Air pollution and your brain: what do you need to know right now
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Primary Health Care Research & Development 2015; 16: 329–345
doi:10.1017/S146342361400036X DEVELOPMENT
Air pollution and your brain: what do you need
to know right now
Lilian Calderón-Garcidueñas1, Ana Calderón-Garcidueñas2, Ricardo Torres-Jardón3, José Avila-Ramírez4,
Randy J. Kulesza5 and Amedeo D. Angiulli6
1
The Center for Structural and Functional Neurosciences, The University of Montana, Missoula, MT, USA
2
Instituto de Medicina Forense, Universidad Veracruzana, Boca del Río, Veracruz, México
3
Centro de Ciencias de la Atmósfera, Universidad Nacional Autónoma de México, Mexico City, Mexico
4
Hospital Médica Sur, México DF, México
5
Auditory Research Center, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
6
Department of Neuroscience, Carleton University, Ottawa, ON, Canada
Research links air pollution mostly to respiratory and cardiovascular disease. The effects
of air pollution on the central nervous system (CNS) are not broadly recognized. Urban
outdoor pollution is a global public health problem particularly severe in megacities and
in underdeveloped countries, but large and small cities in the United States and the
United Kingom are not spared. Fine and ultrafine particulate matter (UFPM) defined
by aerodynamic diameter (330 L. Calderón-Garcidueñas et al.
Mills, 2014). Cohort longitudinal studies across better lung penetration and diffusion and major
Europe show 7% increase in natural cause mor- particle deposition in the respiratory tract and direct
tality with each 5 μg/m3 in fine PM2.5 (Beelen et al., translocation into the brain. A significant threat not
2013; Langrish and Mills, 2014). According to a contemplated by health care workers are man-made
report by the European Topic Centre on Air and particles 90% of their time
MCMA is an example of a polluted megacity with indoors, so indoor air pollution is very important:
over 40 000 industries, >4 million vehicles that smoking, cooking, candle/incense burning, cleaning
consume more than 40 million liters of petroleum and use of plastics and conglomerates all contribute
fuels per day and produce thousands of tons of to indoor pollution (Habre et al., 2013). Poor air
pollutants (INE, 2011). Since MCMA lies in an quality in schools and in-vehicle concentrations of
elevated basin 2240 m above sea level, surrounded pollutants are also of deep concern (Brown et al.,
on three sides by mountain ridges, surface, as 2012; Annesi-Maesano et al., 2013).
well as surface-based air temperature inversions As in any city, air quality in MCMA is deter-
occur frequently, trapping pollutant emissions mined by the balance between pollutant emissions
close to the surface and aggravating the pollution and the capacity of the geographical site to elim-
(Bravo-Alvarez and Torres-Jardón, 2002). MCMA inate, disperse or concentrate those air pollutants.
geographical setting and the climatological char- Despite MCMA rapid growth and development,
acteristics along with the relatively little mobility of air quality has improved during the past two
their residents allows for the opportunity of study- decades. Nevertheless, residents remain exposed
ing health effects associated to sustained yearlong to concentrations of airborne pollutants exceeding
exposures to concentrations of air pollutants above ambient air quality standards, especially for PM
the current US National Ambient Air Quality and ozone, the two most important pollutants
Standards. from the standpoint of public health (Brook et al.,
2010). The higher socioeconomic status (SES)
MCMA population lives toward the south and
PM air pollution west of the urban area with access to vegetation,
water and better road networks. The industry is
Air pollution is a complex mixture of PM, gases, located primarily in the northeast and northwest,
organic and inorganic compounds present in out- whereas the east side has been covered by large
door and indoor air. Urban outdoor pollution is a housing low SES developments in areas of difficult
global public health problem (Molina and Molina, access and poor services. This distribution of the
2004). PM defined by aerodynamic diameter (>2.5 population, as well as the intensity and type of
toAir pollution and brain 331
carbon, sulfate, nitrate, ammonium and crustal current standards, every year, in such a way that
components, with site- and time-dependent varia- residents are living in a very effective exposure
tions (Aiken et al., 2009). Particle species are typi- chamber from conception to death. Is this scenario
cally categorized as ‘primary’ if they are emitted in exclusive for Mexico City residents? The answer
the particle phase and ‘secondary’ if their precursors is no, Salt Lake City, Tacoma, San Francisco
(volatile organic compounds, NOx, SO2, NH3 and Bay, Los Angeles, Fairbanks, London, Greater
others) are emitted in the gas-phase and subsequent Manchester and Oxfordshire residents to name a
chemical reactions bring them to the particle phase. few have similar scenarios, albeit less severe (Bell
Diesel and gasoline exhausts emissions have been et al., 2007; Maheswarang et al., 2010; Williams
responsible for a significant fraction of the fine par- et al., 2011; Beelen et al., 2013; UK Air Data). On
ticle primary emissions in MCMA (Molina et al., the other hand, millions of Shanghai residents are
2010). Polycyclic aromatic hydrocarbons (PAH) are covered with heavy haze substantially increasing
a family of species, some of which are highly muta- cardiovascular, respiratory and cerebrovascular
genic and carcinogenic, that are generally associated morbidity and mortality (Xu et al., 2013).
with black carbon as their emissions are largely from
combustion sources (Valle-Hernández et al., 2010).
