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The Safety Concerns Of Organic UV-Filters: A Special Focus On Their Endocrine

Disrupting Properties

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 Journal of Environmental Pathology, Toxicology and Oncology, 39(3):201 – 212 (2020)

Safety Concerns of Organic Ultraviolet Filters: Special

Focus on Endocrine-Disrupting Properties
Didem Oral,a Anil Yirun,a,b & Pinar Erkekoglua,*
a
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Ankara, Turkey; bÇukurova
University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Adana, Turkey
*Address all correspondence to: Pinar Erkekoglu, Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, 06100
Ankara, Turkey; Tel.: +903123053357; Fax: +903123114777, E-mail: erkekp@yahoo.com

ABSTRACT: Acute and chronic effects of ultraviolet radiation (UVR) on human health have long been a concern.
It is well known that acute UVR causes epidermal hyperplasia, erythema, delayed tanning, pigment darkening, and
free-radical formation. Apart from acute effects of UVR, its chronic effects involve immunosuppression, photoaging,
exacerbation, photodermatoses, and photocarcinogenesis. To protect skin from harmful effects of UVR, UV filters were
developed. But these may cause harmful effects in humans and on the environment; adverse effects of these chemicals
have been evaluated for > 20 yr. Studies show that UV filters may lead to endocrine disruption, hepatotoxicity, muta-
genicity, and systemic toxicity. Literature on environmental effects of UV filters suggests that they are bioaccumulative,
pseudopersistent, and possibly toxic to aquatic ecosystems. The objective of this review is to summarize toxic effects
and safety concerns of organic UV filters on human beings and the environment. We focus on UV filters’ organic endo-
crine-disrupting effects by reviewing both in vivo and in vitro studies.

KEY WORDS: organic UV filter, sunscreen, UV radiation, endocrine disruption, toxicity

I. INTRODUCTION lotions. Moreover, they are present in personal-care

Solar ultraviolet radiation (UVR), comprised of
UVC (270–290 nm), UVB (290–315 nm), and UVA
(315–400 nm) rays, make up ~ 94% of the UVR ap-
proach to the earth’s surface. UVA is subdivided into
UVA2 (315–340 nm) and UVA1 (340–400 nm) (Fig.
1). Acute toxic effects of UVR on human health in-
clude erythema, epidermal hyperplasia, persistent or
immediate pigment darkening, and free-radical for-
mation. Additionally, chronic consequences of UVR
exposure can be more serious (photoaging, photo-
dermatoses, immunosuppression, and photocarcino-
genesis).1 UV filters are commonly used to protect
human skin from UVR’s adverse effects in that they
contain materials that inhibit harmful UVR.2 In re-
cent years, due to widespread public awareness of
skin cancer, UV filters have been abundantly used.3
UV filters can be divided into two groups: inor-
ganic and organic. Inorganic filters contain mineral
particles (titanium dioxide [TiO2] and zinc oxide) that
reflect and scatter UV light from the skin. Organic
filters have aromatic constitutions that absorb and
stabilize solar UVR (Table 1).4–6 UV filters are com-
monly used in sunscreen creams, sprays, oils, and
products such as cosmetics (foundations, lip balms/
creams, powders, body lotions), hair shampoos/
creams, insect repellents, and laundry detergents.4,7
It is estimated that ~ 10,000 tons of UV filters are
produced worldwide each year, and these products
spread to the environment, particularly surface wa-
ters.8–10 They are detected widely in fresh/sea water, tap
water, wastewater, sewage sludge, sediments, biota,
and biological fluids such as serum, urine, and breast
milk.11 UV-filter ingredients can reach the aquatic en-
vironment via wash off from the skin during different
activities (diving, swimming, etc.), industrial dis-
charge, or wastewater treatment plants (WWTPs).2,10
Studies indicate that UV filters have light li-
pophilicity and are pseudopersistent environmen-
tal contaminants. Most of the substances have the
ability to bioaccumulate, causing serious concerns,
and many studies suggest that 256–7112 ng/g of UV
filters can be found in various aquatic organisms.2
They may cause adverse effects such as genotoxic-
ity, mutagenicity, and endocrine disruption (particu-
larly estrogenic activity), both in vitro and in vivo.2,10
This review focuses on organic UV-filter
toxic effects and safety concerns, emphasizing

