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Neurotoxicity of Ortho-Phthalates: Recommendations for Critical Policy Reforms to Protect Brain Development in Children

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Abstract

Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning, attention, and behavioral disorders in childhood. This growing body of evidence, along with known adverse effects on male reproductive tract development, calls for immediate action. Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simultaneously. We thus recommend that a class approach be used in assessing health impacts as has been done with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from products that lead to exposure of pregnant women, women of reproductive age, infants, and children. Specific attention should be focused on reducing exposures among socially vulnerable populations such as communities of color, who frequently experience higher exposures. Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multipronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is feasible. (Am J Public Health. Published online ahead of print February 18, 2021: e1–e9. https://doi.org/10.2105/AJPH.2020.306014 )
Neurotoxicity of Ortho-Phthalates:
Recommendations for Critical Policy
Reforms to Protect Brain Development
in Children
Stephanie M. Engel, PhD, Heather B. Patisaul, PhD, Charlotte Brody, RN, Russ Hauser, MD, ScD, MPH, Ami R. Zota, ScD, MS, Deborah
H. Bennet, PhD, Maureen Swanson, MPA, and Robin M. Whyatt, DrPH
Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals
indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning,
attention, and behavioral disorders in childhood. This growing body of evidence, along with known
adverse eects on male reproductive tract development, calls for immediate action.
Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simulta-
neously. We thus recommend that a class approach be used in assessing health impacts as has been done
with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from
products that lead to exposure of pregnant women, women of reproductive age, infants, and children.
Specic attention should be focused on reducing exposures among socially vulnerable populations such
as communities of color, who frequently experience higher exposures.
Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multi-
pronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have
already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is
feasible. (Am J Public Health. Published online ahead of print February 18, 2021: e1e9. https://doi.org/
10.2105/AJPH.2020.306014)
As experts in toxic chemicals and
neurodevelopment who are
members of Project TENDR (Targeting
Environmental Neuro-Development
Risks), we have determined that expo-
sure to ortho-phthalates can impair
child brain development and increase
childrens risks for learning, attention,
and behavioral disorders. There are robust
data from longitudinal birth cohort studies
conducted over the last decade that have
shown associations between prenatal ex-
posures to ortho-phthalates and attention-
decit hyperactivity disorder (ADHD), other
behavioral problems, adverse cognitive
development including lower IQ, poorer
psychomotor development, and impaired
social communication.
This growing body of evidence, along
with the known adverse eects on male
reproductive tract development of
ortho-phthalates, calls for immediate
action. Given that general population
exposure is ubiquitous and is to a
mixture of multiple ortho-phthalates si-
multaneously, we recommend that as-
sessment of hazard use a class approach,
as has been done for a number of other
chemical classes. To protect child brain
development, ortho-phthalates need to
be removed from consumer products
that contribute to exposure of pregnant
women, women of reproductive age, in-
fants, and children. We summarize the
epidemiological evidence on adverse
neurodevelopmental eects following
prenatal exposure to ortho-phthalates,
discuss sources of exposure and what is
known about potential mechanisms, and
propose urgently needed reforms to
substantially reduce exposures to
ortho-phthalates over critical periods of
child brain development.
WHAT ARE PHTHALATES?
Ortho-phthalates are diesters of
phthalic acid and are the predominate
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ANALYTIC ESSAYS
type of phthalate used in commerce.
(For simplicity, we will refer to them as
phthalates.) They are high-production-
volume chemicals used most often as a
plasticizer in polyvinyl chloride (PVC) and
other plastics. Phthalates are used in
numerous consumer products, includ-
ing food production materials and
packaging; medical supplies and coat-
ings of medicines; ooring, wall cover-
ings, and other home materials; and
cosmetics and other personal care
products.
1
Approximately 4.9 million
metric tons are produced annually
worldwide (reviewed in Ejaredar et al.
2
).
The highest-production phthalates are
di-2-ethylhexyl phthalate (DEHP), diiso-
nonyl phthalate (DiNP), butylbenzyl
phthalate (BBzP), dibutyl phthalates
(DBPs), and diethyl phthalate (DEP).
3
Diet is a particularly important expo-
sure pathway for some phthalates, in-
cluding DEHP and DiNP.
4
Phthalates
have been shown to leach into food
from plastic equipment like tubing used
in commercial dairy operations, lid gas-
kets, food preparation gloves, conveyor
belts, and food packaging materials.
5
As
such, consumption of fast food and
other dining-out sources,
5
as well as li-
pophilic foods such as dairy,
4
can be
important dietary sources of phthalate
exposures.
Building products containing phtha-
lates, such as vinyl ooring and wall
coverings, have a large surface area
from which phthalates can migrate into
the indoor air and household dust, also
resulting in human exposure.
6
Histori-
cally, phthalates were added to chil-
drens toys, although use of multiple
phthalates in toys has been banned by
the Consumer Product Safety Commis-
sion (CPSC; see Box 1).
1,7
Phthalates including DEP and DBPs
are commonly used in cosmetics and
other personal care products, and are
sometimes used as excipients in medi-
cations and supplements (Box 1).
2
For
example, DEP and DBPs are used in a
wide range of personal care products
including nail polish, lotions, fragrances,
and hair-styling products.
41
Numerous
studies have found correlations be-
tween personal care product use and
the concentrations of phthalate me-
tabolites in urine.
41
Overall, women have
higher exposure to phthalates found in
personal care products than men, and
Black and Latina women have higher
exposure to certain phthalates com-
pared with White women, independent
of socioeconomic status.
42
Phthalates
are readily transferred from mother to
fetus during pregnancy.
2
US population exposure to phthalates
has changed in the last decade.
7
Expo-
sures to di-n-butyl phthalate (DnBP),
BBzP, and DEHP have declined, while
exposures to replacement phthalates
such as DiNP and diisobutyl phthalate
(DiBP) have increased. The observed
temporal trends are likely a reection of
legislative activity and advocacy eorts
of nongovernmental organizations, as
well as changes by manufacturers and
retailers in response to consumer prefer-
ence (see the box on page e3).
