumln A et al Env Health 2008
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Floods
Malaria
Diarrhoea
Malnutrition
020406080100120 0 2 4 6 8 10
Deaths (thousands) DALYs (millions)
2000 2030
Estimated deaths and DALYs attributable to climate change Selected conditions in developing countries
WHO 2004
Now (2000)
Future (2030)
Impact of the environment on health by country Pruumlss-Uumlstuumln A et al Env Health 2008
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Impact of the environment on health by country Pruumlss-Uumlstuumln A et al Env Health 2008
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Costello et al Lancet 2009
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Costello et al Lancet 2009
Climate-related Mortality (per million pop) by WHO region 2000
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Global deaths and Disability-Adjusted Life-Years (DALYs) attributable to selected environmental risk factors 2000
Males Females
20 15 10 05 0 0 10 20 30 40 50 60
Millions of deaths Millions of DALYs
160000 deaths
Climate change
Lead
exposure
Urban air pollution
Indoor smoke
solid fuel
Unsafe water
sanitation
55 million DALYs
Based on McMichael et al 2004 (WHO Comparative Risk Assessment 2000)
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Quantifying health impacts of climate change Burdens of disease by region (i) Climate change (ii) air pollution
World Health Report 2002
Climate change Air pollution
050010001500200025003000 0 500 1000 1500 2000 2500 3000
Africa region
South-East Asia region
Eastern Mediterranean region
Latin America and Caribbean region
Western Pacific region
Developed countries
bull Cardio- pulmonary diseases bull Respiratory infections bull Trachea bronchus lung cancers
bull Diarrhoeal diseases bull Malaria bull Unintentional injuries bull Protein-energy malnutrition
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters
in 21 regions 1990ndash2010 (Lancet 2012)
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
httpwwwwhointphehealth_topicsoutdoorairdatabasesen
Globally 7 million deaths were attributable to the joint effects of household and ambient air pollution in 2012 The Western Pacific and South East Asian regions bear most of the burden with 28 and 23 million deaths respectively Almost 680rsquo000 deaths occur in Africa about 400rsquo000 in editerranean region 287rsquo000 in Europe and 131rsquo000 in the Americas
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Air pollution (PM10 μgm3) by cities (WHO 2011)
bull Ahvas (Iran) 327
bull Ulam Bator (Mongolia) 279
bull Quetta (Pakistan) 263
bull Kampur (India) 244
bull Gabarone (Botswana) 240
bull Barcelona 38
bull Stockholm 18
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Figure 5 Risk factors ranked by attributable burden of disease 2010 by region
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
NIH library Pubmed air pollution AND health
papersyear
1
10
100
1000
10000
1976-
1980
2006-
2010
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Particulate matter (PM) eg PM25 ie Oslash le 25 μm
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
bull PARTICULATE MATTER (PM)
bull Compostos de Carboni
bull CIS (NO3- SO4
= NH4+)
bull Mategraveria mineral
bull Metalls traccedila
bull Aerosol mariacute
PM10
PM25
UFP
bull Compostos de Carboni bull CIS (NO3
- SO4= NH4
+) bull Metalls traccedila
GRAN COMPLEXITAT Diferent naturalesa propietats i fonts drsquoemissioacute
bullNOx SOx O3 CO NH3 COVs
Air pollutants in urban atmospheres
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Impact by PM size
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Health Effects of Fine Particles Lines that Connect (Pope et Dockery 2006)
Mechanisms by which exposure to PM damages our health
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
COPD emergency room admissions and daily air
pollution levels in Barcelona Sunyer et al Am J Epidemiol 1991
Winter
Summer Dai
ly C
OP
D
Emer
gen
cy a
dd
mis
sio
ns
Black Smoke concentrations in μgm3