0731-8898/20/$35.00 © 2020 by Begell House, Inc. www.begellhouse.com201

202 Oral, Yirun, & Erkekoglu
FIG. 1: UVR and its various types. UVA, ultraviolet ra-
diation A; UVB, ultraviolet radiation B; UVC, ultraviolet
radiation C; UVR, ultraviolet radiation
endocrine-disrupting consequences. In addition, we
review the presence of UV filters in different organ-
isms and biological fluids.
II. BENZOPHENONES
During the past four decades, benzophenone (BP)-
type UV filters have been abundantly used in sun-
screens and cosmetics. Today, BP-3 and -4 are more
widely used than any other BP-type UV filter.4,12
BPs have been detected at levels of up to 125 ng/L in
Swiss bathing lakes, 3.3 µg/L on the Mediterranean
coast, 700 ng/L WWTP effluents in the US, and 27
ng/L in sediments of northeastern Spain.13,14
BP-3 is photostable, lipophilic, and accumula-
tive. Because of its high logKow value, it slowly biode-
grades. A persistent compound, it is frequently found
in sediments. BP-3 has a half-life of a few weeks in
surface waters during the summer. However, its half-
life becomes 7 to 9 times longer in winter. Addition-
ally, BP-3 has low-volatilization potency from water
surfaces and tends to adsorb to suspended solids.4,14
A. BP Biotransformations
In humans, BP-3 can be absorbed at a rate of up
to 2% following topical application and is readily
absorbed after ingestion. In humans, 2,4-dihydroxy
BP (2,4-diOH BP) is the main metabolite of BP-3.
Oxidation of 2,4-diOH BP is catalyzed primarily
by cytochrome P450 2C6 (CYP2C6), CYP1A1,
CYP1A2 and CYP2E1.15 Oxidation of BP-3 to 5-OH
BP-3 is catalyzed primarily by CYP1A2 but also by
CYP1A1, CYP2C6, CYP2D1, and CYP2B1. These
metabolites are suggested to show stronger estro-
genic activity than BP-3.4,14
BP-3 metabolizes mainly to 2,4-diOH BP and
2,2’-diOH-4-methoxy BP, and to a lesser extent in
rats, to 2,3,4-triOH BP. It has been demonstrated that
in rat-liver microsomes, CYP1A1 catalyzes oxidation
of BP-3 to 3-OH BP-3. On the other hand, CYP1A1/2,
CYP2B1, CYP2C6, CYP2D1, and CYP2C6 mainly
catalyze oxidation of BP-3 to 5-OH BP-3.4,14 After
systematic absorption, BP-3 and metabolites can be
detected in blood, urine, breast milk, semen, and ad-
ipose tissue. Moreover, it has been shown that BP-3
can pass through the blood–placenta barrier and thus
be detected in amniotic fluid, placenta, umbilical-cord
blood, follicular fluid, and fetal serum.15
In 2013, Zhang et al. studied concentrations of
BP-type UV filters in blood and urine samples of
children, adults, and pregnant women in China and
measured BP fetal cord blood levels.16 The research-
ers obtained 101 urine samples from a general adult
population and collected matched blood samples
from 50 participants. In addition, 20 paired blood
and fetal cord blood samples were collected from
pregnant women and whole blood from ten chil-
dren. BP-3 was found in blood of 83% of adults,
35% of pregnant women, and 30% of children. In a
female adult who often used sunscreens, very high
concentrations of BP-3 (475 ng/mL) and BP-1 (338
ng/mL) were found. Additionally, exposure to BP-3
was shown to be higher in females than in males.16
These findings caused concern and led to additional
investigations on BP-3 toxicity during recent years.
B. BP Endocrine-Disrupting Effects and
Reproductive/Developmental Toxicity
1. Human Studies
Studies suggest that BP-3 exposure is linked to re-
productive toxicity in humans and animals.17–19 In
Journal of Environmental Pathology, Toxicology and Oncology
Endocrine-Disrupting Properties of Organic UV Filters203

TABLE 1: Organic UV filters

Substance Molecular formula
Cinnamate derivates (e.g., EHMC)

OCT

OMC

AVB

BP-1, -2, -3, -4

Camphor derivates (e.g., 4-MBC)

PABA derivatives (e.g., ET-PABA, OD-PABA)

BZT

AVB, avobenzone; BZT, benzotriazole; BP, benzophenone; EHMC, 2-ethyl-hexyl-4-trimethoxycinnamate; ET-PABA, ethyl-4-
aminobenzoate; 4-MBC, 4-methlybenzylidene camphor; OCT, octocrylene; OD-PABA, octyl-dimethyl-aminobenzoate; OMC,
octyl-methoxycinnamate; PABA, para-aminobenzoic acid; UV, ultraviolet.

2017, Ghazipura et al. observed that prenatal expo-
sure to BP-3 was responsible for decreased gesta-
tional age, earlier-onset childbirth, increased male
infant birth weights, and decreased female infant
birth weights. In the developing fetus, exposure
to BP-3 caused endocrine disruption and targeted
sex hormone precursors that affected estrogen and
testosterone levels.17 In another study, Wollf et al.
investigated the relationship between prenatal ex-
posure to BP-3 and birth outcomes including birth
weight and gestational age in a multiethnic cohort
of pregnant women.18 These researchers demon-
strated that prenatal (third tertile) exposure to BP-3
was associated with higher birth weight in boys but
lower birth weight in girls, in agreement with the
findings of Ghazipura et al.
In 2012, Philippat et al. conducted a case-con-
trol study between 2002 and 2006 in two different
mother-child cohorts, investigating the relationship
between male birth outcomes and BP-3 exposure.19
Maternal urinary samples were collected between
the sixth and 30th gestational week. The research
group found that high maternal BP-3 exposure was
linked to an increase of 26 g in male birth weight
and 0.1 cm in head circumference at birth. Addition-
ally, boys born of the highest-exposed mothers were