Peak concentrations of PAHs in MCMA are The impact of polluted air on an adult
reached during the morning rush hour and are of the brain
order of 120 ngm−3, which is significantly higher than
in United States (Marr et al., 2004; Molina et al., The first important statement to be made is that
2010). High levels of anthropogenic metals including age and disease status are key factors on the
chromium (Cr), zinc (Zn), copper, lead (Pb), impact of air pollutants. Associations between
antimony, arsenic, tin and barium complete the toxic stroke, ambient pollution and coal fumes were
potential of fine PM (Molina et al., 2010). As suggested in the 1980s (Knox, 1981; Zhang et al.,
expected, these metals exhibit strong temporal var- 1988). Cigarette smoking as a stroke risk factor
iations in concentration and are largely associated (and of course an excellent source of large
with industrial and mobile sources. Elements amounts of PM) was published a decade later
representing mostly road traffic, that is, Cr, Mn, Zn (Howard et al., 1998). Ischemic stroke mortality
and Pb, are typically associated with engine emis- and transient ischemic attacks relate to fine and
sions and abrasion of tires and brake pads. V and Ni UFPM exposures even at concentrations below
are interpreted as tracers of long-range transport the current standards (Hong et al., 2002; Kettunen
from the use of heavy fuel oil in the north of the et al., 2007; Lisabeth et al., 2008; Bedada et al.,
basin (Querol et al., 2008). Pb deserves a special 2012; Leiva et al., 2013) and very important from
mention. Before 1986, Pb was probably the most the clinical point of view, outdoor air pollution and
harmful pollutant in MCMA, associated with the proximity to high-traffic roadways impact stroke
exclusive use of leaded gasoline and resulting in Pb survival (Maheswarang et al., 2010; Wilker et al.,
concentrations three times the air quality standard. 2013). The largest association between PM2.5 and
In response to a very strong social pressure and to a ischemic stroke risk was seen with stroke due
growing international trend to control car emissions to large-artery atherosclerosis and small-vessel
with catalytic converters, PEMEX, the federal occlusion: diabetic patients are particularly at risk
Mexican oil company, was forced to reduce the (O’Donnell et al., 2011). Moreover, the associa-
gasoline content of tetra-ethyl-lead (Bravo-Alvarez tions involve not only urban pollutants but also
and Torres-Jardón, 2002) resulting in Pb concen- dust storms and unfortunate events like 9/11
trations ∼2 μg/m3 in 1988 and reaching ∼0.5 μg/m3 World Trade Center (Yang et al., 2005; Brackbill
by 1998. Although Pb is no longer an air pollutant et al., 2006). Although most of the literature asso-
problem, lipopolysaccharides (products of the outer ciating stroke with air pollution emphasizes PM,
membrane of Gram-negative bacteria) associated ozone – a key photochemical pollutant affecting
with PM, are detected in very high concentrations in our populations in Mexico City, Los Angeles, San
southern Mexico City (Rosas-Pérez et al., 2007). The Joaquin Valley, Riverside, Sacramento, Baltimore,
grim scenario for MCMA residents is a sustained Dallas, south-east of England, etc. – is also a big
exposure to PM2.5 several hours per day above the player (Parrish, et al., 2011; Carlsen et al., 2013;
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Suissa et al., 2013). Depression and mood disorders (Block and Calderón-Garcidueñas, 2009). UFPM,
have been associated with air pollution. Increases particulate matter-associated lipopolysaccharides,
in PM10, PM2.5, NO2, CO, SO2, O3 and biomass and metal uptake could take place through olfactory
burning are associated with depression in the neurons, cranial nerves such as the trigeminal and
elderly, and emotional symptoms and suicide vagus, the systemic circulation and macrophage-like
attempts in younger subjects (Szyszkowicz et al., cells loaded with PM from the lungs (Calderón-
2010; Wisnivesky et al., 2011; Banerjee et al., 2012; Garcidueñas et al., 2008c; 2012a). Activation of the
Lim et al., 2012). Exposure of animal models to brain innate immune responses resulting from the
ambient PM2.5 results in depressive responses and interaction between circulating cytokines and con-
increase hippocampal pro-inflammatory cytokines stitutively expressed cytokine receptors located in
(Fonken et al., 2011), whereas prenatal nano-PM brain endothelial cells is followed by activation of
impacts neonatal neurons and adult behavior in cells involved in adaptive immunity (Lampron et al.,
mice (Davis et al., 2013). 2013). Monocytes are the main innate immune
response mediator cells, producing and secreting
TNFα, interleukin-1β (IL-1β) and IL-6, which in turn
The impact of polluted air on a developing recruit and increase the activity of other immune
brain cells. Fine and UFPM could serve as the crucial
trigger for a chain of events leading to endothelial
Clean air is fundamental for children’s health and activation, disruption of blood–brain barrier (BBB),
well-being. Millions of children are showing an altered response of the innate immune system,
array of adverse short- and long-term health out- production of autoantibodies to cell junction and
comes related to air pollution exposures. Widely neural proteins, neuroinflammation and neuro-
recognized among pediatric health providers is degeneration. These early changes, amenable to
the impact of intrauterine factors, parent–child intervention and viewed initially as a compensa-
interactions, cognitive stimulation, maternal SES tory phenomenon by some groups including ours
during pregnancy and the child’s nutrition and (Perry et al., 2002; Castellani et al., 2006; Calderón-
exposure to complex learning stimuli, all vital for Garcidueñas et al., 2012a; 2013a) are likely critical
brain development (Calderón-Garcidueñas and to onset and progression of the neurodegenerative
Torres-Jardón, 2012a). However, air pollution changes and the full clinical picture seen in AD
brain effects rooted in intrauterine life and child- patients (Castellani et al., 2006).
