Environmental Health Perspectives • volume 119 | number 6 | June 2011
Research | Children’s Health
Autism is a developmental disorder charac-
terized by significant deficits in social inter-
action and communication, accompanied by
repetitive behaviors (American Psychiatric
Association 2000). Data from family and twin
studies have long supported the role of genetics
in autism etiology (Abrahams and Geschwind
2008; Muhle et al. 2004). Results from linkage,
copy number variation, and genomewide asso-
ciation studies further support the importance
of genetic risk in this disease (Abrahams and
Geschwind 2008; Ma et al. 2009; Wang et al.
2009). Over the last 10 years, the prevalence of
diagnoses of autism, and all autism spectrum
disorders, has increased (Centers for Disease
Control and Prevention 2007a, 2007b, 2009).
Although changes in diagnostic criteria and
improved ascertainment have been thought
to contribute to this increase, recent reports
suggest that these factors may not fully explain
the rising incidence of autism spectrum disor-
ders (Hertz-Picciotto and Delwiche 2009; King
and Bearman 2009). Therefore, it is likely that
environmental factors may augment the strong
genetic risks implicated in autism etiology.
Air pollution exposure during pregnancy
has been reported to have physical and devel-
opmental effects on the fetus. High levels of air
pollution, including carbon monoxide, nitro-
gen dioxide, and ambient particulate matter
(PM), have been associated with very low and
low birth weight, preterm birth, and infant
mortality (Currie et al. 2009; Ritz and Yu
1999). Specific pollutants, including ozone,
sulfur dioxide, PM, and carbon monoxide,
have also been associated with significant dif-
ferences in biparietal diameter and head cir-
cumference measured both during pregnancy
and at birth (Hansen et al. 2008; Vassilev
et al. 2001). Maternal exposure to polycy-
clic aromatic hydrocarbons (PAHs) during
pregnancy has been associated with impaired
cortical function and cognitive developmental
delay (Bocskay et al. 2005; Perera et al. 2003,
2004, 2006, 2007).
Exposure to air pollution and its compo-
nents, not only in the prenatal period but also
in early postnatal life, has been linked to poor
developmental outcomes as well. A recent epi-
demiologic study reported that use of gas appli-
ances and increased nitrogen dioxide in the
home during the first 3 months of life are asso-
ciated with decreased cognitive test scores and
increased inattention at 4 years of age (Morales
et al. 2009). In a separate study, Suglia et al.
(2008) estimated lifetime residential exposure
to black carbon, a proxy for traffic-related PM,
among 8- to 11-year-old children and reported
decreased performance on intelligence and
memory tasks with increasing black carbon
levels. Additionally, autism has been associ-
ated with estimated regional concentrations of
hazardous air pollutants, including arsenic and
nickel, and with diesel PM exposure in early
childhood (Windham et al. 2006).
Thus, an emerging literature suggests that
near roadways, traffic-related air pollutants,
possibly influenced by specific components
such as PM or PAHs, affect neurodevelop-
ment. However, the role of timing for this
exposure during pregnancy or early life is not
clear, nor has the relationship between traffic-
related air pollutants and autism been tested.
In this study, we examined the relationship
between autism and traffic proximity (a
marker of traffic-related air pollution) during
the prenatal period and at the time of birth.
Materials and Methods
We used data from 304 autism cases and 259
typically developing general-population con-
trols from the Childhood Autism Risks from
Genetics and the Environment (CHARGE)
study, a population-based case–control study
of preschool children. The study design is
described in detail elsewhere (Hertz-Picciotto
et al. 2006). Briefly, CHARGE subjects
were between 24 and 60 months of age at
the time of recruitment, which occurred
during 2003–2009; lived with at least one
English- or Spanish-speaking biological par-
ent; were born in California; and resided in
one of the study catchment areas at the time
of enrollment. Recruitment was facilitated by
the California Department of Developmental
Services (DDS) and the regional centers with
which they contract to coordinate services for
Address correspondence to H.E. Volk, Keck School
of Medicine, University of Southern California,
1540 Alcazar St. CHP 209G, Los Angeles, CA
90033 USA. Telephone: (323) 442-5101. Fax: (323)
442-3272. E-mail: firstname.lastname@example.org
This work was supported by National Institute of
Environmental Health Sciences grants ES019002,
ES009581, ES013578, ES007048, ES11269,
ES015359, and RD831861; U.S. Environmental
Protection Agency Science to Achieve Results
(STAR) grants R-823392 and R-833292; the MIND
Institute matching funds and pilot grant program;
and Autism Speaks.
F.L. is employed by Sonoma Technology Inc.,
which provided expert services in exposure assessment
for this work. The other authors declare they have no
actual or potential competing financial interests.
The authors declare they have no actual or potential
competing financial interests.
Received 6 August 2010; accepted 13 December
Residential Proximity to Freeways and Autism in the CHARGE Study
Heather E. Volk,1 Irva Hertz-Picciotto,2 Lora Delwiche,2 Fred Lurmann,3 and Rob McConnell4
1Departments of Preventive Medicine and Pediatrics, Zilkha Neurogenetic Institute, Keck School of Medicine, Children’s Hospital
Los Angeles, University of Southern California, Los Angeles, California, USA; 2Department of Public Health Sciences, University of
California–Davis, Davis, California, USA; 3Sonoma Technology Inc., Petaluma, California, USA; 4Department of Preventive Medicine,
Keck School of Medicine, University of Southern California, Los Angeles, California, USA
Background: Little is known about environmental causes and contributing factors for autism.