Volume 39, Issue 3, 2020

204 Oral, Yirun, & Erkekoglu
105 g heavier than boys born of lowest-exposed
mothers.19
In a 2012 prospective study, Krause et al. simul-
taneously paired samples of amniotic fluid, mater-
nal serum, and urine from 200 pregnant women.20
During cordocentesis, the researchers collected
human fetal blood (n = 4) and cord blood (n = 23)
samples at delivery, both paired with maternal se-
rum and urine samples. All samples were analyzed
using liquid chromatography–tandem mass spec-
trometry for seven different BP derivatives. BP-1,
BP-3, 4-methyl-BP (4-MBP), and 4-OH BP were all
detected in amniotic fluid and cord blood samples.
BP-1 and -3 were found in lower concentrations (~
10 times lower) in fetal and cord blood compared to
maternal serum samples. In addition, both BPs had
1000 times lower concentrations in fetal and cord
blood versus those of maternal urine levels. The
researchers stated that BP-1 and -3 could only be
detected in fetal circulation when high maternal ex-
posure was present. This could indicate a protective
effect of the placental barrier. However, 4-MBP was
found to pass into fetal and cord blood more freely,
with a median ratio of 1:3 in cord blood and maternal
serum levels. BP-3 concentrations in amniotic fluid
correlated with maternal urine and serum levels.
The investigators suggested that maternal urinary
levels seem to be a valid proxy for fetal exposure
to BP-3, but this was not the case for other tested
BPs. Moreover, BP-3 had highest concentrations in
maternal serum than other detected BPs. Krause et
al. concluded that detectable levels of several BP
derivatives in human amniotic fluid and fetal and
cord blood suggest potential endocrine-disrupting
properties of these compounds, and they should be
investigated to better understand potential risks to a
developing fetus.20
Hirschsprung’s disease (HSCR) is a complex
congenital disorder that is caused by the effects of
environmental factors on certain genes. The disease
leads to neonatal intestinal abnormality brought on
by the failure of enteric neural crest cells to migrate
to the hindgut during embryogenesis occurring at 5
to 12 wk. Patients suffer from intestinal obstruction
and chronic constipation. The incidence of HSCR is
1:2000–1:5000 in live births. Males are four times
more likely than females to be at risk.21 In a 2016
case-control study, Huo et al. investigated the associ-
ation of maternal BP-3 exposure to their offspring’s
HSCR risk.22 The researchers recruited 101 HSCR
patients’ mothers and 322 mothers as controls from
Nanjing Medical University hospitals from October
2009 to May 2014. HSCR was confirmed by “the
observation of no ganglion cells in colorectum,”
identified by a distal rectal biopsy of the submucosa.
The researchers later conducted in vitro experiments
to show the underlying mechanism of HSCR in re-
lation to microRNA (miR)-218–mediated pathways.
To detect BP-3 levels, spot urine samples were col-
lected from mothers with HSCR and from 322 con-
trols. The maximum detection concentration was
found to be 400.72 ng/mL. BP-3 levels at 50th, 75th,
90th, and 95th percentiles were 0.08, 0.17, 0.54, and
1.10 ng/mL, respectively. Women in both median
and high-BP-3–exposure groups were more likely
to give birth to children with HSCR compared to
women in the lowest-exposure group. On the other
hand, in vitro experiments on human 293T and
SH-SY5Y cells, which are well-known models for
HSCR, revealed that BP-3 suppressed cell migra-
tion and regulated receptor tyrosine kinase (RET),
miR-218, Pleomorphic adenoma gene 1 (PLAG1),
Slit-family protein gene 2 (SLIT2), and Round-
about homolog 1 (ROBO1) expression. The authors
concluded that the SLIT2/ROBO1-miR-218-RET/
PLAG1 pathway was involved in HSCR pathogene-
sis that was induced by BP-3.22
2. Animal Studies
Several reports in the literature show endocrine-dis-
rupting effects of different BPs. In 2014, Kim et al.
investigated reprotoxic and endocrine-disrupting
effects of BP-3 exposure in Japanese medaka (Ory-
zias latipes).14 In this study, 4-mo-old adult male
and female medaka (five adult fish per sex and dose
group; F0 generation) were exposed to BP-3 for 28 d
at different doses (0, 4.7, 8.4, 26, or 90 μg/L or 0, 15,
50, 150, or 500 μg/L, based on nominal concentra-
tions) for 14 d. In the last 14 d, the authors counted
the F1 eggs and further exposed them to BP-3 at
different concentrations until 30 d after hatching
(0, 5.4, 12, or 30 μg/L or 0, 15, 50, or 150 μg/L,
based on nominal concentrations). Transformation
Journal of Environmental Pathology, Toxicology and Oncology
Endocrine-Disrupting Properties of Organic UV Filters205
of BP-3 to BP-1, a more potent estrogen agonist,
was confirmed by chemical analysis of exposed me-
dia. During the last 2 d, adult fish and eggs were
collected from controls and each treatment group.
At the close of 28 d, blood, brain, liver, gonads, and