hood are not generally acknowledged. Air pollu- There is growing recognition of the role of sys-
tion is not broadly recognized in the context of temic and neural inflammation and the interplay
children’s brain effects including the presence of between immunity, neurodegeneration and mala-
neuroinflammation, cognitive deficits, structural daptive activation of innate/adaptive immunity as
brain alterations and neuropathological hallmarks key pathogenic phenomenon in AD (Blasko et al.,
of Alzheimer (AD) and Parkinson’s diseases (PD) 2004; Dik et al., 2005; Finch and Morgan, 2007;
(Calderón-Garcidueñas et al., 2003; 2008a; 2008b; Bonotis et al., 2008; Gomez-Ravetti and Moscato,
2008c; 2009; 2010; 2011a; 2011b; 2012a; 2012b; 2008; Cunningham et al., 2009; Keene et al., 2011).
2012c; 2013a; 2013b). Likewise, change in immune status has been
A coherent pathway linking exposure to air suggested as a plausible biological mechanism by
pollution and brain damage starts with a chronic which PM could cause adverse health effects
inflammatory process involving the respiratory (Eikelenboom et al., 2011). PM has the capability
upper and lower tracts, which result in a systemic of crossing barriers, including the BBB resulting in
inflammatory response with the production of neuroinflammation and intrinsically disordered
inflammatory mediators capable of reaching the neural proteins associated with neurodegenerative
brain (Calderón-Garcidueñas et al., 2003; 2008a; diseases (Campbell, 2004; Win-Shwe et al., 2008;
2008b; 2008c; 2009; 2011a; 2011b; 2012a; 2012b; Levesque et al., 2011).
2013a; 2013b). Continuous expression of potent The emerging picture reveals highly exposed
inflammatory mediators in the central nervous sys- urban children exhibit significant neuroinflammation
tem (CNS) and the formation of reactive oxygen and brain oxidative stress (Calderón-G arcidueñas
species are major findings in urban residents et al., 2008c; 2012a; 2013a; 2013b). In addition, these
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children have extensive abnormal white matter potentials (BAEPs), auditory impairment and ves-
blood vessels, perivascular inflammation and a tibular dysfunction in exposed children is likely
breakdown of the BBB (Calderón-Garcidueñas et al., related to the extensive brainstem inflammation
2008c). Fine tuning of immune-to-brain commu- with accumulation of β-amyloid and α-synuclein in
nication is crucial to neural networks appropriate key auditory and vestibular nuclei (Calderón-
functioning, thus our recent finding of autoantibodies Garcidueñas et al., 2011). Neurodegenerative
to actin and occludin/zonulin in the presence of BBB changes in the dorsal motor nucleus of the vagus,
compromise might represent one more factor the nucleus of the solitary tract, arcuate nucleus,
contributing to initiation and/or pathogenesis of raphe midline, and extra-raphe medial and lateral
neurodegenerative changes. Current data support tegmental neurons (Calderón-Garcidueñas et al.,
a role for air pollution in CNS damage and urban 2011) are similar to the PD stages I and II of Braak
children shared mechanistic pathways potentially et al. (2004). The brainstem pathology we are
conducting to AD and PD (Calderón-Garcidueñas observing in highly exposed children has strong links
et al., 2013a). with both AD and PD (Braak et al., 2004; 2011).