7
EPIDEMIOLOGICAL
EVIDENCE OF
NEUROTOXICITY
Historically, most of the health concerns
and regulations pertaining to phthalates
were motivated by strong toxicological
evidence showing adverse antiandrogenic
eects on male reproductive tract de-
velopment.
1
More recently, an increasing
number of prospective epidemiological
studies have found associations between
prenatal exposure to phthalates and ad-
verse neurodevelopment in ospring.
43
A
recent systematic review of the human
data concluded that prenatal exposure to
DEHP, DBPs, DEP, and BBzP has an ad-
verse impact on cognitive and psycho-
motor development, internalizing and
externalizing behaviors, attention, gender-
related play behaviors, social responsive-
ness, and visual spatial abilities of chil-
dren.
43
As of 2019, there were more than
30 published studies that have measured
prenatal exposure to phthalates using
validated exposure biomarkers
4349
or
environmental estimates of prenatal
exposure
50,51
in longitudinal cohorts as-
sembled from 11 dierent countries or
territories around the globe. Children
have been followed for altered neonatal
behavior or infant visual recognition
memory, cognitive development, behav-
ior, executive function, reciprocal social
behavior, gender-related play behaviors,
and for symptoms of, or clinical diagnosis
with, developmental disabilities including
autism and ADHD. Examples of key nd-
ings from this extensive literature base are
discussed in the following paragraphs.
The most consistent pattern across
multiple studies is associations with
behaviors commonly associated with
ADHD (including hyperactivity, aggression/
deance, and emotional reactivity),
43
def-
icits in executive function,
52,53
or ADHD
clinical diagnosis.
54
For example, a 2018
study nested within the Norwegian
Mother and Child Cohort leveraged a
linkage between this cohort and the
Norwegian National Patient Registry,
which collects all outpatient diagnoses
from specialty clinics. Engel et al. mea-
sured second-trimester urinary phtha-
lates and found that children of mothers
that fell in the highest quintile of pre-
natal exposure to DEHP metabolites
had almost 3 times the odds of being
diagnosed with ADHD as those with
mothers in the lowest quintile (odds
ratio [OR] = 2.99; 95% condence in-
terval [CI] = 1.47, 5.49).
54
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Phthalates, particularly metabolites of
DBP and DEHP, have also been associ-
ated with more problem behaviors, as
estimated by validated inventory-based
behavioral rating scales in these largely
subclinical populations. For example,
Lien et al. reported that third-trimester
urinary concentrations of DnBP and
DEHP metabolites were associated with
more externalizing problems, more de-
linquent behaviors, and more aggressive
behaviors, as measured by the Child
Federal Regulatory, Manufacturer, and Retailer Action on Phthalates
I. Federal Regulatory Action
A. US Environmental Protection Agency (EPA)
·Set a drinking water standard for DEHP (6 ppb).
8
·Listed DEHP and DBP as hazardous air pollutants and as substances on the Toxic Release Inventory that must be reported to EPA if released into any media.
8
·Listed phthalates as hazardous waste if discarded as commercial chemical products under the Resource Conservation and Recovery Act.
8
·Recently designated 5 phthalates (DnBP, DiBP, BBzP, DEHP, and DCHP) as high-priority substances for risk evaluation under the Toxic Substances Control Act.
9
B. US Consumer Product Safety Commission
·Banned 8 ortho-phthalates from use in childrens toys and childcare articles: DEHP, DBP, BBzP, DINP, DiBP, DPENP, DHEXP, and DCHP.
10
The regulation is under
legal challenge by the National Association of Manufacturers, the American Chemistry Council, and other industry groups.
11
C. US Food and Drug Administration (FDA)
·Set maximum concentration of DEHP in bottled water at the same concentration that EPA had set in drinking water.
12
·Issued guidelines (but not regulation) recommending that DBP and DEHP be avoided as excipients in prescription and nonprescription products,
13
advised
manufacturers to label medical devices that contain DEHP,
14
and concluded that exposure to DEHP received by some infants from medical devicerelated
sources could be substantially greater than the agencys estimate of the Tolerable Intake.
15
·Approved use of 28 phthalates as food additives in food contact articles.
16,17
Uses include as plasticizers, binders, coating agents, defoamers, and gasket
closures, in materials such as cellophane, paper and paperboard, and plastics.
·Has failed to meet the statutory deadline for nal decisions on 3 recently submitted petitions that could substantially reduce dietary exposure to phthalates.
17
o Two were submitted by 11 environmental and public health organizations and requested that FDA strike from its existing regulations its approvals of all 28
phthalates as food additives in food contact articles, as the agency could no longer conclude that such use is safe, as is required by law.
17
o The third petition was submitted by the Flexible Vinyl Alliance and requested that FDA revoke its approval of 24 phthalates that the Alliance claims are no
longer used as food additives in food contact applications.
17
The industry petition did not include several approved uses of these phthalates and continued the
approval of DEHP, DINP, DCHP, and DIDP as food additives.
II. Examples of Voluntary Action by Retailers and Manufacturers
·Home Depots safer chemicals policy includes restrictions on phthalates as a class in vinyl ooring and wall-to-wall carpet.
18,19
·Lowes, Lumber Liquidators, and Menards have taken action to remove phthalates as a class from vinyl ooring.
19,20
·Apple has removed phthalates as a class from almost all products.
21
·Hewlett Packard has removed multiple phthalates from commercial personal computer products and a lesser number from other products.
22
·IKEA has removed phthalates from a number of its products.
23
·Mohawk,
24
Tarkett,
24
SC Johnson,
25
and Steelcase
26
have restricted use of phthalates in some products, including household products.
·Ahold Delhaize, the fourth largest grocery chain in the United States (with 2000 stores including Food Lion, Giant Food, Giant/Martins, Hannaford, and Stop &
Shop) recently announced restrictions on phthalates and other chemicals in its own branded products in the following categories: all grocery, baby food and
infant formula, and formulated laundry products, as well as personal care, cosmetic, and baby products.