egg samples were collected for analyses. Transcrip-
tion of androgen receptor α (ARα), aromatase B
(cyp19b), estrogen receptor α (ERα), and ERβ in
brain; vitellogenin 1 (vtg1) and vtg2 genes in liver;
and Star, cyp11a, cyp17, hydroxysteroid 17-β de-
hydrogenase 3 (hsd17b3), hsd173b, and cyp19a
genes in gonad were evaluated by quantitative re-
al-time–polymerase chain reaction. Blood samples
were analyzed for plasma sex steroid hormones
(estradiol and testosterone concentrations) and vtg1
levels. Results indicated that in make fish, transcrip-
tions of cyp19b and ERβ genes in the brain were
considerably down-regulated, and transcriptions of
vtg1 and vtg2 genes in liver were significantly in-
creased in a dose-dependent manner. However, no
changes occurred in transcriptions of these genes in
female fish. The Cyp1a gene was up-regulated in all
treatment groups in male fish. However, in female
fish, up-regulation of Cyp1a occurred only at higher
doses. Most of the genes related to steroidogenesis
in gonad were down-regulated in a dose-depen-
dent manner. Moreover, transcription of cyp19a
decreased in both sexes, but marked down-regula-
tion of Star and cyp19a occurred at higher concen-
trations of BP-3 in the female ovary. Transcription
of hsd17b3 was substantially down-regulated in
females, even at lower doses. However, no signifi-
cant changes occurred in males. On the other hand,
down-regulation of cyp11a, cyp17, and 3β-hydrox-
ysteroid dehydrogenase (hsd3b) in testis occurred
at higher doses of BP-3. For reproduction toxicity,
the researchers found significant decrease to 150
µg/L (nominal concentration) between d 26 and 28.
Estradiol and testosterone plasma concentrations
were markedly elevated in a concentration-depen-
dent manner in both male and female adult fish. The
researchers suggested that these significant changes
in steroid-related gene transcriptions, sex hormones,
and vitellin levels after BP-3 exposure could lead to
endocrine disruption in fish.14
In 2012, Blüthgen et al. studied the effects
of low-concentration BP-3 on molecular and
Volume 39, Issue 3, 2020
physiological parameters in adult male zebrafish
and unattached embryos.23 All experimental groups
contained six animals and experiments were repli-
cated five times. Fish were exposed to 2.4–312 µg/L
BP-3 for 14 d. Additionally, embryos were subjected
to 8.2–438 µg/L BP-3 for 120 h after fertilization.
BP-3 became metabolized to BP-1 in adult fish but
not in embryos. BP-3 caused similar toxicological
effects in both adult fish and embryos. At 84 µg/L,
BP-3 exposure caused down-regulation in the tran-
scription of estrogen receptor 1 (er1), cyp19b, and
AR genes in brain. In testes, down-regulation of
hsd3b, hsd17b3, corticosteroid 11-β-dehydrogenase
isozyme 2 (hsd11b2), and cyp11b2 genes were de-
tected. However, no histological alterations occurred
in fish testes after BP-3 exposure. The researchers
concluded that at lower concentrations, BP-3 ex-
hibited similar multiple hormonal activities at the
transcriptional level in two different life stages of
zebrafish. They also found that further studies were
needed to clearly demonstrate endocrine-disrupting
effects of BP-3.23
In another study of zebrafish, endocrine-dis-
rupting effects of BP-3 were determined according
to the Organisation for Economic Co-operation
and Development (OECD) Test Guideline (TG)
234 (fish sexual development).13 The authors de-
termined that induction of vtg1 and phenotypic sex
changes occurred in both in juvenile and adult ze-
brafish. Adult male zebrafish and newly fertilized
eggs were exposed to BP-3 for 12 d during d 1 post-
fertilization to 60-d posthatch (dph), respectively.
Both adult and juvenile male and female fish were
grouped as follows: aquarium controls, positive
controls (2 ng/L of 17β-estradiol [E2]–applied ani-
mals), BP-3 groups, and solvent controls. The dph
exposure (0 to 60) resulted in a monotonic dose-de-
pendent skew of the phenotypic sex ratio toward
fewer males and more females. The value of no
observed effect concentration (NOEC) was found
to be 191 μg/L and lowest observed effect concen-
tration (LOEC) was 388 μg/L. After 12 d of expo-
sure, a mild but significant enhancement in vtg1
was observed in adult male zebrafish at 268 μg/L
but not at 63-  and 437-μg/L concentrations. BP-3
exposure affected gonad maturation stages in both
female and male fish. Both genders at highest–BP-3
206 Oral, Yirun, & Erkekoglu
concentrations were unable to develop to advanced
gametogenesis stages.13
In 2016, Balázs et al. investigated BP-3 terato-
genic effects (at 10 • 10–1, 7.89 • 10–2, 5.26 • 10–2,
3.07 • 10–2, 2.19 • 10–2, and 4.38 • 10–3 mm) in ze-
brafish hatched embryos according to OECD TG
236 (modified fish embryo acute toxicity test).9 The
researchers demonstrated that BP-3 exposure could
decrease the number of hatched embryos and lead to
different malformations in developing fish. In con-