Recent studies have reported associations between
prenatal and perinatal exposures to air pollutants and
The short- and long-term effects of air autism spectrum disorder (ASD) in children (van
pollution upon the CNS den Hazel et al., 2006; Larsson et al., 2009; Herbert,
2010; Volk et al., 2011; 2013; 2014; Becerra et al.,
We have discussed plausible mechanistic pathways 2013; Roberts et al., 2013; Visser et al., 2013). ASD is
causing CNS effects associated with sustained likely caused by complex interactions between
exposures of ambient pollutants during a lifetime, genetic and environmental factors. ASD is associated
however, it should be clear that acute, subchronic to air pollution exposures during pregnancy in US
or chronic exposures to air pollutants all have cities with significant air pollution from traffic sources
detrimental CNS effects. An example of acute and (Becerra et al., 2013). Activation of the maternal
subchronic massive exposures was the World immune system during pregnancy and abnormal
Trade Center 9/11-related environmental disaster behavioral development in Rhesus monkey offspring
(Bills et al., 2008; Jordan et al., 2013; Ozbay et al., brings up key questions regarding the role of air
2013). Massive exposure to a complex mixture of pollution and autism among vulnerable populations
inhalable fine PM, nanoparticles (NPs) and toxic (Bauman et al., 2013). To complicate matters
chemicals, resulted in persistent mental detri- for clinicians in real-world settings, the changes
mental effects and evolution toward unknown in the diagnostic criteria for autism in DSM-5 is
brain health outcomes beyond posttraumatic stress causing significant controversies and concerns
disorder (Bills et al., 2008; Jordan et al., 2013; among health providers without formal training in
Ozbay et al., 2013). research instruments and complicated assessment
The olfactory bulb (OB) pathology needs special processes (Hazen et al., 2013).
attention because large segments of the world
population inhale toxic substances on daily basis
that have the potential for harming the olfactory Reflections from practice
system and penetrating the brain via the olfactory
epithelium (Calderón-Garcidueñas et al., 2010). The This paper is the product of discussions among the
issue is very important in the context of air pollution authors, all of us familiar with MCMA air pollution.
because olfactory dysfunction is among the earliest We are physicians, pathologists, neuropathologists,
‘pre-clinical’ features of AD and PD, occurring in auditory system experts, toxicologists, psychologists
~90% of early onset cases (Wang et al., 2010; Doty, and atmospheric researchers dealing with children,
2012). Early olfactory deficits in MCMA young worried parents and school officials, looking at
residents appear to be associated with the presence neurodegenerative pathologies in autopsy materials
of β-amyloid, α- synuclein, PM in glomerular from seemingly healthy children dying in accidents
structures and the massive distortion of the OB and having significant trouble in explaining parents
organization (Calderón-Garcidueñas et al., 2010). plausible biological pathways that will solve all their
The central delayed brainstem auditory evoked questions. Several concerns have been raised in this
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short review about the influence of air pollutants Levesque et al., 2011; Win-Shwe and Fujimaki,
upon the adult and the developing brain that involve 2011; Wu et al., 2011; Brun et al., 2012; Guo et al.,
a wide spectrum of pathologies the clinician should 2012; Sharma and Sharma, 2012; Trickler et al.,
take into account for short- and long-term CNS 2012). The chronic effects of PM2.5 in mice result in
impact. spatial learning and memory deficits with neu-
In adults, it is imperative to take care of chronic roinflammation and hippocampal dendritic altera-
diseases that aggravate vascular, metabolic and tions (Fonken et al., 2011). Metal accumulation is
structural brain changes, while advising the patient associated with memory dysfunction, especially if
about tobacco and cigarette smoking and harmful the metal is administered during the neonatal
occupations and hobbies. In children, the cognitive, period, a clear example being iron loading in
auditory and vestibular effects have immediate rodents resulting in impaired spatial memory
early school negative effects, while the prefrontal and in long-term retention of object recognition
lesions and the diffuse cortical neuroinflammation deficient memory (Schröder et al., 2013). Equally
will be reflected in decreased career opportunities, important in the context of urban environments is
negative social health outcomes, including increases the massive exposure to NPs entering the body
in delinquent or criminal activity and violence and mostly through inhalation (Win-Shwe et al., 2011;
consequently a major negative impact on the Brun et al., 2012). Gold and silver NPs have an
economy in which those individuals reside. An issue effect on human embryonic neural precursor
everybody ignores is that the teens reduced capa- cell growth, suggesting a negative impact of NPs on
city to block impulsive antisocial behavior that the developing CNS (Söderstjerna et al., 2013).
accompanies impaired fluid cognition is having a Intense oxidative damage and lipid, protein and
significant impact on society. DNA peroxidation are observed in mice after
Next, we review more in detail the specific air intranasal administration of TiO2 NPs (Ze et al.,
pollution effects of brain impairment on cognition 2014). Ferromagnetic mineral magnetite (Fe(3)O
and behavior that support the practical reflections (4)) NPs cause structural changes of microtubule
presented in this paper. Table 1 summarizes in and tau protein, essential in the memory mechan-
schematic form selected studies examining neuro- ism and memory dysfunction (Dadras et al., 2013).
cognitive/neurophysiological effects of air pollution Ozone, the main component of photochemical
in children, adolescents and young adult popula- pollution in urban areas has been shown to alter
tions. The table shows the populations and the air adult neurogenesis and produce progressive hippo-
pollutants studied, the tests and deficits found, other campal neurodegeneration along with memory
tests used and the city/cities/country where the deficits in rats exposed to low subchronic con-
study took place. In what follows we will be focus- centrations (Rivas-Arancibia et al., 2010).