Basic science and epidemiologic research suggest that oxidative stress and inflammation may play
a role in disease development. Traffic-related air pollution, a common exposure with established
effects on these pathways, contains substances found to have adverse prenatal effects.
Objectives: We examined the association between autism and proximity of residence to freeways
and major roadways during pregnancy and near the time of delivery, as a surrogate for air pollution
Methods: Data were from 304 autism cases and 259 typically developing controls enrolled in the
Childhood Autism Risks from Genetics and the Environment (CHARGE) study. The mother’s
address recorded on the birth certificate and trimester-specific addresses derived from a residential
history obtained by questionnaire were geocoded, and measures of distance to freeways and major
roads were calculated using ArcGIS software. Logistic regression models compared residential prox-
imity to freeways and major roads for autism cases and typically developing controls.
Results: Adjusting for sociodemographic factors and maternal smoking, maternal residence at the
time of delivery was more likely be near a freeway (≤ 309 m) for cases than for controls [odds ratio
(OR) = 1.86; 95% confidence interval (CI), 1.04–3.45]. Autism was also associated with residential
proximity to a freeway during the third trimester (OR = 2.22; CI, 1.16–4.42). After adjustment for
socioeconomic and sociodemographic characteristics, these associations were unchanged. Living
near other major roads at birth was not associated with autism.
Conclusions: Living near a freeway was associated with autism. Examination of associations with
measured air pollutants is needed.
Key words: autism, epidemiology, gene–environment interaction, roadway proximity, traffic
emissions. Environ Health Perspect 119:873–877 (2011). doi:10.1289/ehp.1002835 [Online
16 December 2010]
Volk et al.
volume 119 | number 6 | June 2011 • Environmental Health Perspectives
persons with autism and other developmental
disabilities. Population-based controls were
recruited from the sampling frame of birth
files from the State of California and were
frequency matched by sex, age, and broad geo-
graphic area to the autism cases. All births
were between 1997 and 2006.
Each participating family was evaluated
in person. Children with a DDS diagnosis
of autism were evaluated using the Autism
Diagnostic Observation Schedules (ADOS),
and parents were administered the Autism
Diagnostic Interview–Revised (ADI-R)
(Le Couteur et al. 2003; Lord et al. 2003).
Children with a diagnosed developmental delay
and general population controls were given the
Social Communication Questionnaire (SCQ)
to screen for the presence of autistic features
(Rutter et al. 2003). If the SCQ score was
≥ 15, the ADOS was then administered to
the child and the ADI-R to the parent. In our
study, autism cases were children with a diag-
nosis of autism from both the ADOS and the
ADI-R. All children were also assessed using
the Mullen Scales of Early Learning and the
Vineland Adaptive Behavior Scales to collect
information on motor skills, language, social-
ization, and daily living skills (Mullen 1995;
Sparrow et al. 1984). Controls were children
sampled from the general population with typ-
ical development, defined as having received a
score ≤ 15 on the SCQ and who scored in the
normal range on the Mullen Scales of Early
Learning and Vineland Adaptive Behavior
Scales, thereby showing no evidence of other
types of delay (cognitive or adaptive).
Parents were also interviewed extensively
to evaluate household exposures and demo-
graphic and medical information and to assess
reproductive, occupational, and residential
histories. The residential history captured
addresses and corresponding dates the mother
and child lived at each location beginning
3 months before conception and extending
to the most recent place of residence. Further
details about the collection of clinical and
exposure data have been previously reported
(Hertz-Picciotto et al. 2006).
We examined associations of autism with
traffic-related pollutant exposure using two
broad proxies: distance to the nearest free-
way and distance to the nearest major road. In
accord with our previous research, a freeway
was defined as a state highway or interstate
highway (Gauderman et al. 2007). A major
road was defined as a state highway, interstate
highway, or major arterial (McConnell et al.
2006). Mother’s residential address at birth, as
recorded on the birth certificate, was geocoded,
and distances to the nearest interstate high-
way, state highway, and major arterial road
were estimated based on the shortest distance
from the residence to the middle of the near-
est side of each of the three road types using
ArcGIS software (version 9.2; Environmental
Systems Research Institute Inc., Redlands,
CA). For each subject, freeway distance was
then assigned as the shorter of the distances
from the birth residence to a state or interstate
highway. Similarly, major road distance was
assigned as the shortest of the three distances:
from a state highway, interstate highway, or
major arterial. Under these definitions, it was
possible for freeway and major road distances
to be the same should the same road type (e.g.,
state highway) provide the shortest distance
measure for a given address. For freeway and
major road distances, we examined the distri-
bution of values among the 563 subjects in
our study and determined exposure cut points
based on the top 10%, next 15%, and subse-
quent 25% of distance values for freeways and
for major roads. The remaining 50% served as
a reference category in each analysis.
Information from the residential history
was used to estimate exposure to residential
traffic during the first, second, and third tri-
mesters of gestation for a subset of subjects
with complete data (n = 485; 257 cases and
228 controls). We determined the conception
date for each child using gestational age from
ultrasound measurements or the date of last
menstrual period, as determined from prenatal
records. Then we calculated dates correspond-
ing to each trimester and selected the appro-
priate address from the residential history. If
more than one address fell into a trimester, we
chose the address where the subjects had spent
the most time. Addresses were geocoded and
distances estimated as described above.