trol and highest-BP-3–exposed groups, all embryos
showed inflated swim bladders at 120 h postfertiliza-
tion (hpf). Jaw deformities were visible in numerous
individuals including in the lowest-BP-3–exposed
group. At 2.19 • 10–2 mm, swim-bladder filling inhi-
bition was observed, and in higher-dose groups the
effect was dose dependent. Embryos treated with
2.19 • 10–2, 3.07 • 10–2, and 5.26 • 10–2 mm of BP-3
showed gut dilatation. Tail deformity was accompa-
nied by somite malformation in 5.26 • 10–2 and 7.89
• 10–2 mm groups, and in these animals, both pericar-
dial and yolk edema were also observed.9
In a recent study of rat frontal cortex and hip-
pocampus, effects of BP-3 on expression of dif-
ferent receptors (estrogen, androgen, and aryl
hydrocarbon [AhR]) and apoptosis were determined
by Krzyżanowska et al.24 During pregnancy, BP-3
was intradermally administered to female rats and
then to their 6- through 7-wk–old male offspring.
In offspring frontal cortex, BP-3 induced the mi-
tochondrial apoptosis pathway, evidenced by in-
creases in caspase 3 and caspase 9, Bax, and Bak
levels. Moreover, BP-3 caused elevations in the
number of cells with apoptotic DNA fragmentation.
In hippocampus, the authors observed elevated lev-
els of caspase 9 and decreased antiapoptotic protein
levels. Both ERβ and membrane G protein-coupled
receptor 30 were markedly reduced in both brain re-
gions. BP-3 significantly increased AhR in offspring
frontal-cortex cytosol but did not affect hippocam-
pal AhR levels. In rat frontal cortex, BP-3 induction
of the mitochondrial apoptotic pathway may have
been caused by decreased estrogen and thus its
neuroprotective effects or increased AhR-mediated
apoptosis.24
In 2016, Jang et al. assessed toxicity in
Daphnia magna using BP-3, 2-ethyl-hexyl-4-
trimethoxycinnamate (EHMC) and TiO2 nanoparti-
cles (NPs), and their different mixtures, to determine
the nominal toxic concentration of each ingredient.
The group later conducted experiments with wild-
type zebrafish embryos. When they observed phe-
notypic alterations (i.e., body deformation), they
further examined specific organs of transgenic ze-
brafish embryos. Both EHMC and BP-3 influenced
phenotypic changes in zebrafish in a dose-dependent
manner, whereas TiO2 NPs did not elicit any de-
fects. Although combinations of different mixtures
at lower doses did not lead to changes in embryo
blood flow, the experimental group that was treated
with high doses of BP-3 (4 μg/mL) and a mixture of
EHMC (0.5 μg/mL), BP-3 (4 μg/mL), and TiO2 NPs
(4 μg/mL) showed signs of cardiac edema. EHMC
treatment caused a slightly smaller liver size change
(84.56% ± 4.73%). However, BP-3 (4 μg/mL) led
to significant decreases in liver size versus controls
(65.33% ± 8.93%; p < 0.05).25
C. Oxidative Stress
In 2015, Liu et al. investigated oxidative stress in
livers of the freshwater fish Cassius auratus, ex-
posing them to the four BP-type UV filters. In this
study, the authors measured four oxidative stress-re-
lated biomarkers (activities of superoxide dismutase
[SOD], glutathione S-transferase [GST], catalase
[CAT], and glutathione [GSH]). Exposure concen-
trations were 0.48 ± 0.03 mg/L for BP-1, 0.48 ± 0.05
mg/L for BP-2, 0.48 ± 0.3 mg/L for BP-3, and 0.49
± 0.03 mg/L for BP-4. Each treatment group was
exposed to the concentrations for 7, 14, and 28 d.
Results showed that BP-1 and -3 enhanced GST ac-
tivity at first and after 7 d, but at the close of d 28
GST levels were not markedly different than those of
controls. BP-1 and -3 considerably increased GSH
levels, which remained high until the end of the ex-
periment. SOD activity decreased in all BP-exposed
groups after 7 d. However, SOD levels progres-
sively increased after 14 and 28 d of exposure. CAT
activity diminished considerably in all BP-exposed
groups after 7 d but progressively increased after 14
and 28 d. Decreases in SOD and CAT activities after
first 7 d was explained by high levels of reactive ox-
ygen species after instant exposure to a toxic insult.
Journal of Environmental Pathology, Toxicology and Oncology
Endocrine-Disrupting Properties of Organic UV Filters207
On the other hand, increases in SOD and CAT lev-
els after 14 and 28 d were interpreted to occur after
adaptive responses to toxicants and defensive gains
against oxidative stress.26
Today, BPs are widely used globally. However,
due to their endocrine-disruptive and reprotoxic ef-
fects, avobenzone (AVB), EHMC, and octocrylene
(OCT) are suggested as alternatives to BP-type UV
filters.10 A summary of BP-3 endocrine-disrupting
effects is found in Table 2.13,14,17,23
III. OCTYL METHOXYCINNAMATE
The UV filter octyl-methoxycinnamate (OMC) is
used in sunscreens and most personal-care products
worldwide.27 This compound is lipophilic and can
accumulate in biota.8 OMC is found at a value of ~
10–390 µg/kg in sewage sludge and can be detected