ing mainly on the available findings concerning Clinically healthy urban children from MCMA
MCMA children and mechanistic studies on brain selected by stringent criteria exhibited structural,
development in animal research literature. neurophysiological and cognitive detrimental
effects compared with matched SES, gender, age
and mother’s IQ low pollution exposed children
Making the links: detrimental brain (Calderón-Garcidueñas et al., 2008a; Calderón-
effects and cognitive/behavioral Garcidueñas et al., 2011a). The cognitive deficits in
functions MC children matched the magnetic resonance
imaging (MRI) volumetric changes in their right
As we have already mentioned, depending on the parietal and bilateral temporal areas (Calderón-
pollutant component, doses, exposure protocol, age Garcidueñas et al., 2012b). Highly exposed children
and gender, health status, etc., the detrimental without white matter hyperintensities (WMH− )
effects range from endothelial dysfunction, BBB displayed the profile of classical pro-inflammatory
breakdown, dopaminergic neuronal damage, DNA defensive responses: high IL-12, production of
damage, white matter lesions, neuroinflammation, powerful pro-inflammatory cytokines and low con-
formation of free radicals and oxidative stress, to centrations of key cytokines and chemokines asso-
the identification of early hallmarks of AD and PD ciated with neuroprotection. Conversely, children
(Campbell et al., 2004; Fonken et al., 2011; with WMH+ exhibited a response involved in
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Table 1 Selected studies examining neurocognitive/neurophysiological effects of air pollution in children, adolescents and young adult populations.
The table shows the populations and the air pollutants studied, the tests and deficits found, other tests used and the city/cities/country where the study
took place
Study Exposed/pollutants Neurobehavioral/ Neurocognitive/neurophysiological Other tests/laboratory longitudinal City, country
measured neurophysiological tests results follow-up
Calderón-Garcidueñas 73 children WISC-R Deficits in a combination of fluid and Brain MRI Mexico City versus
et al. (2008a) 9.85 ± 2.15 years crystallized cognition tasks: object ApoE genotyping Control City, Mexico
Urban Mexico City assembly, picture arrangement, digit Comparative neuropathology
atmosphere span, information, arithmetic, mazes, Dog brain RT-PCR
vocabulary
Suglia et al. (2008) 202 children Wide range assessment of Decreases on the visual subscale and na Boston, MA, USA
9.7 ± 1.7 years memory and learning general index
Black carbon Kaufman Brief Intelligence Test Decreases in vocabulary, matrices and
composite intelligence quotient scores
Wang et al. (2009) 861 children Line discrimination (LDT) Visual simple reaction time with na Quanzhou, China
8–10 years Visual retention (VRT) preferred hand and with nonpreferred
NO2 and PM10 Visual simple reaction time, hand, continuous performance, digit
preferred hand (VRT-Prh) symbol, pursuit aiming, and sign
Visual simple reaction time, register
nonpreferred hand (VRT-Nprh)
Continuous performance (CPT)
Digit erase (DET)
Digit symbol (DSB)
Pursuit aiming (PAT)
Primary Health Care Research & Development 2015; 16: 329–345
Sign register (SRT)
Calderón-Garcidueñas 87 teens, young adults The University of Pennsylvania Olfaction deficits in 35.5% of Mexico Olfactory bulb neuropathology in Mexico City versus
et al. (2010) 21.2 ± 2.7 years Smell Identification Test City subjects children and young adults: βA 1–42 Control City, Mexico
Urban Mexico City (UPSIT) ApoE 4 carriers failed 10-items related to and α-synuclein immunoreactivity,
atmosphere Alzheimer’s disease P = 0.01 versus ultrafine particles and vascular
low air pollution controls changes
ApoE genotyping
Freire et al. (2010) 210 children from rural McCarthy Scales of Children’s Decreases in general cognitive scores One-year follow-up from age four Granada, Spain
and urban areas Abilities (MSCA) and in quantitative, working memory years
Five-year-olds and gross motor areas
NO2
Air pollution and brain 335
Calderón-Garcidueñas 51 children Brainstem auditory evoked Significant delays in wave III Brainstem pathology in nine Mexico City versus
et al. (2011) 8.0 ± 0.7 years potentials (BAEPs) (P < 0.0001), and wave V (P < 0.0001) in children aged 13.9 ± 4.0 years Control City, Mexico
Urban Mexico City Mexico City versus controls consisting Brainstem inflammation and
atmosphere with delayed central conduction time accumulation of βA 1–42 and α-
of brainstem neural transmission synuclein in auditory and
vestibular nuclei. α-synuclein in
pigmented neurons of the
substantia nigrae
Haynes et al. (2011) Rate of criminal Criminal behavior Airborne exposure to Mn, Hg and PM Antisocial behavior Ohio counties, USA
adjudications/10 000 are associated with increased risk of Ecological relationship between
people/10–19 years criminal activity adjudication county-wide reported airborne
emissions of air metals, PM and
youth adjudicated for criminal
activityhttps://www.cambridge.org/core/terms. https://doi.org/10.1017/S146342361400036X
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Primary Health Care Research & Development 2015; 16: 329–345