We used logistic regression to estimate the
association between distance to the nearest free-
way or major road and autism. Pertinent cova-
riates were included in the model to adjust for
potential confounding due to socio demographic
or lifestyle characteristics. Specifically, we
included child’s sex and ethnicity, maximum
education level of the parents, maternal age,
gestational age at birth, and maternal smoking
during pregnancy. We obtained 95% confi-
dence intervals (CIs) as measures of precision
and determined statistical significance using an
alpha level of 0.05.
Description of sample. The study popula-
tion was 84% male, and most participants
were Caucasian (51%) or Hispanic (29%).
We found no significant differences between
cases and controls for any demographic or
socioeconomic variables examined (Table 1).
For most participants, geocoded birth cer-
tificate addresses (mother’s residence at deliv-
ery) indicated that residences at birth were
concentrated in the areas around Sacramento,
Los Angeles, and the San Francisco East and
Distance to freeway. We examined the
distribution of distance from the nearest free-
way among subjects in our study and deter-
mined exposure cut-points to define the closest
10% (< 309 m), the next 15% (309–647 m),
and the next 25% (647–1,419 m) as expo-
sure groups. The remaining 50% (> 1,419 m)
served as the reference group in our analysis.
Living within 309 m of a freeway at birth was
associated with autism [odds ratio (OR) =
1.86; 95% CI, 1.04–3.45]. This association
was not altered by adjustment for child sex or
ethnicity, maximum education in the home,
maternal age, or maternal smoking during
pregnancy (Table 2). When we categorized
our distance measure into deciles, only the top
10%, corresponding to the < 309-m category,
showed evidence of an increased autism risk
compared with those living farthest from the
freeway (lowest decile, > 5,150 m; unadjusted
OR = 2.48; 95% CI, 1.17–5.39).
Among the subset of subjects with avail-
able residential history data, measures for
Table 1. Demographic characteristics of CHARGE cases with autism and controls with typical develop-
ment (n = 563).
Maximum education in home
High school or less
Graduate or professional degree
Maternal smoking during pregnancyb
Maternal age ≥ 35 years
Preterm delivery (< 259 days)c
Cases (n = 304)
Controls (n = 259)
a“Other” refers to mixed race/ethnicity or other reported race/ethnicity, including Native American, Indian, East Indian,
Cuban, or Mexican American. bMother reported smoking at any time during pregnancy. cEquivalent to 37 completed
Freeway proximity and autism risk
Environmental Health Perspectives • volume 119 | number 6 | June 2011
distance to the freeway were highly correlated
across trimesters, reflecting the limited num-
ber of subjects who changed residence during
pregnancy (n = 17 between first and second,
13 between second and third, 30 between first
and third). In each trimester, living closest to
the freeway (< 309 vs. > 1,419 m) was associ-
ated with autism, but the OR reached statisti-
cal significance only during the third trimester
(adjusted OR = 1.96; 95% CI, 1.01–3.93).
Effect estimates for the first and second tri-
mesters were slightly lower in magnitude
(first trimester: adjusted OR = 1.66; 95% CI,
0.91–3.10; second trimester: adjusted OR
= 1.65; 95% CI, 0.85–3.28). After restrict-
ing the sample with birth certificate addresses
to those with residential history data for all
three trimesters (n = 485; 257 cases and 228
controls), the OR for autism was more than
doubled among those living within 309 m of
a freeway versus > 1,419 m (adjusted OR =
2.22; 95% CI, 1.16–4.42), consistent with a
late-pregnancy or early-life effect.
Distance to major road. The distribution
of distance from a major road among sub-
jects in our study was reflected in exposure
cut-points corresponding to ≤ 42 m (the clos-
est 10%), 42–96 m (subsequent 15%), and
96–209 m (next 25%) as exposure groups.
The remaining 50% (> 209 m) served as the
reference group in our analysis. We found
no consistent pattern of association of autism
with proximity to a major road, and results
were changed only slightly after adjusting for
distance to the freeway (Table 3). Inclusion
of child sex or ethnicity, maximum education
in home, maternal age, or prenatal smoking
in the model did not alter these associations.
Results were similar for the three trimesters.
We observed an increased risk of autism
among the 10% of children living within
309 m of a freeway around the time of
birth. Our findings appeared to be limited
to only this group because analysis of further
distances did not demonstrate associations.
Analysis of trimester-specific residential infor-
mation yielded associations of roughly similar
magnitude, although only the effects for the
third trimester and at birth reached statisti-
cal significance. The high correlations across
trimesters, and lack of analysis of postnatal
residences, imply that we cannot precisely
define a potentially critical window.
The association of autism with proximity to
freeway, and not to major road, may be related
to the larger volume of traffic and concentra-
tions of pollutants observed near freeways. In
Los Angeles, for example, some freeways have
more than 300,000 vehicles daily and high
concentrations of traffic-related pollutants
with steep gradients extending several hundred
meters from the traffic corridor (Caltrans 2008;
Zhu et al. 2002, 2006). Specifically, studies
measuring concentration and size distribution
of ultrafine PM near a major California free-
way demonstrate that the PM is high nearest
the freeway and becomes closer to background
levels at distances ≥ 300 m (Zhu et al. 2002).