in biological samples (i.e., blood, urine, and breast
milk).28 Results of different studies suggest that
OMC can act as an endocrine disruptor.29,30 During
the last decade, in vivo and in vitro studies found
OMC to interfere with hypothalamus–pituitary–go-
nadal and hypothalamus–pituitary–thyroid (HPT)
axes.30,31 Additionally, OMC possesses estrogenic
and estrogen-independent activities.29
A. In Vitro/In Vivo Studies on OMC
Endocrine-Disrupting Effects and
Reproductive/Developmental Toxicity
In vivo and in vitro studies have shown that OMC
acts as an estrogenic compound. In 2005, Gomez
TABLE 2: BP-3 Endocrine-disrupting effects
Estrogenic activity
In vitro studies: Binding to hERα; induction to transactivation of ERα and ERβ
In vivo studies: Uterotrophic effects on rats; decreased ERβ levels in rodents
Progesterone activity
In vitro studies: Antagonism with hPR transactivation
Antiandrogenic activity
In vitro and in vivo studies: Antagonism with hAR transactivation
Thyroidal activity
Induction of TR transcription; decreased ERR1 expression
ER, estrogen receptor; ERR1, estrogen-related receptor 1; hAR, human androgen receptor; hPR, human progesterone receptor; TR,
thyroid receptor.
Volume 39, Issue 3, 2020
et al. demonstrated the estrogenic activity of OMC
in the Cellosaurus HELN ERα cell line.32 In 2001,
Schlumpf et al. found that OMC exposure (0.1 ×
10–7, 1 × 10–6, 5 × 10–6, 1 × 10–5, and 5 × 10–5 m con-
centrations, for 6 d) caused dose-dependent cell pro-
liferation in MCF-7 human breast cancer cells.33
Klammer et al. investigated OMC effects at dif-
ferent doses (10, 33, 100, 333, and 1000 mg/kg) for
5 d on the HPT axis in bilaterally ovariectomized
rats.30 The authors applied E2-valerate to the posi-
tive-control group. At the close of d 5, all animals
were decapitated. Levels of thyroid-stimulating
hormone (TSH), thyroxine (T4), and triiodothy-
ronine (T3) were detected in serum. Additionally,
the authors measured thyroid gland expression of
sodium iodide symporter, pro-thyroid–releasing
hormone (pro-TRH), TSH receptor, TRH messen-
ger RNA (mRNA), and thyroid peroxidase activ-
ities. Hepatic deiodinase activity was detected in
the liver. Expression of pro-TRH in the mediobasal
hypothalamus did not change in any OMC-applied
groups or in positive controls. Serum TSH levels
decreased in a dose-dependent manner in all study
groups, with the difference significant in 333 and
1000 mg/kg exposed groups versus controls. Se-
rum T3 levels decreased by 63% in the 1000 mg/
kg OMC-exposed group compared to controls.
Mean serum T4 levels decreased by 75% and 59%
in 333 and 1000 mg/kg OMC-exposed groups, re-
spectively, versus controls. TSH receptor expres-
sion in thyroid increased by 144% in highest-OMC
animals compared to controls. Hepatic deiodinase
activity decreased by 72% and 64% in 333 and
208 Oral, Yirun, & Erkekoglu
1000 mg/kg OMC-applied groups compared to
controls.30
In 2011, Axelstad et al. demonstrated endocrine
disruption caused by OMC.31 The researchers inves-
tigated OMC effects on developing reproductive and
thyroid hormone systems and addressed neurologi-
cal development related to thyroid hormone levels
in rat offspring. Eighteen pregnant Wistar rats were
exposed to OMC at 0, 500, 750, and 1000 mg/kg
during gestation and lactation. T4 levels sharply and
significantly decreased during the dosing period in
all dosed dams. However, this effect was not as se-
vere in offspring. On postnatal d 16, a dose-depen-
dent relative decrease in prostate occurred, and testis
weights and testosterone levels were significantly
less in 1000 mg/kg OMC-exposed male offspring.
Female offspring showed decreased motor activity.
However, in lowest- and highest-dose groups, im-
proved spatial learning abilities were observed in
males. In 500, 750, and 1000 mg/kg OMC-exposed
groups, sperm counts and prostate weights were
markedly lower than those of controls. The inves-
tigators suggested that perinatal exposure to OMC
could cause disturbances in both reproductive and
neurological development in rat offspring.31
In 2001, Schlumpf et al. reported that OMC ex-
posure (1035 mg/kg for 4 d) in immature female rats
caused increases in uterine weight.28 Klammer et al.
showed that OMC at 1000 mg/kg for 5 d resulted
in increased uterine weight, decreased insulin-like
growth factor 1 gene expression, and reduced serum
levels of cholesterol, triglyceride, and low density
lipoprotein in ovariectomized adult rats.34
IV. OCT
OCT, one of the most widely used UV filters, is also
found in personal-care products. Because of its high
lipophilicity (logKow = 6.9) and low biodegradabil-
ity, OCT can accumulate in biota.35 This compound
is hydrophobic and more refractory than other UV
filters.36 It has been detected at up to 642 µg/kg dw
in lake sediment, 25 µg/kg dw in river sediment,
and up to 12 µg/L in wastewater. In 2006, Buser et
al. and in 2014, Blüthgen et al. found OCT at up to