20 30 40 50 60
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Total mortality and PM10 concentration vs time
Barcelona 2003-2004
0
20
40
60
80
100
120
010
1200
3
010
2200
3
010
3200
3
010
4200
3
010
5200
3
010
6200
3
010
7200
3
010
8200
3
010
9200
3
011
0200
3
011
1200
3
011
2200
3
010
1200
4
010
2200
4
010
3200
4
010
4200
4
010
5200
4
010
6200
4
010
7200
4
010
8200
4
010
9200
4
011
0200
4
011
1200
4
011
2200
4
Time
De
ath
pe
r d
ay
0
20
40
60
80
100
120
140
160
180
200
PM
10 (
ug
m3)
Death per day PM10 (ugm3)
Mortalitat diagraveria i contaminacioacute atmosfegraverica anagravelisis de series temporals
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Percent increase in daily mortality (95 CI) per
10μgm3 PM10 The European APHEA Study
Katsouyanni et al
Epidemiology 2001 12 (5) 521-31
Cambridge1ppt
0 1 2-1
Percent increase in mortality
-1 0 1 2
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Oxford Street
Hyde Park
sense tragravefic
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
OXFORDSTREET
RE
GE
NT
ST
RE
ET
OR
CH
AR
DS
TR
EE
T
Diesel exposure on a 2h-walk in asthmatics McCreanor NEJM 2007 3572348
Busos diesel per Oxford Street
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
Kensington Palace
Round
Pond
The Serpentine
The Long W
ater
Old Police
House amp
Rangers
Lodge
WEST
CAR
RIA
GE
DR
IVE
SOUTH CARRIAGE DRIVE
NORTH CARRIAGE DRIVE
PA
RK
LA
NESubjects
enter here
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
FEV1 after 2h-walk McCreanor et al NEJM 2007
Hyde Park
Oxford Street
0 1 2 3 4 5 6 7
-10
-8
-6
-4
-2
0
2
Hores (desde el inici de lrsquoexposicioacute)
c
amb
io e
n la
FEV
1
p lt 0001
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Presence of carbon in airway macrophages in healthy children exposed to traffic
Kulkarni et al (NEJM 2006)
Figure 1 Representative Images of Carbon in Airway Macrophages from Healthy Children Panel A shows a macrophage with no carbon Increasing levels of carbon are shown in Panels B through E
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Carbon in airway macrophages impairs lung function in healthy children
Kulkarni et al (NEJM 2006)
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
35 30 25 20 15 10
09
10
11
12
13
bull Portage W bull Topeka KS
bull Waterown MA (Boston)
bull Harriman TN (Knoxville) bull St Louis MO
bull Stebenville OH
Long-term mortality 6 cities Dockery 1993
The six cities study PM25 ndashMORTALITY (Dockery NEJM 1993)
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Ultrafine particles (UFP) promote early atherosclerosis and
systemic oxidative stress (Araujo 2008 Brook 2010)
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Placas en las arterias despueacutes exposicioacuten a New York PM en ratolins
Sun et al JAMA Dec 2005
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Diesel exhaust exposure chamber
Mills et al New England Journal of Medicine 2007 (13Sept)
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
1 hour diesel exposure in a chamber in 20 IAM survivors (Mills et al N Engl J Med 2007)
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
AIR POLLUTION AND COGNITIVE DECLINE IN HUMAN POPULATIONS
bull Ranft U et al Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly Environ Res 20091091004-11
bull Chen JC et al Neurobehavioral effects of ambient air pollution on cognitive performance in US adults Neurotoxicology 200930231-9
bull Powers MC et al Air Pollution and Cognitive Function in a Cohort of Older Men Environ Health Perspect 2011 119682-7
bull Weuve J et al Exposure to particulate air pollution and Cognitive Decline in Older Women Arch Intern Med 2012 Feb 13172(3)219-27
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
EARLY ALZHEIMERS AND PARKINSONS DISEASE PATHOLOGY IN URBAN CHILDREN (CALDEROacuteN-
GARCIDUENtildeAS 2013) WHITE MATTER LESIONS AND PERIVASCULAR PATHOLOGY
CONTRIBUTING THE THE NEUROINFLAMATION (CALDERON-G 2012)
In dogs and children autopsies higher prevalence of diffuse amyloid-β peptide deposits (C-G 2008)