27,28
·CVS Health,
29
Loblaw,
29
Rite Aid,
30
and Walmart
31
are also reducing the use of phthalates in beauty and personal care products and household products with
the goal of elimination.
·Sephora set a goal to reduce high-priority chemicals including 8 phthalates by 50% over the next 3 years.
32,33
·Panera Bread has replaced vinyl gloves, which must be softened with phthalates or other plasticizers, with safer alternatives such as polyethylene gloves that
require no such chemical additives.
33
III. Examples of Health Care Organization and Medical Supplier Actions
·Dignity Health,
34
Hackensack Meridian Health,
35
and Kaiser Permanente
36
have a stated preference for products made without phthalates.
·Warner Chilcott recently brought a new product to market, Delzicol (mesalamine), which does not contain DBP in the medication coating.
37
In totality, these examples demonstrate the feasibility of reformulating a vast array of products to remove phthalates. Cited references can help inform steps
necessary in selection of safer alternatives when replacing phthalates.
3840
Note. BBzP = butylbenzyl phthalate; DBP = dibutyl phthalate; DCHP = dicyclohexl phthalate; DEHP = di-2-ethylhexyl phthalate; DHEXP = di-n-hexyl phthalate;
DiBP = diisobutyl phthalate; DIDP = di-isodecyl phthalate; DINP = diisononyl phthalate; DnBP = di-n-butyl phthalate; DPENP = di-n-pentyl phthalate; and
ppb = parts per billion.
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Behavior Checklist, in a population of 8-
year-old children in Taiwan.
55
Also using
the Child Behavior Checklist and leveraging
a US-based multicenter pregnancy cohort
enrolled in California, Minnesota, Missouri,
and Iowa, Kobrosly et al. reported that
third-trimester urinary DiBP metabolites
were associated with more inattention,
rule-breaking behavior, aggression, and
conduct problems.
56
DEHP and BBzP
metabolites were also linked with altered
behavior that was in some cases sex-spe-
cic. Another recent study found an
association between prenatal exposure
to the sum of low-molecular-weight
phthalates (which includes metabolites
of DBPs and DEP) and hyperactivity,
attention problems, and anxiety at the
age of 16 years.
49
In addition, phthalates have been
associated with altered child executive
functions using both rater-based and
performance-based assessments. Ex-
ecutive functions are higher-order cog-
nitive processes that support goal-
directed behaviors and are typically
impaired in children with ADHD. Factor-
Litvak et al. reported that prenatal DBP
metabolites were associated with
poorer working memory in a birth co-
hort enrolled in New York City and ad-
ministered the Wechsler Intelligence
Scale for Children-IV at age 7 years.
53
Engel et al. reported that prenatal me-
tabolites of DBP were associated with
poorer working memory on the Behav-
ior Rating Inventory of Executive Func-
tion.
52
Factor-Litvak et al. also found that
prenatal metabolites of DBPs were as-
sociated with a signicant linear reduc-
tion in child IQ. Overall, child IQ was 7
points lower in the highest versus lowest
quartile of DBP exposure. DBP metab-
olites were also associated with index-
specic decrements in processing
speed, perceptual reasoning, and verbal
comprehension.
53
Maternal urinary
concentrations of BBzP metabolites
were also associated with reductions in
child perceptual reasoning.
53
It is important to note that the liter-
ature is not entirely consistent, partic-
ularly among studies that focus on
cognitive development during infancy
and early childhood. Among these
studies, there is often a lack of overlap in
the specic metabolites implicated, the
gender most aected, or the direction of
the relationship. Even among studies of
neurobehavior, not all have found
associations,
48,49,57,58
and some have
found associations primarily with inter-
nalizing domains.
59,60
Some of these
dierences may be attributable in part
to dierences in the study designs, in-
cluding the age of the child at testing, the
gestational age at urine sample collec-
tion, and the instruments used for
assessing neurodevelopmental outcomes
measures. In addition, early studies of
phthalates and neurobehavior summed
phthalate metabolites into low- and high-
molecular-weight groupings, which makes
it dicult to compare results to those
reporting ndings on individual phthalates,
particularly in light of temporal changes
of the contribution of speci cphthalates
to the overall exposure mixture.
Despite these dierences, the weight
of evidence strongly supports a rela-
tionship between certain phthalates and
altered neurobehavioral development.
This interpretation is additionally sup-
ported by the Chronic Hazard Advisory
Panel for the CPSC, which concluded that
poorer neurodevelopment test scores
are generally associated with higher
maternal prenatal urinary concentrations
of metabolites of DEHP, DBPs, and DEP,
and that human exposure to these
phthalates should be reduced.
1
Consis-
tent with the systematic review by Zhang
et al.,
43
a 2015 review also concluded that
prenatal exposures to DEP, BBzP, DEHP,
and DBPs were associated with adverse
cognitive and behavioral outcomes in
children, including lower IQ and prob-
lems with attention, hyperactivity, and
poorer social communication.
2
EXPERIMENTAL EVIDENCE
OF NEUROTOXICITY
Studies of gestational and early life ex-
posure in animal models, which have
mostly focused on DEHP, are generally
consistent with the observations from
epidemiological studies. The most con-
sistently observed eects include hy-
peractivity, anxiety and depressive
behaviors, and cognitive impairments
including impacts on learning and
memory.
61
Disruption of the organiza-
tion and function of the hypothalamic
pituitarygonadal axis by phthalates
known to inhibit fetal testosterone
production is also frequently reported.
61
A particularly compelling study showed
that rats perinatally (both before and
after birth) exposed to a human-relevant
phthalate mixture displayed lower cog-
nitive exibility in a set-shifting task, an
outcome that correlated with fewer
synapses in the prefrontal cortex.
62
Sensitive windows of exposure span
pre- and postnatal life through adoles-
cence
63
including puberty
6466
and
possibly adulthood,
6770
which is un-
surprising given that complex structures
including the prefrontal cortex, hippo-
campus, and cerebellum undergo sig-
nicant development well into early
adulthood.