2400 ng/g lipid weight and 30 ng/g dry weight in
Switzerland river fish.37,38
Several studies investigated OCT potential
health risks. In 2016, Zhang et al. studied multiple
endocrine-disrupting effects of OCT in zebrafish
(Danio rerio).7 Adult zebrafish were OCT exposed
at 100, 1000, and 3000 µg/L–1 for 28 d. Control
groups (blank and solvent) were also included. Wa-
ter samples were measured for realization of OCT
exposure concentrations at 0 h, after 24 h, and be-
fore water renewal after 48 h and on d 1–3, 10–12,
and 19–21. All actual concentrations were lower
than prepared levels, and OCT was detected in
all exposure groups. The researchers reported that
OCT showed little bioaccumulation, OCT uptake
was rapid, and its elimination occurred within 24
h. At the close of d 28, zebrafish was extracted and
tissues were homogenized. Ovaries of female ze-
brafish were examined to detect distribution of pri-
mary and previtellogenic oocytes and vitellogenic
ovaries, and the authors measured the gonad–so-
matic index. Results showed a decreased percent-
age of oocytes along with increased vtg in oocytes
in highest OCT-exposed fish. It is suggested that
high levels of OCT accumulation could directly ex-
pedite ovaries and induce vtg1. VTG1, steroid me-
tabolism genes, and nuclear receptor genes (ER1
and AR) were analyzed in brain, liver, and gonad.
ER1 down-regulation was associated with OCT an-
tiestrogenic activity in brain. AR gene expression
was found significantly inhibited in male gonad at
medium and high total-body OCT accumulation and
in female fish with high OCT levels. cyp19b was
significantly up-regulated in brain at medium and
high OCT accumulations. Researchers observed
significant up-regulation of vrg1 in liver at high
OCT accumulation levels in both sexes. Addition-
ally, the retinol-binding protein 2a (Rbp2a) gene
was found to be induced in liver in both sexes. On
the basis of these results, it was suggested that OCT
can easily accumulate and cause endocrine-disrupt-
ing effects in aquatic life.7
V. 4-METHYLBENZENE CAMPHOR
4-Methylbenzylidene camphor (4-MBC) is an or-
ganic UV filter. Studies in rats indicate that after oral
administration of 4-MBC, the substance is metabo-
lized by CYP450s and subject to intensive hepatic
Journal of Environmental Pathology, Toxicology and Oncology
Endocrine-Disrupting Properties of Organic UV Filters209
and gut-wall first-pass metabolism. 4-MBC has high
lipophilicity (logKow = 5.1).39
Several studies reported that 4-MBC can act
as an endocrine disruptor and cause developmental
defects. Moreover, 4-MBC has a terpene group that
acts as an acetylcholinesterase (AChE) inhibitor.33
In 2016, Li et al. investigated 4-MBC teratogenic
effects in wild-type zebrafish that were cultured and
embryos collected.40 Treatment concentrations at
72 hpf were 19.82, 14.5, and 15 µm. Embryos that
were exposed to 15 µm 4-MBC at 72 hpf showed
no escape response to touch stimulation, contrary
to untreated control embryos. The embryos were
found to be totally paralyzed, showing no swim-
ming activity. Only 20% of embryos exhibited fin
paddling motions in the highest-exposure group, but
untreated embryos displayed normal axial curvature
and rapid swimming. To detect effects of 4-MBC
on AChE activity, 4-MBC–exposed embryos at 24
hpf were analyzed using AChE staining (for which
a brown signal indicates AChE activity). Both con-
trol and exposed embryos displayed brown signals.
However, a much lighter signal was detected in
4-MBC–exposed embryos. Additionally, to support
AChE inhibitory effects of 4-MBC on neuronal
cells, experiments on the Nero-2a cell line found
that 4-MBC exposure induced AChE inhibition in a
dose-dependent manner.40
In 2005, Klann et al. investigated 4-MBC en-
docrine-disrupting effects on Xenopus laevis cell
proliferation and gene induction in the Michigan
Cancer Foundation (MCF)-7 cell line.41 To deter-
mine the cell proliferation index, researchers treated
TABLE 3: 4-MBC Endocrine-disrupting effects
Estrogenic activity
In vitro studies: Binding to hERβ and cytosolic ER; induction in hERα and hERβ activation
In vivo studies: Uterotrophic effects in rats
Progesterone activity
Antagonism of hPR transactivation
Antiandrogenic activity
Antagonism of hAR transactivation (unclear)
Thyroidal activity
Decreased iodide uptake; increased TSH and T3 levels; decreased T4 levels
ER, estrogen receptor; hAR, human androgen receptor; hER, human estrogen receptor; hPR, human progesterone receptor; T3,
triiodothyronine; T4, thyroxine; TR, thyroid receptor; TSH, thyroid-stimulating hormone.
Volume 39, Issue 3, 2020
MCF-7 cells with 1 µmol/L of E2 and 10 µmol/L
of 4-MBC for 18 h. Exposure to both compounds
caused significantly higher numbers of cells synthe-
sizing DNA compared to untreated controls. This
finding showed that micromolar concentrations of
4-MBC expedite cell proliferation in the MCF-7