Thus, our findings are consistent with the rela-
tionship between freeway proximity and PM
exposures in California. Our study did not
find evidence of associations with residential
proximity beyond the 300-m range, and we
currently lack adequate sample size to estimate
the effect of living in even closer proximity to
the freeway (< 100 m) where high concentra-
tions of PM have been detected. To exam-
ine the effects of proximity at closer distances
to major roadways, we estimated autism risk
among subjects living within 96 m (the top
quartile of exposure vs. > 96 m) and among
those living within 300 m (corresponding to
the region of highest exposure vs. > 300 m)
and found slightly elevated non-statistically sig-
nificant risks (within 96 m: OR = 1.17; 95%
CI, 0.80–1.72; within 300 m: OR = 1.19;
95% CI, 0.84–1.68).
The traffic volumes on the classes of other
major roadways used in this analysis are likely
to be highly variable across California, so
exposure to traffic-related pollutants on the
spatial scale of interest may be less well clas-
sified by residential proximity to other major
roadways than by proximity to freeways. For
example, we found that the average distance to
a freeway among subjects living in the second
major road exposure group (42–96 m), with
slightly increased risk of autism, was much
shorter (mean ± SD = 1,481 ± 1,761 m) than
in other major road categories (major road
< 42 m, 2,643 ± 2,245 m to freeway; major
road 96–209 m, 1,917 ± 3,946 m). Residential
traffic proximity has been associated with
childhood asthma and lung function growth
in previous studies we have conducted in
Southern California, and some of these
associations have been restricted to freeway
proximity or traffic modeled from freeway
traffic volume (Gauderman et al. 2005, 2007;
McConnell et al. 2006, 2010).
We found little evidence of confounding
by the socioeconomic and sociodemographic
characteristics included in this analysis. We
hypothesized these confounders a priori based
on literature reporting increased autism rates
in higher socioeconomic areas, whereas lower
socioeconomic areas are more likely to have
higher levels of air pollutants (Sexton et al.
1993). In our study, we observed no differ-
ence in level of education in the home among
autism cases and controls, and adjusting for
these factors had little effect on the traffic and
autism association, suggesting that our results
were not biased by such factors. In California,
clusters of autism tend to have higher levels
of parental education, and in countries with
highly variable access to health care, diag-
nosed cases of autism tend to be in families
with higher socioeconomic status than the
general population; at the same time, controls
that participate in studies are almost always of
higher socioeconomic status than nonpartici-
pants (Van Meter et al. 2010).
To date, little research has examined the
association of air pollutants and autism. Using
the U.S. Environmental Protection Agency
Hazardous Air Pollutants monitoring net-
work, Windham et al. (2006) identified an
increased autism risk with modeled estimates
of regional census tract ambient exposure to
diesel exhaust particles, as well as metals (mer-
cury, cadmium, and nickel) and chlorinated
solvents, in the San Francisco Bay Area of
northern California. Additional research using
Table 2. Exposure ORs (95% CIs) for autism, by category of distance from residence to the nearest free-
way at time of birth (n = 563).
Exposure categoryn (cases/controls)
< 309 m from freeway (closest 10%)
309–647 m from freeway (10th to 25th percentile)
647–1,419 m from freeway (25th to 50th percentile)
> 1,419 m from freeway (further 50%)
aModel was adjusted for child sex (male vs. female), child race/ethnicity (Hispanic vs. white, black/Asian/other vs.
white), maximum education of parents (parent with highest of four levels: college degree or higher vs. some high school,
high school degree, or some college education), maternal age (> 35 years vs. ≤ 35 years), and maternal smoking during
pregnancy (mother reported any smoking during pregnancy vs. mother reported no smoking during pregnancy)
Table 3. Exposure ORs (95% CIs) for autism, by category of distance from residence to the nearest major
road at time of birth (n = 563).
Exposure categoryn (cases/controls)
≤ 42 m from major road (closest 10%)
42–96 m from major road (10th to 25th percentile)
96–209 m from major road (25th to 50th percentile)
> 209 m from major road (further 50%)
aModel was adjusted for child sex (male vs. female), child race/ethnicity (Hispanic vs. white, black/Asian/other vs.
white), maximum education of parents (parent with the highest of four levels: college degree or more education vs.
some high school, high school degree, or some college education), maternal age (> 35 years vs. ≤ 35 years), and mater-
nal smoking during pregnancy (mother reported any smoking during pregnancy vs. mother reported no smoking during
pregnancy), and freeway distance categories (< 309 m, 309–647 m, 647–1,419 m vs. referent of > 1,419 m).
Volk et al.
volume 119 | number 6 | June 2011 • Environmental Health Perspectives
models from the Hazardous Air Pollutants
program found associations between autism
and air toxics at the birth residence of chil-
dren from North Carolina and West Virginia
(Kalkbrenner et al. 2010). Our analysis builds
on this work by examining associations with
individual-level indicators of exposure based
on traffic proximity, prenatally and at birth.
Toxicologic studies suggest a biologically
plausible role of air pollution in disrupting
brain development and function during critical
time points in gestation and early life. Diesel
exhaust particles present in traffic-related pol-
lution have been shown to have endocrine-
disrupting activity and to transplacentally affect
sexual differentiation and alter cognitive func-
tion in mice (Hougaard et al. 2008; Watanabe
and Kurita 2001). Prenatal exposure to ozone
in rats has been seen to alter monoamine con-
tent in the cerebellum, which may then alter
neural circuitry formation (Gonzalez-Pina et al.