Consistent with the epidemiological
ndings, animal outcomes are fre-
quently sex-specic. It is known that
many phthalates are antiandrogenic
1
although antiestrogenic eects have
also been reported in vitro.
71
It has been
hypothesized that the dierential eect
of phthalates on neurobehavioral
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outcome by sex seen in many studies
may result from disrupted fetal testos-
terone production. Critically, unlike ro-
dents in which testosterone is
aromatized to estrogen in the develop-
ing brain and then acts via estrogen
receptors to masculinize the male brain,
in genetically male humans testosterone
acts primarily via the androgen recep-
tor.
70
Thus, while the phenomenon of
sex-speciceects may be conserved
across species, speciceects within sex
may vary based on taxonomical dier-
ences in steroid hormone function.
Phthalates can also modulate aromatase
activity in the developing brain, which can
interfere with estrogen synthesis.
72,73
This is of concern because estrogen plays
a critical role in brain plasticity and other
developmental renements,
74
and there
is also growing evidence that estrogen
synthesis can be extragonadal, including
in the brain.
75
The hippocampus and, consequently,
aspects of neural plasticity, cognitive
exibility, anxiety-like behavior, learning,
and memory, are thought to be partic-
ularly vulnerable to phthalates. For ex-
ample, male mice prenatally exposed to
DEHP had evidence of oxidative stress,
neuronal loss, and neuroinammation
in the hippocampus as adults, along with
elevated anxiety behavior and impaired
recognition memory.
76,77
Similarly, male
rats perinatally exposed to DEHP had
impaired dendritic complexity in the
hippocampus, particularly in CA1 pyra-
midal neurons.
78
A recent review of the phthalate lit-
erature discussed several additional
potential mechanisms to explain the
epidemiological and animal toxicity lit-
erature.
3
Disruption of thyroid hormone
pathways is one potential mechanism of
interest, given that thyroid hormone is
essential for brain development. There
is also evidence of altered ion
homeostasis including calcium signaling,
peroxisome proliferator-activated re-
ceptors activation, and lipid metabolism,
particularly in the hippocampus.
In summary, multiple longitudinal
studies of human prenatal phthalate
exposure have found evidence of al-
tered neurobehavioral development.
These ndings are of concern especially
in light of the supporting evidence from
experimental studies and a growing
understanding of the mechanisms
whereby phthalates may adversely af-
fect fetal brain development. Given the
widespread exposures to phthalates,
including among women and children,
and the limited existing US regulations,
none of which focus on pregnant
women, health-protective regulatory
actions are required to eliminate these
potentially harmful exposures.
RECOMMENDATIONS FOR
SENSIBLE POLICY
REFORMS
Mounting evidence on the impacts of
phthalates on childrens brain develop-
ment compels meaningful actions to
eliminate exposure for women of re-
productive age, pregnant women, in-
fants, and children. As discussed, human
exposure to phthalates ranges from
foods to building materials to medical
products, pharmaceuticals, cosmetics,
and other personal care products.
Therefore, reducing human exposure
necessitates a multipronged approach
through regulations at the federal and
state levels, as well as through voluntary
action on the part of retailers and
manufacturers.
To date, federal regulation of phtha-
lates in the United States has been
minimal with several exceptions, in-
cluding restrictions on 8 phthalates in
childrens toys and childcare articles
(Box 1). We strongly urge both federal
and state agencies to move rapidly to
eliminate phthalate use. Specic atten-
tion should be focused on reducing
exposures among socially vulnerable
populations such as communities of
color, who frequently experience
higher exposures.
42
States should not
wait for the federal government to act,
as state action can galvanize federal
regulation. It is encouraging that volun-
tary action on the part of manufacturers,
retailers, and health care organizations
has removed phthalates from a wide
range of products (Box 1). Consumer
pressure is critical to motivate additional
manufacturers and retailers to act, as
well as to encourage federal and state
regulation.
We recommend that the evaluation of
hazards of phthalates use a class ap-
proach as has been done for other
classes of chemicals (e.g., organophos-
phate pesticides, dioxin-like com-
pounds) and as has recently been
recommended by a National Academy
of Sciences report on organohalogen
ame retardants.
79,80
This approach is
appropriate given that general pop-
ulation exposure is to mixtures of
phthalates, coupled with the fact that
phthalates have similarities in chemical
structures, metabolism, and biological
activity, including disruption of
multiple endocrine systems, and
have common health outcomes, in-
cluding adverse eects on child neuro-
development and male reproductive
tract development, as well as other
adverse eects.
Following are 5 critical
recommendations for reducing phtha-
late exposures:
1to reduce dietary exposure,
2to reduce exposure from medical
supplies and medication,
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3to reduce exposure from personal
care products and other household
products,
4to reduce exposure from a broad
range of other products including
building materials, and
5to reduce risk of regrettable
substitution.
Dietary
The US Food and Drug Administration
(FDA) must remove from its existing
regulations its approvals of all 28
phthalates for use in food packaging
and other materials that come in con-
tact with food. There is no longer any
basis for the agency to conclude that
there is reasonable certainty of no
harmfrom these uses, which is the
legal standard for safety of food contact
materials under the federal Food, Drug,
and Cosmetic Act (see 21 CFR [updated
September 19, 2019]), which governs
FDAs actions. All of the phthalates that
have been associated with adverse
child neurodevelopment, discussed
previously, are currently approved by
FDA for food contact use.
Until the FDA takes action to protect
the food supply from phthalates, the
food industry, including producers,
processors, retailers, and restaurant
chains, should investigate, identify, and
remove sources of phthalates from their
food products.
Medical Supplies and
Medication
The use of phthalates in medications
and medical devices also falls under FDA
jurisdiction. While FDA has published
guidelines to address many of these
sources (Box 1), the agency must pro-
mulgate regulations to eliminate their uses.