336 L. Calderón-Garcidueñas et al.
Table 1 Continued
Study Exposed/pollutants Neurobehavioral/ Neurocognitive/neurophysiological Other tests/laboratory longitudinal City, country
measured neurophysiological tests results follow-up
Calderón-Garcidueñas 20 children WISC-R Progressive deficits in digit span and Brain MRI Mexico City versus
et al. (2011) 6.95 ± 0.67 years vocabulary in Mexico City children Control City, Mexico
Urban Mexico City versus controls
atmosphere The cognitive deficits in highly exposed
One-year follow-up children matched the significant
differences in white matter volumes
involving right parietal and bilateral
temporal lobes
Clark et al. (2012) 719 children Suffolk Reading Scale 2 Aircraft noise exposure at school was Parents completed a self-report
9–10 years Child Memory Scale significantly associated with poorer questionnaire that included
22 schools around The Search and Memory recognition memory, reading questions on sociodemographic
London’s Heathrow Task Health comprehension, information recall, factors, as well as questions on the
airport and conceptual recall perceived health of their children
and psychological distress
measured using the parental
version of the Strengths and
Difficulties Questionnaire
Calderón-Garcidueñas 20 children WISC-R MC WMH − children displayed classical Brain MRI Mexico City versus
et al. (2012c) 6.95 ± 0.67 years pro-inflammatory defensive Measurement of white matter Control City, Mexico
Urban Mexico City responses versus WMH + children hyperintensities (WMH)
atmosphere responses involving resolution of Inflammatory mediators
Baseline and one-year inflammation, immunoregulation, and
follow-up tissue remodeling. The MC WMH +
group responded to the air pollution-
associated brain volumetric alterations
with white and gray matter volume
increases in temporal, parietal, and
frontal regions and better cognitive
performance compared to MC WMH −
van Kempen et al. 553 children Simple Reaction Time Test Exposure to NO2 at school was na Amsterdam, The
(2012) 10.5 ± 0.6 years (SRTT) statistically significantly associated Netherlands
Schiphol-Amsterdam Switching Attention Test (SAT) with a decrease in the memory span
Airport Hand–Eye Coordination Test length
NO2 exposures Symbol Digit Substitution Test Statistically significant associations
(SDST) were observed between road and air
Digit Memory Span Test traffic noise exposure at school and the
(DMST) number of errors made during the
‘arrow’ and ‘switch’ conditions of the
SAT
The table shows the populations and the air pollutants studied, the tests and deficits found, other tests used and the city/cities/country where the study
took place.Air pollution and brain 337
resolution of inflammation, immunoregulation and Jian et al., 2013). The associations between cognition
tissue remodeling. The WMH+ group responded and urban pollution has been established in cities
to the air pollution-associated brain volumetric like Boston, where black carbon – a marker for
alterations with white and gray matter volume traffic PM – predicted decreased cognitive function
increases in temporal, parietal and frontal regions across assessments of verbal and nonverbal intelli-
and better cognitive performance compared with gence and memory in nine-year-olds (Suglia et al.,
the WMH− group. We conclude that complex 2008).
modulation of cytokines and chemokines influences
children’s CNS structural and volumetric responses
and cognitive correlates resulting from environ- A working framework for prevention and
mental pollution exposures. Regardless of the pre- intervention
sence of prefrontal WMH, MC children performed
more poorly across a variety of cognitive tests, Although genetic factors play a key role in CNS
compared with control children. responses (as evidenced by the acceleration of
We have identified a number of abnormalities neurodegenerative pathology in children carrying an
also within the auditory brainstem nuclei in chil- APOE 4 allele), studies such the above mentioned
dren exposed to severe air pollution. Specifically, ones in Boston and others, sketch a complex
we have observed that neuronal cell bodies within scenario where air pollution and SES can influence
the medial superior olive (MSO) are significantly neural development and cognition, as well as genet-
smaller and more round than those in age-matched ics, nutrition, access to a cognitively stimulating
control brains (Calderón-Garcidueñas et al., 2011b). environment, thereby influencing and determining
We interpret this dysmorphology to indicate mental health, academic achievements and overall
injury and dysfunction in the MSO. The MSO is the life performance (D’Angiulli et al., 2009; Siddique
largest nucleus within the human superior olivary et al., 2011; Calderón-Garcidueñas & Torres-Jardón,
complex and has clear roles in localization of sound 2012a; Becerra et al., 2013).
sources, encoding temporal features of sound and Thus, identification of children at risk for cogni-
likely plays an important role in brainstem encoding tive deficits, brain structural/volumetric and neuro-
of speech. Incidentally, similar morphological altera- degenerative accelerating changes should be
tions were observed in autistic children (Kulesza and prioritized in populations exposed to significant
Mangunay, 2008; Kulesza et al., 2011). Confirming concentrations of air pollutants. There is growing
brainstem pathology, MCMA children showed public concern about the direct and indirect influ-
clearly abnormal BAEPs with delays in wave III ences air pollution may have on several develop-
and wave V but no delay in wave I. These findings mental outcomes such as school performance,
are consistent with delayed central conduction behavioral changes and mood disorders in children
time of brainstem neural transmission, and and teens. Moreover, childhood aggression and
increased risk for auditory and vestibular impair- teen delinquency are increasing in megacities,
ment (Calderón-Garcidueñas et al., 2011b). We establishing early environmental health risk
are assessing the integrity of the auditory system in factors for violence prediction and prevention
highly exposed children through a number of (Haynes et al., 2011; Liu, 2011) in populations at
noninvasive techniques, such as BAEPs, otoa- risk will be absolutely critical. New concerns
coustic emissions, speech recognition tasks and involve the association between air pollution
listening in background noise. exposure and increased risk of attention deficit
It is clear that air pollution exposed children hyperactive disorder (Siddique et al., 2011) and
experience a chronic, intense state of oxidative autism (Becerra et al., 2013) in young and older
stress and exhibit an early brain imbalance in genes children.