2008). Recent work examining the effects of
benzo[a]pyrene, a common PAH, indicates
that prenatal oral exposure in mice results in
decreased neuronal plasticity and behavioral
deficits (Brown et al. 2007). Specifically, pre-
natal exposure was associated with reduced
glutamate receptor development when syn-
apses are formed. Additionally, exposure to
benzo[a]pyrene via breast-feeding in mice dur-
ing the early postnatal period, corresponding
to the rapid human brain development taking
place during the third trimester, affected neuro-
maturation as measured by classic developmen-
tal behavior tests and to reduce expression of
the serotonin receptor 5HT1A (Bouayed et al.
2009; Pan et al. 2009).
Traffic-related air pollutants have been
observed to induce inflammation and oxida-
tive stress after both short-term and long-term
exposures in toxicologic and human studies,
and these pathways are thought to mediate
effects of air pollution on respiratory and car-
diovascular disease, and perhaps on neurologic
outcomes (Block and Calderon-Garciduenas
2009; Calderon-Garciduenas et al. 2009;
Castro-Giner et al. 2009; Gilliland et al. 2004;
Künzli et al. 2010). The emerging evidence
that oxidative stress and inflammation are also
involved in the pathogenesis of autism may
suggest a biologically plausible rationale for
the observed associations in our study (Boso
et al. 2006; Enstrom et al. 2009a, 2009b;
James et al. 2004, 2006, 2009). In particular,
research examining serum biomarkers reported
increased levels of the proinflammatory cytok-
ines tumor necrosis factor-α, interleukin
(IL)-6, IL-8, and colony-stimulating factor II,
as well as two markers of T-helper 1 immune
response (interferon-γ and IL-8), in postmor-
tem brain tissue of autism cases compared with
controls (Li et al. 2009). Additional research
from the CHARGE study has shown increased
plasma levels of immunoglobulin (Ig) G-4
and reduced concentrations of tumor growth
factor-β, related to immune response and
inflammatory processes, in plasma of children
with autism compared with typically develop-
ing controls and children with developmental
delay (Ashwood et al. 2008; Enstrom et al.
2009a, 2009b). Other recent work indicates
that exposure to air pollution exposure during
pregnancy is associated with changes in IgE
and in lymphocytes measured from cord blood,
supporting the idea that maternal exposure to
air pollution is associated with altered immune
profiles in the fetus (Herr et al. 2010a, 2010b).
Moreover, published evidence links maternal
antibodies to fetal brain tissue with a subset of
autism cases (Braunschweig et al. 2008).
Genetic variation in oxidative stress and
inflammatory pathways has also been associ-
ated with autism. Oxidative stress endophe-
notypes and corresponding genotypes related
to metabolism of methionine transmethyla-
tion and transsulfuration were significantly
decreased in children with autism compared
with controls, indicating increased susceptibil-
ity to oxidative stress (Boso et al. 2006; James
et al. 2004, 2006). Markers of lipid peroxida-
tion have also been associated with autism, as
have increased levels of nitric oxide and mito-
chondrial dysfunction, which may be related
to the formation of reactive oxygen species
(Chauhan and Chauhan 2006; Filipek et al.
2004; Ming et al. 2005; Sogut et al. 2003;
Yao et al. 2006). Polymorphisms in glutathi-
one S-transferase mu 1 (GSTM1), glutathione
S-transferase pi 1 (GSTP1), and glutathione
peroxidase 1 (GPX1), which modulate the
response to oxidative stress, have been associ-
ated with increased autism risk (Buyske et al.
2006; Ming et al. 2009; Williams et al. 2007).
These genetic variants have also been shown
to modify the association between exposure
to air oxidant pollutant associations and respi-
ratory outcomes (Islam et al. 2009; Salam
et al. 2007). Examination of the interaction
between these oxidant-associated genes and
environmental exposures may help to clarify
susceptibilities to environmental pollutants
among children with autism.
We recognize that the moderate relative
risks associated with freeway proximity in our
study may have been attributable to chance or
bias. The study is currently limited by sample
size and potential exposure misclassification.
Analysis of larger data sets would provide
additional valuable insight into these findings
and the potential for replication. Although we
used a residential history questionnaire (avail-
able for a subset of the study participants) to
choose the appropriate address for trimester,
there still may be misclassification of exposure
in these data due to inaccurate date reporting
on the part of the mother, or in our choice
among multiple addresses in each trimester.
We could not distinguish the potential effect
of noise from that due to pollutant exposures,
both resulting from residential location near a
freeway or other road in this study. Addresses
on the birth certificate could also be in error,
but this would probably be less likely. We
were not able to examine specific pollutant
concentrations in this study, and the traffic
proximity metrics were subject to misclas-
sification of exposure because they did not
account for traffic volume or prevailing wind
speed and direction. However, this exposure
misclassification was unlikely to have been
systematically related to disease, and our
results may therefore have underestimated the
magnitude of a true causal association.
Despite these limitations, this study has
several strengths. We assessed autism through
well-validated instruments that are recognized
as the gold standard in the field. We examined
exposure prenatally and at birth, two pivotal
times in gestational development, whereas
prior work on air pollution has been limited
to the birth address or a cumulative lifetime
exposure measure. To our knowledge, these
results are the first to show an association of
autism with residential traffic proximity.