Personal Care and Other
Household Products
Authority to regulate phthalates in cos-
metics (which are dened broadly to
include many personal care products)
also falls under FDA jurisdiction. How-
ever, the agencys authority is much less
comprehensive and health protective
than its authority to ensure the safety of
food or drugs. This needs to be rectied
by congressional action.
The CPSC has authority to ensure the
safety of consumer products and is to be
commended for eliminating a number of
phthalates from childrens toys. How-
ever, the agency must also take action
to prohibit the sale of other phthalate-
containing products that fall under its
jurisdiction.
In addition to federal action, elimina-
tion of phthalates from personal care
and household products requires action
on the part of states, manufacturers,
and retailers.
Personal care and household prod-
ucts must be labeled if they contain
phthalates so consumers can make in-
formed decisions to avoid these sub-
stances if desired.
Building Materials and Other
Products
The US Environmental Protection
Agency (EPA) must use its authority
under the Toxic Substances Control Act
(TSCA; 15 USC Ch 53 [2016]) to regulate
phthalates. EPA has recently embarked
on a multiyear process for evaluating the
risk of several phthalates under TSCA.
The agency must broaden this eort
using a class approach in assessing
health impacts. Furthermore, EPA
should aggressively exercise its author-
ity to regulate the manufacture, import,
processing, distribution in commerce,
disposal, and known and reasonably
foreseeable uses of phthalates.
Regrettable Substitution
Assessment to identify safer alternatives
to phthalates must consider adverse
eects to human health and the envi-
ronment as well as societal impacts
along with performance and costs.
80
This is critical given the potential for
regrettable substitution and the avail-
ability of lower-hazard alternatives (see
Box 1 for resources on approaches for
selecting safer alternatives). No phtha-
late should be used as a substitute for
another phthalate, as has already been
done with DiNP for DEHP. In addition,
PVC plastics should be replaced with
safer materials that do not require
plasticizers. The substitution of safer
alternatives for phthalates is critical
given the risk these chemicals pose to
child brain development.
CONCLUSION
Substantial evidence links exposure to
phthalates with increased risks for child
learning, attention, and behavioral
problems. We therefore recommend
that phthalates be eliminated from
products that may lead to exposure of
women of reproductive age, pregnant
women, infants, and children. As dis-
cussed, this will necessitate a multi-
pronged approach through regulations
at the federal and state levels, as well as
through voluntary action on the part of
retailers and manufacturers. However,
given that manufacturers have already
successfully removed phthalates from a
wide range of products, including food,
medicine and medical supplies, per-
sonal care products, and other house-
hold and building materials (Box 1), we
e6 Analytic Essays Peer Reviewed Engel et al.
ANALYTIC ESSAYS
AJPH Published online ahead of print February 18, 2021
believe the goal of phthalate elimination
is achievable.
ABOUT THE AUTHORS
Stephanie M. Engel is with the Department of Epi-
demiology, Gillings School of Global Public Health,
University of North Carolina at Chapel Hill. Heather
B. Patisaul is with the Department of Biological
Sciences, Center for Human Health and the Envi-
ronment, North Carolina State University, Raleigh.
Charlotte Brody is with Healthy Babies Bright Fu-
tures, Charlottesville, VA. Russ Hauser is with the
Department of Environmental Health at the Harvard
T. H. Chan School of Public Health, Boston, MA. Ami
R. Zota is with the Department of Environmental
and Occupational Health, George Washington
University Milken School of Public Health, Wash-
ington, DC. Deborah H. Bennet is with the Depart-
ment of Public Health Sciences, School of Medicine,
University of California at Davis. Maureen Swanson
is with The Arc of the United States, Washington, DC.
Robin M. Whyatt is with the Department of Envi-
ronmental Health Sciences, Mailman School of
Public Health, Columbia University, New York, NY.
CORRESPONDENCE
Correspondence should be sent to Stephanie M.
Engel, PhD, 135 Dauer Drive, Gillings School of
Global Public Health, CB# 7435, Chapel Hill, NC
27599-7435 (e-mail: stephanie.engel@unc.edu).
Reprints can be ordered at http://www.ajph.org by
clicking the Reprintslink.
PUBLICATION INFORMATION
Full Citation: Engel SM, Patisaul HB, et al. Neuro-
toxicity of ortho-phthalates: recommendations for
critical policy reforms to protect brain development
in children. Am J Public Health. Published online
ahead of print February 18, 2021: e1e9.
Acceptance Date: October 15, 2020.
DOI: https://doi.org/10.2105/AJPH.2020.306014
CONTRIBUTORS
All authors contributed equally to this article in
conceptualization and drafting of all components.
ACKNOWLEDGMENTS
We acknowledge that authors of this article have
received funding from the following entities: The
National Institute of Environmental Health Sciences:
P30ES010126 (S. M. E.), R01ES021777 (S. M. E.),
P30ES023513 (D. H. B.), P30ES025128 (H. P.), and
R01ES009718 (R. H.); the John Merck Fund (C. B.,
M. S.); the Passport Foundation, Ceres Trust, and
Pediatric Epilepsy Research Foundation (M. S.);
theClarenceE.HellerCharitableFoundation
(C. B.); the Marisla Foundation; and the Forsythia
Foundation (A. Z.).
CONFLICTS OF INTEREST
The authors report no conicts of interest.
HUMAN PARTICIPANT PROTECTION
This is a review article and, thus, institutional board
review was not required.
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ANALYTIC ESSAYS
AJPH Published online ahead of print February 18, 2021
... Some phthalates and their metabolites are known endocrine-disrupting chemicals (EDCs) [14][15][16][17], that is, chemicals or mixtures of chemicals able to interfere with different aspects of hormone action [18]. Additionally, some phthalates are known or suspected neurotoxicants [19]. Thus, exposure to both individual phthalate compounds and their mixtures has been shown to alter brain function and behavior in rodent models [20], often in a sex-specific manner [21]. ...