MIF PrP(C) IL-6 IL-1Ra IL-2 in cerebrospinal fluid in
urban children exposed to severe vs low air pollution (Calderoacuten-Garciduentildeas 2013)
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Basis for the role of PM (diesel or UFP)
in rodents
bull Direct translocation (Elder 2006 Yokota 2011)
bull BBB integrity (Poumlss 2013 Oppenheim 2013 Heidari 2014)
bull Microglia activation (Levesque 2011 Poumlss 2013 Oppenheim 2013
Heidari 2014 Allen 2014)
bull Brain inflammation (Campbell 2005 2009 Kleinman 2008 van
Berlo 2010 Gerlofs-Nijland 2010 Levesque 2011 Fonken 2011 Allen 2014)
bull Dopaminergic neurotoxicity (Curtis 2010 Levesque 2013)
bull Glutamatergic neuronal dysfunction (Morgan 2011
Davis 2013 Cory-Slechta 2014)
bull Memory impairment (Zanchi 2010 Forben 2011 Yokota 2013)
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
How do air pollutants reach the brain - based on animal studies -
Genc et al J Toxicol 20122012782462
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Mental capital (cognitive and emotional
resources) over the course of life (Beddington
Nature 2008)
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Early origins of development and
health (DOHAD)
Undernutrition in utero
permanently changes the
bodyrsquos structure physiology
and metabolism and
leads to IHD in adult life
Programming by early nutrition in man (Lucas 1991)
A given genotype can give rise to different phenotypes
depending on adaptation to environment triggered
during sensitive periods
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Brain development the brain at
ages four (90 cortex)
40000 synapses per minute
during first two years of life
(wiring)
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
INMA Birth Cohort
INMA Childhood and Environment
The INMA project is a network of prospective birth cohort studies in Spain following more than 3500 mother-child pairs in total
AIM to study the role of environmental pollutants in air water and diet during pregnancy and early in life and their effects on child growth and development
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Population Enrolment Number of children
Ribera drsquoEbre 1997-1999 102
Menorca 1997-1998 482
Granada 2000-2002 668
Asturias 2004-2007 485
Gipuzkoa 2006-2008 611
Sabadell 2004-2007 622
Valegravencia 2003-2005 787
Total 3757
INMA
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
INMA - Exposures
Air pollution
bullOutdoor NO2 VOCs
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
IndoorPersonal monitoring
Water DBPs
Noise Questionnaires
Radiation
bullOccupation (EMF)
bullMedical ionizing radiation
Smoking Questionnaires
Air pollution
bullOutdoor NO2 VOCs
LUR models
Air pollution
bullOutdoor NO2 VOCs
LUR models
bullIndoor Questionnaires
Water DBPs
Smoking Questionnaires
12-32 weeks Delivery 14 months 4 years
Air pollution
bullOutdoor NO2 PM10 PM25
Personal monitoring
LUR models
bullIndoor NO2 VOCs
Questionnaires
Indoor monitoring
Water DBPs
Noise Questionnaires
Smoking Questionnaires
Childhood Birth Pregnancy
Passive sampler (air pollution personal monitoring)
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
INMA - Biomarkers
Blood
bullOCs
bullThyroid hormones
bullC-reactive protein
bullIgEs
bullTG cholesterol
bullFolic acid ferritina
bullVitamin D B12 C
bullFatty acids
bullDNA
Urine
bullCotinineCreatinine
bullPhenols Phthalates
bullMetals
bullIodineHidroxipirene
Childhood Birth Pregnancy
Cord blood
bullFatty acids
bullLead
bullTotal mercury
bullDNA
Placenta
bullTBEX
Hair
bullMethylmercury
Colostrum
bullFatty acids
bullOCs
bullPAHs
MOTHER
Urine Iodine
Saliva cortisol
CHILD
Urine
bullCotinine
bullCreatinine
Saliva cortisol
Placenta Hair Colostrum
Saliva Nail
4 years 7-8 years
Blood
bullOCs PFCs
bullTG cholesterol
bullPb
bull-omics
bullDNA miRNA
Urine
bull-omics
bullCotinineCreatinine
bullPhenols Phthalates
bullOP pesticides
bullTMS
Hair
bullMethylmercury
bullNicotine
Hair Faeces
12 weeks Delivery 14 months
Blood
bullTG cholesterol