Little is known about potential environmental
contributions to autism. The observed asso-
ciations with traffic proximity merit further
research to determine whether these results are
reproducible in populations with improved
estimates of exposure to specific ambient air
pollutants. Examination of gene–pollution
interactions may also help us learn about causal
pathways involved in autism and identify
potentially susceptible populations and may
lead to prevention strategies. Our analysis is the
first step in examining a hypothesized relation-
ship between air pollutants and autism. It has
been estimated that 11% of the U.S. popula-
tion lives within 100 m of a four-lane highway,
so a causal link to autism or other neurodevel-
opmental disorders would have broad public
health implications (Brugge et al. 2007).
Abrahams BS, Geschwind DH. 2008. Advances in autism genet-
ics: on the threshold of a new neurobiology. Nat Rev Genet
American Psychiatric Association. 2000. Diagnostic and
Statistical Manual of Mental Disorders. 4th ed, Text Revision.
Washington, DC:American Psychiatric Association.
Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I,
Hansen RL, Croen LA, et al. 2008. Decreased transforming
growth factor beta1 in autism: a potential link between
immune dysregulation and impairment in clinical behav-
ioral outcomes. J Neuroimmunol 204(1–2):149–153.
Block ML, Calderon-Garciduenas L. 2009. Air pollution: mecha-
nisms of neuroinflammation and CNS disease. Trends
Bocskay KA, Tang D, Orjuela MA, Liu X, Warburton DP,
Perera FP. 2005. Chromosomal aberrations in cord blood
are associated with prenatal exposure to carcinogenic
polycyclic aromatic hydrocarbons. Cancer Epidemiol
Biomarkers Prev 14(2):506–511.
Boso M, Emanuele E, Minoretti P, Arra M, Politi P, Ucelli di Nemi S,
Freeway proximity and autism risk Download full-text
Environmental Health Perspectives • volume 119 | number 6 | June 2011
et al. 2006. Alterations of circulating endogenous secretory
RAGE and S100A9 levels indicating dysfunction of the AGE-
RAGE axis in autism. Neurosci Lett 410(3):169–173.
Bouayed J, Desor F, Rammal H, Kiemer AK, Tybl E, Schroeder H,
et al. 2009. Effects of lactational exposure to benzo[alpha]
pyrene (B[alpha]P) on postnatal neurodevelopment, neu-
ronal receptor gene expression and behaviour in mice.
Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I,
Hansen R, Croen LA, et al. 2008. Autism: maternally derived
antibodies specific for fetal brains. Neurotoxicology
Brown LA, Khousbouei H, Goodwin JS, Irvin-Wilson CV,
Ramesh A, Sheng L, et al. 2007. Down-regulation of early
ionotrophic glutamate receptor subunit developmental
expression as a mechanism for observed plasticity defi-
cits following gestational exposure to benzo(a)pyrene.
Brugge D, Durant JL, Rioux C. 2007. Near-highway pollutants in
motor vehicle exhaust: a review of epidemiologic evidence
of cardiac and pulmonary health risks. Environ Health 6:23;
doi: 10.1186/1476-069X-6-23 [Online 9 August 2007].
Buyske S, Williams TA, Mars AE, Stenroos ES, Ming SX,
Wang R, et al. 2006. Analysis of case-parent trios at a
locus with a deletion allele: association of GSTM1 with
autism. BMC Genet 7:8; doi:10.1186/1471-2156-7-8 [Online
10 February 2006].
Calderon-Garciduenas L, Macias-Parra M, Hoffmann HJ,
Valencia-Salazar G, Henriquez-Roldan C, Osnaya N, et al.
2009. Immunotoxicity and environment: immunodysregula-
tion and systemic inflammation in children. Toxicol Pathol
Caltrans. 2008. Traffic and Vehicle Data Systems Unit: All
Traffic Volumes on the California State Highway System.
trafdata/2008all.htm [accessed 27 July 2010].
Castro-Giner F, Künzli N, Jacquemin B, Forsberg B, de Cid R,
Sunyer J, et al. 2009. Traffic-related air pollution, oxida-
tive stress genes, and asthma (ECHRS). Environ Health
Centers for Disease Control and Prevention. 2007a. Prevalence
of autism spectrum disorders—autism and developmental
disabilities monitoring network, 14 sites, United States,
2002. MMWR Surveill Summ 56(1):12–28.
Centers for Disease Control and Prevention. 2007b. Prevalence
of autism spectrum disorders—autism and developmental
disabilities monitoring network, six sites, United States,
2000. MMWR Surveill Summ 56(1):1–11.
Centers for Disease Control and Prevention. 2009. Prevalence
of autism spectrum disorders—autism and developmen-
tal disabilities monitoring network, United States, 2006.
MMWR Surveill Summ 58(10):1–20.
Chauhan A, Chauhan V. 2006. Oxidative stress in autism.
Currie J, Neidell M, Schmieder JF. 2009. Air pollution and
infant health: lessons from New Jersey. J Health Econ
Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I,
Hansen RL, et al. 2009a. Increased IgG4 levels in children
with autism disorder. Brain Behav Immun 23(3):389–395.
Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen RL, Pessah IN,
et al. 2009b. Altered gene expression and function of
peripheral blood natural killer cells in children with autism.
Brain Behav Immun 23(1):124–133.
Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ.