... Notwithstand-ing, it should be noted that these phthalates can also act through other modes of action including thyroid disruption, oxidative stress, peroxisome proliferator-activated receptors (PPARs) and estrogen pathways [25,94]. Overall, scientific findings including ours support that MnBP and DEHP metabolites, individually and as a mixture, may have a deleterious impact on children's neurodevelopment, calling for further policies aiming at reducing children's exposure to phthalates [19,95]. ...
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Based on toxicological evidence, children’s exposure to phthalates may contribute to altered neurodevelopment and abnormal regulation of brain-derived neurotrophic factor (BDNF). We analyzed data from five aligned studies of the Human Biomonitoring for Europe (HBM4EU) project. Ten phthalate metabolites and protein BDNF levels were measured in the urine samples of 1148 children aged 6–12 years from Italy (NACII-IT cohort), Slovakia (PCB-SK cohort), Hungary (InAirQ-HU cohort) and Norway (NEBII-NO). Serum BDNF was also available in 124 Slovenian children (CRP-SLO cohort). Children’s total, externalizing and internalizing behavioral problems were assessed using the Child Behavior Checklist at 7 years of age (only available in the NACII-IT cohort). Adjusted linear and negative binomial regression models were fitted, together with weighted quantile sum (WQS) regression models to assess phthalate mixture associations. Results showed that, in boys but not girls of the NACII-IT cohort, each natural-log-unit increase in mono-n-butyl phthalate (MnBP) and Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) was cross-sectionally associated with higher externalizing problems [incidence rate ratio (IRR): 1.20; 95% CI: 1.02, 1.42 and 1.26; 95% CI: 1.03, 1.55, respectively]. A suggestive mixture association with externalizing problems was also observed per each tertile mixture increase in the whole population (WQS—IRR = 1.15; 95% CI: 0.97, 1.36) and boys (IRR = 1.20; 95% CI: 0.96, 1.49). In NACII-IT, PCB-SK, InAirQ-HU and NEBII-NO cohorts together, urinary phthalate metabolites were strongly associated with higher urinary BDNF levels, with WQS regression confirming a mixture association in the whole population (percent change (PC) = 25.9%; 95% CI: 17.6, 34.7), in girls (PC = 18.6%; 95% CI: 7.92, 30.5) and mainly among boys (PC = 36.0%; 95% CI: 24.3, 48.9). Among CRP-SLO boys, each natural-log-unit increase in ∑DINCH concentration was associated with lower serum BDNF levels (PC: −8.8%; 95% CI: −16.7, −0.3). In the NACII-IT cohort, each natural-log-unit increase in urinary BDNF levels predicted worse internalizing scores among all children (IRR: 1.15; 95% CI: 1.00, 1.32). Results suggest that (1) children’s exposure to di-n-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) metabolites is associated with more externalizing problems in boys, (2) higher exposure to DINCH may associate with lower systemic BDNF levels in boys, (3) higher phthalate exposure is associated with higher urinary BDNF concentrations (although caution is needed since the possibility of a “urine concentration bias” that could also explain these associations in noncausal terms was identified) and (4) higher urinary BDNF concentrations may predict internalizing problems. Given this is the first study to examine the relationship between phthalate metabolite exposure and BDNF biomarkers, future studies are needed to validate the observed associations.
... Children are particularly vulnerable, facing greater exposure to PAEs than adults, which poses significant health risks (Wang et al., 2019). Early life exposure to PAEs has been associated with neurodevelopmental and behavioral effects (Engel et al., 2021;Tran et al., 2021). Additionally, circadian rhythm disturbances linked to PAE exposure can contribute to sleep disorders, such as insomnia, which can alter sleep duration, reduce nighttime sleep, and increase daytime napping (Hatcher et al., 2020;Leng et al., 2019). ...
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The zebrafish, a diurnal vertebrate, is commonly used in circadian rhythm studies due to its genetic and neurological similarities to humans. Circadian rhythms, which regulate sleep, neurotransmitter, behavior, and physiological responses to environmental changes, can be disrupted by various environmental factors. Phthalic acid esters (PAEs) are pervasive endocrine disruptors that individuals are frequently exposed to in daily life. However, the impact of PAEs on circadian rhythms during early development remains poorly understood. This study aimed to investigate the effects of exposure to diethyl phthalate (DEP) and butyl benzyl phthalate (BBzP) on the behavior and circadian rhythms of developing zebrafish larvae using a series of layered assays. Zebrafish larvae were exposed to the two PAEs from less than 2 hour post-fertilization (hpf) until 96 hpf. The results demonstrated a concentration-dependent reduction in tail coiling (TC), touch-evoked response (TER), and lo-comotor activity, alongside an increase in sleep time and alterations in sleep bouts and sleep latency during both 24-hour and Light1/Dark/Light2 (7/10/7-hour) periods. Additionally, exposure to BBzP led to increased acetylcholinesterase (AChE) and dopamine (DA) levels, and a decrease in 5-hydroxytryptamine (5-HT) levels. Gene expression analysis revealed that DEP and BBzP exposure increased the expression of circadian rhythm and light-response-related genes. In conclusion, exposure to these PAEs disrupts the circadian rhythm of zebrafish larvae, providing novel insights into the developmental impact of these common environmental contaminants. Further research is needed to understand the broader implications of these findings for human health and environmental safety.
... Phthalates are ubiquitous chemicals commonly found in personal care products, plastics, and household items (Wang et al., 2021). Phthalates are endocrine disruptors, and prenatal and early childhood exposure to phthalates has been associated with numerous endocrine-related health effects, such as pregnancy loss, preterm birth, reproductive system development, and precocious puberty, and with non-endocrine effects, such as neurodevelopmental alterations and respiratory diseases (Wang et al., 2021;Engel et al., 2021). There is also some evidence linking prenatal organophosphate exposure to neurodevelopmental outcomes (Sapbamrer and Hongsibsong, 2019). ...