involved in inflammation, innate and adaptive Strong support for the need of neurocognitive
immune responses, cell proliferation and apoptosis. screening comes from a growing psychological and
Neuroinflammation, endothelial activation and the epidemiological literature suggesting evidence
breakdown of the BBB contribute to cognitive of suboptimal cognitive functioning across the
impairment and pathogenesis and pathophysiology developmental span in clinically healthy children
of neurodegenerative states (Roher et al., 2012; (Guxens and Sunyer, 2012; Calderón-Garcidueñas
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et al., 2012b). Importantly, a significant proportion Table 2 Suggested battery of neuropsychological and
of urban schools are situated near major traffic- psychoeducational tests for the initial screening of school-
aged children and teens exposed to urban air pollution
related air pollution sources (Amram et al., 2011;
Amato et al., 2014), and cognitive outcomes may 1. Rapid mental health screening tool for pediatric use that
be partly associated with air pollution levels includes: education, activities/peers, drugs/alcohol,
around schools (Mohai et al., 2011). suicidality, emotions/behavior discharge resources like
Consistent with these observations, the National HEADS-ED (Cappelli et al., 2012)
2. Test for episodic memory
Institute of Environmental Health Sciences/National Rey Auditory Verbal learning Test (RAVLT): learning,
Institute of Health panel on outdoor air pollution immediate and delayed recall
indicated cognitive, neuropsychological (and possibly Weschler’s Logical Memory (WLM): immediate and
neuroimaging) screening of children as one of the delayed recall
3. Speed/executive functions
priority target areas for future research advocating Digit symbol WAIS-R
a multidisciplinary collaborative approach wherein 4. Visuospatial function
brain-related cognitive (henceforth, neurocognitive) Rey Complex Figure Test
development testing would have a prominent role Block design WAIS-R
(Block et al., 2012). 5. Semantic memory/verbal functions
Similarities WAIS-R
Hence, the use of standard neurocognitive tasks 6. Verbal working memory/fluency
to screen clinically healthy children in schools Digit Span WAIS-R
or pediatric offices seems not only desirable but Word fluency (COWA)
also highly beneficial. Because the primary goal
would be to identify children at risk, possibly at
the largest scale, the first step could be to screen pediatric populations at risk, should be prioritized
entire schools in different neighborhoods with dif- (Forastiere et al., 2007; Ou et al., 2008).
ferent air pollutant profiles. Multidisciplinary According to the American Neuropsychiatric
approaches for early risk identification could include Association and the Shulman criteria (Malloy et al.,
using air pollution databases from available moni- 1997; Shulman, 2000), the ideal cognitive screening
toring stations to gather: (1) Air pollutant profiles in instrument should (i) be relatively brief to admin-
selected geographic area; (2) exposures to traffic- ister; (ii) be easy to score; (iii) well tolerated and
related air pollutants at each child’s school and accepted by participants, in our cases both child
current residence with land use regression models and parent; (iv) test all targeted cognitive domains;
that combine a geographic information system (v) be valid and reliable; and (vi) relatively inde-
with ambient passive monitoring in the target area; pendent of or controlling for age and education.
(3) cumulative ambient exposures to fine PM2.5; A possible battery of tests (easily translatable in
(4) robust baseline information on the oxidative many languages) for the initial screening of school-
potential and metal content of PM found in the tar- aged children is described in Table 2. The measures
geted regions; (5) cognitive screening first and, when in this table have reference to previous neuroima-
applicable, more elaborate neurocognitive/neuro- ging findings implicating functional, maturational or
physiological follow-ups, which could include EEG/ structural correlates of frontal, parietal and temporal
ERPs, BAEPs, MRI, f MRI and MRS. regions and/or neurocognitive tests applied to air
The first goal in targeted areas will be to define pollution studies in children as seen on Table 1.
the cohorts with the most risk for neurocognitive Because several studies link risk of negative effects
deficits based on traffic emissions, fixed sources of of air pollution to early development, from infancy
contaminants, profile of toxic pollutant compo- to preschool, screening could start in daycare or
nents (ie, metals) and cumulative concentrations during transition from kindergarten to first grade, for
of fine PM. The initial studies should be followed example using tools such as the Early Development
by interventions aimed at breaking the cycle of air Instrument (D’Angiulli et al., 2009). With advances
pollution, indoor air pollution, tobacco use, high in wireless neuroimaging technology, neurocognitive
body mass index, low fruit and vegetable intake screening may even incorporate rapid EEG/ERP
and physical inactivity. Since health risk factors are recording procedures.