2004. Relative carnitine deficiency in autism. J Autism Dev
Gauderman WJ, Avol E, Lurmann F, Kuenzli N, Gilliland F,
Peters J, et al. 2005. Childhood asthma and exposure to
traffic and nitrogen dioxide. Epidemiology 16(6):737–743.
Gauderman WJ, Vora H, McConnell R, Berhane K, Gilliland F,
Thomas D, et al. 2007. Effect of exposure to traffic on lung
development from 10 to 18 years of age: a cohort study.
Gilliland FD, Li YF, Saxon A, Diaz-Sanchez D. 2004. Effect of glu-
tathione-S-transferase M1 and P1 genotypes on xenobiotic
enhancement of allergic responses: randomised, placebo-
controlled crossover study. Lancet 363(9403):119–125.
Gonzalez-Pina R, Escalante-Membrillo C, Alfaro-Rodriguez A,
Gonzalez-Maciel A. 2008. Prenatal exposure to ozone
disrupts cerebellar monoamine contents in newborn rats.
Neurochem Res 33(5):912–918.
Hansen CA, Barnett AG, Pritchard G. 2008. The effect of
ambient air pollution during early pregnancy on fetal
ultrasonic measurements during mid-pregnancy. Environ
Health Perspect 116:362–369.
Herr CEW, Dostal M, Ghosh R, Ashwood P, Lipsett M,
Pinkerton KE, et al. 2010b. Air pollution exposure dur-
ing critical time periods in gestation and alterations in
cord blood lymphocyte distribution: a cohort of livebirths.
Environ Health 9:46; doi:10.1186/1476-069X-9-46 [Online
2 August 2010].
Herr CEW, Ghosh R, Dostal M, Skokanova V, Ashwood P,
Lipsett M, et al. 2010a. Exposure to air pollution in critical
prenatal time windows and IgE levels in newborns. Pediatr
Allergy Immunol; doi: 10.1111/j.1399-3038.2010.01074.x
[Online 1 July 2010].
Hertz-Picciotto I, Croen LA, Hansen R, Jones CR, van de Water J,
Pessah IN. 2006. The CHARGE study: an epidemiologic
investigation of genetic and environmental factors contrib-
uting to autism. Environ Health Perspect 114:1119–1125.
Hertz-Picciotto I, Delwiche L. 2009. The rise in autism and the
role of age at diagnosis. Epidemiology 20(1):84–90.
Hougaard KS, Jensen KA, Nordly P, Taxvig C, Vogel U,
Saber AT, et al. 2008. Effects of prenatal exposure to die-
sel exhaust particles on postnatal development, behavior,
genotoxicity and inflammation in mice. Part Fibre Toxicol
5:3; doi:10.1186/1743-8977-5-3 [Online 11 March 2008].
Islam T, Berhane K, McConnell R, Gauderman WJ, Avol E,
Peters JM, et al. 2009. Glutathione-S-transferase (GST) P1,
GSTM1, exercise, ozone and asthma incidence in school
children. Thorax 64(3):197–202.
James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW,
et al. 2004. Metabolic biomarkers of increased oxidative
stress and impaired methylation capacity in children with
autism. Am J Clin Nutr 80(6):1611–1617.
James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH,
Wong DH, et al. 2006. Metabolic endophenotype and
related genotypes are associated with oxidative stress in
children with autism. Am J Med Genet B Neuropsychiatr
James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O,
et al. 2009. Cellular and mitochondrial glutathione redox
imbalance in lymphoblastoid cells derived from children
with autism. FASEB J 23(8):2374–2383.
Kalkbrenner AE, Daniels JL, Chen JC, Poole C, Emch M,
Morrissey J. 2010. Perinatal exposure to hazardous
air pollutants and autism spectrum disorders at age 8.
King M, Bearman P. 2009. Diagnostic change and the increased
prevalence of autism. Int J Epidemiol 38(5):1224–1234.
Künzli N, Jerrett M, Garcia-Esteban R, Basagana X, Beckermann B,
Gilliland F, et al. 2010. Ambient air pollution and the progres-
sion of atherosclerosis in adults. PLoS One 5(2):e9096.
Le Couteur A, Lord C, Rutter M. 2003. Autism Diagnostic
Interview–Revised (ADI-R). Los Angeles:Western
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, et al.
2009. Elevated immune response in the brain of autistic
patients. J Neuroimmunol 207(1–2):111–116.
Lord C, Rutter M, DiLavore P, Risi S. 2003. Autism Diagnostic
Observation Schedule Manual. Los Angeles:Western
Ma D, Salyakina D, Jaworski JM, Konidari I, Whitehead PL,
Andersen AN, et al. 2009. A genome-wide association
study of autism reveals a common novel risk locus at
5p14.1. Ann Hum Genet 73(pt 3):263–273.
McConnell R, Berhane K, Yao L, Jerrett M, Lurmann F,
Gilliland F, et al. 2006. Traffic, susceptibility, and childhood
asthma. Environ Health Perspect 114:766–772.
McConnell R, Islam T, Shankardass K, Jerrett M, Lurmann F,
Gilliland F, et al. 2010. Childhood incident asthma and
traffic-related air pollution at home and school. Environ
Health Perspect 118:1021–1026.
Ming X, Johnson WG, Stenroos ES, Mars A, Lambert GH,
Buyske S. 2009. Genetic variant of glutathione peroxi-
dase 1 in autism. Brain Dev 32(2):105–109.