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Background: Previous studies suggest that prenatal exposure to phthalates, ubiquitous synthetic chemicals, may adversely affect neurodevelopment. However, data are limited on how phthalates affect cognition, executive function, and behavioral function into adolescence. Objective: We aimed to investigate associations of prenatal phthalate exposure with neurodevelopment in childhood and adolescence in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. Methods: We examined associations between maternal urinary phthalate metabolite concentrations measured twice during pregnancy and a range of neurodevelopmental outcomes from ages 7 through 16 y in the CHAMACOS birth cohort ( n = 334 ). We used age-specific linear regression models and generalized estimating equation models to assess longitudinal effects and examined differences by sex. Results: Phthalate metabolites were detected in 88%-100% of samples, depending on the metabolite. Associations of phthalates with neurodevelopmental outcomes were largely null with some noteworthy patterns. Higher prenatal concentrations of metabolites of low-molecular weight phthalates ( Σ LMW ) were associated with more self-reported hyperactivity [ β = 0.8 , 95% confidence interval (CI): 0.1, 1.4 per 2-fold increase in Σ LMW phthalates], attention problems ( β = 1.5 , 95% CI: 0.7, 2.2), and anxiety ( β = 0.9 , 95% CI: 0.0, 1.8) at age 16. We observed sex-specific differences for the sums of high-molecular-weight and di(2-ethylhexyl) metabolites and cognitive outcomes (e.g., β for Full-Scale IQ for boys = - 1.9 , 95% CI: - 4.1 , 0.3 and - 1.7 , 95% CI: - 3.8 , 0.3, respectively; β for girls = 1.8 , 95% CI: 0.1, 3.4 and 1.6, 95% CI: 0.0, 3.2, respectively; p -int = 0.01 for both). Conclusion: We found predominantly null associations of prenatal phthalates with neurodevelopment in CHAMACOS, and weak associations of Σ LMW phthalates with internalizing and externalizing behaviors in adolescence. No previous studies have examined associations of prenatal phthalate exposure with neurodevelopment into adolescence, an important time for manifestations of effects. https://doi.org/10.1289/EHP5165.
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Background Evidence from experimental and observational studies suggests that prenatal phthalate exposures may be associated with autism spectrum disorder (ASD). We examined whether prenatal phthalate exposures were associated with an increased risk of ASD. Methods We quantified 14 metabolites of eight phthalates in 636 multiple maternal urine samples collected during 2nd and 3rd trimesters of pregnancy from 201 mother-child pairs in MARBLES (Markers of Autism Risk in Babies – Learning Early Signs), a high-risk ASD longitudinal cohort. At 3 years old, children were clinically assessed for ASD and classified into three diagnostic categories: ASD (n = 46), non-typical development (Non-TD, n = 55), and typical development (TD, n = 100). We used multinomial logistic regression to evaluate the association of phthalate metabolite concentrations with ASD and Non-TD. Results Most associations of phthalate biomarkers with both ASD and Non-TD were null, with the exception that monoethyl phthalate (MEP) was significantly associated with an increased risk of Non-TD (per 2.72-fold relative increase in concentration: Relative risk ratio (RRR) = 1.38; 95% confidence interval (CI): 1.01, 1.90). When stratified by prenatal vitamin use during the first month of pregnancy, among mothers who took vitamins, ASD risk was inversely associated with mono-isobutyl phthalate (MiBP, RRR = 0.44; 95% CI: 0.21, 0.88), mono(3-carboxypropyl) phthalate (MCPP, RRR = 0.41; 95% CI: 0.20, 0.83) and mono-carboxyisooctyl phthalate (MCOP, RRR = 0.49; 95% CI: 0.27, 0.88), but among mothers who did not take prenatal vitamins, Non-TD risk was positively associated with MCPP (RRR = 5.09; 95% CI: 2.05, 12.6), MCOP (RRR = 1.86; 95% CI: 1.01, 3.39), and mono-carboxyisononyl phthalate (MCNP, RRR = 3.67; 95% CI: 1.80, 7.48). When stratified by sex, among boys, MEP, monobenzyl phthalate, MCPP, MCNP, and sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP) were positively associated with Non-TD risk, but associations with ASD were null. Among girls, associations with both ASD and Non-TD were null. Conclusions Our study showed that phthalate exposures in mid- to late pregnancy were not associated with ASD in children from this high-risk ASD cohort. Further studies should be conducted in the general population without high-risk genes to confirm our findings. Electronic supplementary material The online version of this article (10.1186/s12940-018-0428-4) contains supplementary material, which is available to authorized users.
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Importance Prenatal exposure to phthalates has been associated with neurodevelopmental outcomes, but little is known about the association with language development. Objective To examine the association of prenatal phthalate exposure with language development in children in 2 population-based pregnancy cohort studies. Design, Setting, and Participants Data for this study were obtained from the Swedish Environmental Longitudinal Mother and Child, Asthma and Allergy (SELMA) study conducted in prenatal clinics throughout Värmland county in Sweden and The Infant Development and the Environment Study (TIDES) conducted in 4 academic centers in the United States. Participants recruited into both studies were women in their first trimester of pregnancy who had literacy in Swedish (SELMA) or English or Spanish (TIDES). This study included mothers and their children from both the SELMA study (n = 963) and TIDES (n = 370) who had complete data on prenatal urinary phthalate metabolite levels, language delay, and modeled covariables. For SELMA, the data were collected from November 1, 2007, to June 30, 2013, and data analysis was conducted from November 1, 2016, to June 30, 2018. For TIDES, data collection began January 1, 2010, and ended March 29, 2016, and data analysis was performed from September 15, 2016, to June 30, 2018. Main Outcomes and Measures Mothers completed a language development questionnaire that asked the number of words their children could understand or use at a median of 30 months of age (SELMA) and 37 months of age (TIDES). The responses were categorized as fewer than 25, 25 to 50, and more than 50 words, with 50 words or fewer classified as language delay. Results In the SELMA study, 963 mothers, 455 (47.2%) girls, and 508 [52.8%] boys were included. In TIDES, 370 mothers, 185 (50.0%) girls, and 185 (50.0%) boys were included in this analysis. The prevalence of language delay was 10.0% in both SELMA (96 reported) and TIDES (37 reported), with higher rates of delay in boys than girls (SELMA: 69 [13.5%] vs 27 [6.0%]; TIDES: 12 [12.4%] vs 14 [7.6%]). In crude analyses, the metabolite levels of dibutyl phthalate and butyl benzyl phthalate were statistically significantly associated with language delay in both cohorts. In adjusted analyses, a doubling of prenatal exposure of dibutyl phthalate and butyl benzyl phthalate metabolites increased the odds ratio (OR) for language delay by approximately 25% to 40%, with statistically significant results in the SELMA study (dibutyl phthalate OR, 1.29 [95% CI, 1.03-1.63; P = .03]; butyl benzyl phthalate OR, 1.26 [95% CI, 1.07-1.49; P = .003]). A doubling of prenatal monoethyl phthalate exposure was associated with an approximately 15% increase in the OR for language delay in the SELMA study (OR, 1.14; 95% CI, 1.00-1.31; P = .05), but no such association was found in TIDES (OR, 0.98; 95% CI, 0.79-1.23). Conclusions and Relevance In findings from this study, prenatal exposure to dibutyl phthalate and butyl benzyl phthalate was statistically significantly associated with language delay in children in both the SELMA study and TIDES. These findings, along with the prevalence of prenatal exposure to phthalates, the importance of language development, and the inconsistent results from a 2017 Danish study, suggest that the association of phthalates with language delay may warrant further examination.