more likely to have a toll on low SES children, In summary, air pollution effects on the deve-
identification of spatial concentrations of low SES loping brain may vary along a continuum from
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minor subclinical deficits in cognitive functioning causes of death like pneumonia, but not the base
to significant cognitive deficits that are identified disease. Therefore, the answer to the central issue
readily by parents and/or teachers. The detri- of incidence of AD/PD in MCMA is very much an
mental effects may also worsen with the age of the open empirical question for future research.
child, thus selected neurocognitive tools ought Our ultimate goal is to protect exposed children
to be useful for longitudinal studies, across educa- through multidimensional interventions yielding
tional backgrounds and expecting overlaps in both impact and reach: cognitive (Diamond and
the functional areas and tests affected. Complex Lee, 2011), family participation (Josephson, 2013)
cognitive responses that may be affected include and modifiable lifestyle factors such as diet and
attention and short-term memory, information micronutrient supply (Villarreal-Calderon et al.,
processing speed and executive function, verbal 2010; Calderón-Garcidueñas et al., 2012c).
abstraction and visuospatial and motor skills. Air pollution brain effects on children and teens
We should also expect deficits in auditory and ought to be key public health targets.
vestibular responses and sound localization, along
with olfaction deficits. The diffuse nature of the Key points to remember
neuroinflammation and the neurodegenerative
changes observed in exposed children obligates ∙ Risk for stroke and depression are associated
us not to rely on a single study or measure but with common ambient air pollutants, including
rather to employ a weight of evidence approach fine and UFPM and ozone.
incorporating current clinical, neurophysiological, ∙ The stroke risk is present even at pollutant
radiological and epidemiological research as concentrations below the current standards,
well as the results of animal exposure studies to sin- meaning there is a wide spectrum of suscept-
gle pollutants/mixtures/or pollutant components. ibility to pollutants likely related to factors such
Inflammatory biomarkers play a key role in the as the presence of chronic diseases, and genetic
identification of children with positive volumetric and nutrition variables.
and cognitive responses to their lifelong pollutant ∙ Stroke is not a stroke, specific patient character-
exposures (Calderón-Garcidueñas et al., 2012b) and istics modify associations between air pollution
since neuroinflammation/vascular damage/neurode- and ischemic stroke (Villeneuve et al., 2012).
generation go hand in hand (Calderón-Garcidueñas ∙ Check for factors that will aggravate the
et al., 2013a and 2013b), definition of inflammatory/ neurological/psychiatric effects of air pollution
endothelial dysfunction biomarkers establishing an such as diabetes, hypertension, infectious pro-
association between brain growth and cognition are cesses, residency in close proximity to a busy
urgently needed. road, changes in occupation, etc.
Of course, in light of the findings reviewed in the ∙ Keep an eye on the air quality index of your city,
present paper, a pressing important question that record proximity of the patient to high density
jumps to mind is whether the prevalence of AD/ traffic (Mohai et al., 2011; van Kempen et al.,
PD is increased in MCMA? Unfortunately we do 2012) or fixed sources of pollutants, check for
not have accurate records from health institutions. acute events such as forest fires or the arrival of
Mexico health care is covered by both private and fumes from a distant area (Chen et al., 2013).
government hospitals and institutes and there is no ∙ PM occupational exposures and tobacco are to
universal statistical information regarding AD and be taken into consideration as important sources
PD prevalence. Empirically, however, neurolo- of pollutants.
gists and general practitioners report a significant ∙ The patient’s occupation and hobbies are
increase in the number of cases for both neurode- important. Is she an outdoor person? Is he
generative diseases (Victor Esquivel MD, protected against toxic substances at work? Is
Neurologist, personal communication). Death there a significant source of PM or NPs at the
certificates that would be a source of information, office? Where is the patient from? A good
unfortunately fail to list AD or PD in the certifi- clinical history is a must.
cate, basically because families are reluctant to link ∙ Parents and school officials should be aware of
their patients to a disease with genetic implica- the high pollutant concentrations in their area
tions, and so only allowed for the writing of acute and keep children indoors.
Primary Health Care Research & Development 2015; 16: 329–345
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https://www.cambridge.org/core/terms. https://doi.org/10.1017/S146342361400036X340 L. Calderón-Garcidueñas et al.
∙ Identification of children at risk for cognitive Annesi-Maesano, J., Baiz, N., Banerjee, S., Rudnai, P. and
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Banerjee, M., Siddique, S., Dutta, A., Mukherjee, B. and
Ray, M.R. 2012: Cooking with biomass increases the risk of
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∙
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Acknowledgment Bedada, G.B., Smith, C.J., Tyrrell, P.J., Hirst, A.A. and
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Gratitude is due to all children and their families and gaseous pollutants on the incidence of transient
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Environmental Health. doi: 10.1186/1476-069X-11-77.
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