bullDNA miRNA
bullOmics
bullIgEs
Urine
bullCotinineCreatinine
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Air pollution effects early in life (Findings 2013-15 at CREAL)
bull Pre-natal growth bull Pre-eclampsia bull Low birth weight bull Congenital anomalies bull Respiratory infections bull Wheezig and asthma bull Impaired lung function bull Motor mental development bull Behaviour
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
46
INMA birth cohort
At birth (n=2505)
11-23 months (n=2348)
Pregnancy (n=2644)
2004-2008 2004-2009
(937)
neurodevelopment and air pollution data (n=2139)
after excluding preterm births and low quality neuropsychological tests (n=1889)
2005-2010
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
47
Design
bull Variables
Pregnancy Pre-pregnancy
11-23 months At birth
bull Education level
bull Social class
bull Country of birth
bull Age
bull Family structure
bull Maternal weight
bull Maternal height
bull Noise annoyance
bull Smoking
bull Alcohol use
bull Maternal diet
bull Use of gas stove
bull TSH level
bull Hemoglobine level
bull Vitamin D level
bull Gender
bull Gestational age
bull Type of delivery
bull Birth weight
bull Birth height
bull Birth head circumference
bull Number of siblings
Bayley test
bull Mental score
bull Psychomotor score bull Age
bull Psychologist
bull Breastfeeding
bull Main childminder
bull Nursery attendance
bull Maternal working status
Air pollutants
bull NO2 exposure
bull Benzene exposure
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
57 sampling points were selected to represent the gradient of exposure in the cohort
Cohort addresses Sampling points 500m- grid
1 SAMPLING SITES SELECTION
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Aguilera 2009
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
50 Association between benzene exposure during pregnancy and
infant MENTAL DEVELOPMENT in antioxidant
detoxification groups (Guxens 2012)
Adjusted for psychologist childs sex maternal education age height and pre-pregnancy body mass index maternal alcohol use during pregnancy maternal large fatty and lean fish consumption at 1st trimesterseason-specific maternal circulating vitamin D level at 1st trimester use of gas stove at home during pregnancy number of siblings at birth
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Faroes
DNBC
CoNER
INUENDO
Duisburg
EDEN
Generation XXI
FLEHS I
HUMIS
INMA-old
REPRO_PL
KANC
LUKAS
PCB cohort INUENDO
RHEA
Czech
Leicester MAS
NINFEA
GASPII
INUENDO
GINIplus
BAMSE
PEacuteLAGIE
MoBa
ABCD
Generation R
KOALA
PIAMA
LISAplus ALSPAC
BiB
Size of circle
lt 1000
1-5000
5-20000
100000
INMA-new
DARC
PARIS
ArcRisk-Norway
Kraacutekow
birthcohortsnet
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Epidemiology 201425636-47
NOTE Weights are from random effects analysis
Overall (I-squared = 348 p = 0120)
GENERATION R The Netherlands
INMA Spain-Asturias
INMA Spain-Sabadell
GASPII Italy
INMA Spain-Valencia
EDEN France-Nancy
Cohort study Country-area
EDEN France-Poitiers
INMA Spain-Granada
DUISBURG Germany
RHEA Greece
INMA Spain-Gipuzkoa
MIDI
BSID-I
MSCA
DDST-II
MSCA
ASQ
Test
ASQ
MSCA
BSID-II
BSID-III
BSID-I
1y
15y
4y
4y
6y
3y
Age
35y
4y
2y
15y
15y
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
-068 (-125 -010)
-009 (-085 067)
-108 (-203 -013)
038 (-091 166)
-105 (-236 027)
-198 (-339 -058)
-151 (-300 -003)
Coef (95 CI)
-034 (-359 292)
096 (-092 284)
-268 (-562 026)
-044 (-287 199)
009 (-312 331)
3759
381
426
547
490
395
N
374
169
178
520
519
0-4 -3 -2 -1 0 1 2
N=9482
Psychomotor development
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Air pollution and autism spectrum disorders
JAMA Psychiatry 201370(1)71-7
Environ Health Perspect 2013121380ndash6
Environ Health Perspect 2015123264-70
Epidemiology 20152630-42
PLoS One 20138(9)e75510
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies