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Phthalates are among the most frequently investigated environmental chemicals influencing children's health and particularly their neuropsychological development. However, the reported effects of these compounds on child behavior, cognitive and psychomotor outcomes are not fully consistent. The aim of this study is to evaluate the associations between prenatal and early postnatal phthalate exposures and child neurodevelopment at age of 7 years. A total of 134 mother-child pairs from Polish Mother and Child Cohort (REPRO_PL) constitute the basis for current analysis. Eleven phthalate metabolites were measured in urine samples collected from mothers in the 3rd trimester of pregnancy and from children at the age of 2 years. Child neuropsychological development at early school age (7 years) was assessed by both the Strengths and Difficulties Questionnaire (SDQ) filled by mothers and the Polish adaptation of the Intelligence and Development Scales (IDS) performed by psychologists. Mono-ethyl phthalate (MEP) concentration during pregnancy was significantly associated with increased risk of peer relationship problems in SDQ (OR = 2.7, p = 0.03). The results of the IDS analyses focused on child's cognitive and psychomotor development are not fully conclusive. Negative associations were evident between some phthalates in early childhood period and fluid intelligence and cognition (MEP: β = −5.2; p = 0.006; β = −4.2; p = 0.006; mono-n-butyl phthalate (MnBP): β = −4.9; p = 0.03; β = −4.0; p = 0.03; respectively), while positive associations have been found in the prenatal period (mono-2-ethyl-5-oxo-hexyl phthalate (oxo-MEHP): β = 3.6; p = 0.03 for fluid intelligence; β = 2.9; p = 0.03 for cognition). Further studies are required in order to elucidate which are the most critical periods of phthalate exposure on children's neurodevelopmental outcomes.
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Background: Phthalate have been detected widely in the environment; while several studies have indicated that prenatal phthalate exposure has adverse effects on neurodevelopment, the results were inconsistent. Objective: We aimed to determine the current research status of the relationship between prenatal exposure to different types of phthalate and cognition and behavioral development in children. We conducted a systematic review to evaluate the current state of knowledge. Methods: We systematically searched PubMed, Web of Science, and EMBASE electronic databases up to May 2018 with manual searches of the references of retrieved publications and relevant reviews. Only birth cohort studies that reported on the association between phthalate exposure and cognitive or behavioral development were included in this review. We evaluated the risk of bias for each of the included studies using a modified instrument based on the Cochrane Collaboration's "Risk of Bias" tool. Result: Twenty-six birth cohort studies met our inclusion criteria, nine of which investigated the impact of phthalate exposure during pregnancy on cognition, 13 on neurobehavior, and 4 on both cognition and neurobehavior. However, ten articles reported that the effect of prenatal exposure to phthalates on cognitive development was statistically significant, 15 articles reported that the effect of prenatal exposure to phthalates on neurobehavior was statistically significant. The effect of prenatal phthalate exposure on neurodevelopment differed according to sex, but the results are inconsistent, for instance, among the five studies investigating the association between mental development index (MDI) and Mono-n-butyl phthalate (MnBP), two of them showed a significantly decreasing MDI scores with increasing concentrations of MnBP among girls, but among boys one study showed the inverse association, another showed the positive association. Conclusion: Di(2-ethylhexyl) phthalate, dibutyl phthalate, butyl-benzyl phthalate and di-ethyl phthalate exposure during pregnancy was associated with lower cognitive scores and worse behavior in offspring, and sex-specific effects on cognitive, psychomotor, and behavioral development were identified, especially the impact of phthalate exposure on neurobehavior in boys.
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A contribution to SBN/ICN special issue. Endocrine-disrupting chemicals (EDCs) are pervasive in the environment. They are found in plastics and plasticizers (bisphenol A (BPA) and phthalates), in industrial chemicals such as polychlorinated biphenyls (PCBs), and include some pesticides and fungicides such as vinclozolin. These chemicals act on hormone receptors and their downstream signaling pathways, and can interfere with hormone synthesis, metabolism, and actions. Because the developing brain is particularly sensitive to endogenous hormones, disruptions by EDCs can change neural circuits that form during periods of brain organization. Here, we review the evidence that EDCs affect developing hypothalamic neuroendocrine systems, and change behavioral outcomes in juvenile, adolescent, and adult life in exposed individuals, and even in their descendants. Our focus is on social, communicative and sociosexual behaviors, as how an individual behaves with a same- or opposite-sex conspecific determines that individual's ability to exist in a community, be selected as a mate, and reproduce successfully.
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The growth and organization of the developing brain are known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, such as mPFC. This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 μg/kg/d through pregnancy and for 10 d while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.