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH,
Wagner GC. 2005. Increased excretion of a lipid peroxida-
tion biomarker in autism. Prostaglandins Leukot Essent
Fatty Acids 73(5):379–384.
Morales E, Julvez J, Torrent M, de Cid R, Guxens M,
Bustamante M, et al. 2009. Association of early-life expo-
sure to household gas appliances and indoor nitrogen
dioxide with cognition and attention behavior in preschool-
ers. Am J Epidemiol 169(11):1327–1336.
Muhle R, Trentacoste SV, Rapin I. 2004. The genetics of autism.
Mullen E. 1995. Mullen Scales of Early Learning. Circle Pines,
MN:American Guidance Services Inc.
Pan IJ, Daniels JL, Goldman BD, Herring AH, Siega-Riz AM,
Rogan WJ. 2009. Lactational exposure to polychlorinated
biphenyls, dichlorodiphenyltrichloroethane, and dichlo-
rodiphenyldichloroethylene and infant neurodevelopment:
an analysis of the pregnancy, infection, and nutrition
babies study. Environ Health Perspect 117:488–494.
Perera FP, Rauh V, Tsai WY, Kinney P, Camann D, Barr D, et al.
2003. Effects of transplacental exposure to environmental
pollutants on birth outcomes in a multiethnic population.
Environ Health Perspect 111:201–205.
Perera FP, Rauh V, Whyatt RM, Tsai WY, Bernert JT, Tu YH, et al.
2004. Molecular evidence of an interaction between prena-
tal environmental exposures and birth outcomes in a multi-
ethnic population. Environ Health Perspect 112:626–630.
Perera FP, Rauh V, Whyatt RM, Tsai WY, Tang D, Diaz D, et al.
2006. Effect of prenatal exposure to airborne polycyclic
aromatic hydrocarbons on neurodevelopment in the first
3 years of life among inner-city children. Environ Health
Perera FP, Tang D, Rauh V, Tu YH, Tsai WY, Becker M, et al.
2007. Relationship between polycyclic aromatic hydrocar-
bon–DNA adducts, environmental tobacco smoke, and child
development in the World Trade Center cohort. Environ
Health Perspect 115:1497–1502.
Ritz B, Yu F. 1999. The effect of ambient carbon monoxide on low
birth weight among children born in Southern California
between 1989 and 1993. Environ Health Perspect 107:17–25.
Rutter M, Bailey A, Lord C. 2003. A Social Communication
Questionnaire (SCQ). Los Angeles:Western Psychological
Salam MT, Lin PC, Avol EL, Gauderman WJ, Gilliland FD. 2007.
Microsomal epoxide hydrolase, glutathione S-transferase
P1, traffic and childhood asthma. Thorax 62(12):1050–1057.
Sexton K, Gong H Jr, Bailar JC III, Ford JG, Gold DR,
Lambert WE, et al. 1993. Air pollution health risks: do class
and race matter? Toxicol Ind Health 9(5):843–878.
Sogut S, Zoroglu SS, Ozyurt H, Yilmaz HR, Ozugurlu F, Sivasli E,
et al. 2003. Changes in nitric oxide levels and antioxidant
enzyme activities may have a role in the pathophysiological
mechanisms involved in autism. Clin Chim Acta 331(1–
Sparrow S, Cicchettim D, Balla D. 1984. Vineland Adaptive
Behavior Scales Interview Edition Expanded Form Manual.
Circle Pines, MN:American Guidance Services Inc.
Suglia SF, Gryparis A, Wright RO, Schwartz J, Wright RJ. 2008.
Association of black carbon with cognition among chil-
dren in a prospective birth cohort study. Am J Epidemiol
Van Meter KC, Christiansen LE, Delwiche LD, Azari R,
Carpenter TE, Hertz-Picciotto I. 2010. Geographic distribu-
tion of autism in California: a retrospective birth cohort
analysis. Autism Res 3(1):19–29.
Vassilev ZP, Robson MG, Klotz JB. 2001. Outdoor exposure to
airborne polycyclic organic matter and adverse reproduc-
tive outcomes: a pilot study. Am J Ind Med 40(3):255–262.
Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS,
et al. 2009. Common genetic variants on 5p14.1 associate
with autism spectrum disorders. Nature 459(7246):528–533.
Watanabe N, Kurita M. 2001. The masculinization of the fetus
during pregnancy due to inhalation of diesel exhaust.
Environ Health Perspect 109:111–119.
Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, Factura-
Santiago MF, et al. 2007. Risk of autistic disorder in affected
offspring of mothers with a glutathione S-transferase P1
haplotype. Arch Pediatr Adolesc Med 161(4):356–361.
Windham GC, Zhang L, Gunier R, Croen LA, Grether JK. 2006.
Autism spectrum disorders in relation to distribution of
hazardous air pollutants in the San Francisco Bay Area.
Environ Health Perspect 114:1438–1444.
Yao Y, Walsh WJ, McGinnis WR, Pratico D. 2006. Altered
vascular phenotype in autism: correlation with oxidative
stress. Arch Neurol 63(8):1161–1164.
Zhu Y, Hinds WC, Kim S, Sioutas C. 2002. Concentration and
size distribution of ultrafine particles near a major high-
way. J Air Waste Manag Assoc 52(9):1032–1042.
Zhu Y, Kuhn T, Mayo P, Hinds WC. 2006. Comparison of daytime
and nighttime concentration profiles and size distributions
of ultrafine particles near a major highway. Environ Sci