Mogravenica Guxens1234 Akhgar Ghassabian45 Tong Gong6 Raquel Garcia-Esteban123 Daniela Porta7 Lise Giorgis-Allemand89 Catarina Almqvist6 Aritz Aranbarri1011 Rob Beelen12 Chiara Badaloni7 Giulia Cesaroni7 Audrey de Nazelle12313 Marisa Estarlich314 Francesco Forastiere7 Joan Forns12312 Ulrike Gehring13 Jesuacutes Ibarluzea31116 Vincent WV Jaddoe51718 Michal Korek19 Paul Lichtenstein6 Mark J Nieuwenhuijsen123 Marisa Rebagliato320 Reacutemy Slama89 Henning Tiemeier41821 Frank C Verhulst4 Heather E Volk22 Goumlran Pershagen19 Bert Brunekreef1223 Jordi Sunyer12324
Environ Health Perspect 2015 (provisionally accepted)
NOTE Weights are from random effects analysis
Overall (I-squared = 00 p = 0431)
INMA Spain-Sabadell
INMA Spain-Valencia
CATSS Sweden
Cohort study Country-area
GENERATION R The Netherlands
INMA Spain-Gipuzkoa
GASPII Italy
CAST
CAST
A-TAC
Test
CBCL
CAST
CBCL
4y
5y
10y
Age
6y
4y
4y
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
095 (081 110)
081 (041 161)
135 (090 201)
092 (053 162)
OR (95 CI)
085 (068 107)
178 (047 679)
094 (070 125)
271
487
2437
N
3706
317
475
14 55 75 1 15 2
NO2 (per 10 microgm3)
Air pollution and autism spectrum disorders
N=8079
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
The BREATHE project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Why primary school children
bull Primary school is a vulnerable age for brain cortex development
bull Schools have higher exposure
bull Children have higher exposure during school time than at home
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
School study
bull Schools stratified by traffic pollution
bull Match each pair by similar social context
bull Two sampling periods of one week by season
bull Five monitoring stations at the same time inout amp highlow fixed site
bull 39 schools 1092 PM filters during 2012
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
SCHOOL ELEMENTAL CARBON (microgm3) IN-OUT BY SEASON
y = 07558x + 01409 Rsup2 = 08442
y = 09083x + 00471 Rsup2 = 08374
0
1
2
3
4
5
6
0 1 2 3 4 5 6
IN
OUT
Cold Season Warm Season
Rivas I 2014
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
SCHOOL PM25 IN-OUT BY SCHOOL
y = 013x + 4823 Rsup2 = 002
y = 035x + 3018 Rsup2 = 032
0
20
40
60
80
100
120
0 20 40 60 80 100 120
ind
oo
r (micro
gmiddotm
-3)
outdoor (microgmiddotm-3)
Rivas I 2014
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Average absolute contributions of PM25 sources identified by PMF (positive matrix factorization)
Fulvio Amato et al 2014
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
bull All school children (n=4085) without special needs in grades 2 - 4 (7-10 years of age) were invited
bull 2897 (59) agreed
bull Every 3 months (4 repeats) computerized tests
bull Groups of 10-20 children were assessed together wearing ear-protectors supervised by one trained examiner per 3-4 children
Neuropsychological study
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
N-back Working memory
ANT Inattentiveness
drsquo (Z hit rate - Z false alarm rate)
hit reaction time standard error for correct responses
Executive functions
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Exposure to air pollution at school
PLoS Med 201512(3)e1001792
Dashed line = high traffic air pollution Continuous line = low traffic air pollution Gray shading = 95 CIs
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Crude and adjusted effects for EC NO2 and UFP on working memory
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Traffic PM25 (in out) and working memory yearly development
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Prohibicioacute del carboacute a Dubliacuten 1990
Reducccioacute Fums negres - 356
SO2 - 113
Reduccioacute Mort cardiovascular - 103
Mort respiratograveria -155
valor mig
valor mig
44 dia
38 dia
Clancy et al Lancet 2002 1991
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
Conclusions
bull Urban pollution and specifically fine and ultrafine particles are an important health hazard
bull Its a global health threat
bull Mechanisms are related to the aging process
bull Itrsquos time for action
jsunyercrealcat
Gragravecies
jsunyercrealcat
Gragravecies