cell line. The researchers also performed competi-
tive binding assays and gene induction assays ([3H]
E2 as tracer and unlabeled E2 as competitor) and
cytosolic protein preparation of Xenopus laevis liver
cells to determine 4-MBC’s estrogen-like effect.
They found that 4-MBC was particularly bound to
cytosolic-binding sites. However, binding affinity
measured medium to low compared to that of E2. To
determine ER-mediated gene induction of 4-MBC,
the gene induction assay was performed using an
endogenous ER transcription product. Results sug-
gested that 4-MBC can induce the ER gene at only
high concentrations (10–100 µmol/L) in X. laevis
hepatocytes.41 See Table 3 for a summary of 4-MBC
endocrine-disrupting effects.20,40,41
VI. AVB
AVB is the most widely used photostabilizer in cos-
metic products. It is also classified as an indirect
food additive by the Food and Drug Administration.
In 2017, Klopcic and Dolenc investigated AVB toxic
effects in MDA-kb2 and GH3.TRE-Luc reporter
cells.42 Cells were treated with the maximum non-
toxic concentration of AVB to detect glucocorticoid,
(anti)androgen, and (anti)thyroid hormone-like ac-
tivity. Results were based on dose–response data
210 Oral, Yirun, & Erkekoglu
at half maximal effective concentration (EC50) and
half maximal inhibitory concentration. AVB showed
glucocorticoid-like activity at 2.7 fm and exerted an-
tiandrogen-like activity at 17 pm. Additionally, AVB
was shown to induce thyroid hormone-like activity
at EC50 (1 nm). AVB significantly acted as an AR
antagonist, glucocorticoid receptor (GR) agonist,
and thyroid receptor (TR) antagonist in gene assays.
Moreover, AVB modulated GR ligand-binding.42
VII. MIXTURE TOXICITY
Several studies investigated the influence of par-
tial agonism in UV-filter mixture activity. In 2017,
Kunz et al. analyzed activities of UV filters alone,
in combination with E2 at different concentrations,
and at NOECs in recombinant yeast.43 In this study,
experiments were based on concentration addition
and independent action models. Investigators used
BP-1, BP-2, 4,4′-dihydroBP (DHB) and ethyl-4-am-
inobenzoate (ET-PABA) because these substances
are comprehensive agonists and exhibit full dose–
response curves but not antiestrogenic activity.
BP-3, 3-benzylidene-camphor, benzyl salicylate,
and phenyl salicylate were chosen because they are
partial human ERα (hERα) agonists with submax-
imal dose–response curves. When coexposed with
E2, they also exhibit full antiestrogenic activity.
Researchers found that BP-1 EC25 and EC75 lev-
els exhibited antagonism with all binary mixtures
(BP-1 + ET-PABA, BP-1 + BP-2, and BP-1 + DHB).
However, all other binary mixtures had synergistic
interactions. Additionally, mixtures of BP-2 with
BP-1 and DHB with ET-PABA exhibited strong syn-
ergism at EC25 concentrations. At NOEC levels, all
mixtures of BP-1, BP-2, DHB, and ET-PABA (pure
hERα agonists) display synergism, and toxic effects
to these compounds in combinations were more se-
vere than in single exposures. These results indicate
that UV-filter mixtures can exhibit remarkable inter-
actions, and because risk can increase using UV fil-
ters as mixtures, risk assessment must be performed
for these products in combinations.43
Because most UV filters are used in combina-
tion in personal-care products, their effects on en-
vironmental ecosystems must also be evaluated. In
2017, Park et al. studied mixture toxicity of EHMC,
OCT, and AVB on D. magna.10 After single, binary,
or ternary exposure, EC50 single and EC50 mix
levels were determined for each UV filter. Results
showed that these UV filters decreased UVR harm-
ful effects more efficiently when used in mixtures.
However, combined exposure to these compounds
caused more endocrine-disrupting effects compared
to single exposures. The researchers suggested that
mixtures of organic filters be classified as “harm-
ful,” and each UV filters as “toxic.”10
VIII. CONCLUSION
Using UV filters in sunscreens, cosmetics, or per-
sonal-care products provides protection against the
UVR, and these compounds are increasingly pro-
duced and consumed. But during the past 20 yr,
concerns about these compounds have increased be-
cause research has shown that they can cause seri-
ous adverse effects to human health and toxic effects
on the environment. Increasing numbers of in vivo
and in vitro studies suggest that some of these UV
filters could lead to endocrine disruption.
UV filters including BP-3, 4-MBC, ET-PABA,
and OCT were shown to exhibit estrogenic activity.
Binding-affinity assays to ERα and ERβ found that
some of these substances can interact with recep-
tors whereas others had antagonistic or partial ago-
nistic activity. Some studies showed that UV filters
can disrupt estrogen or androgen synthesis, protein
binding, or different hormone receptor expression.
Moreover, UV filters BP-3, 4-MBC, and OMC dis-
played antiandrogenic activity. For instance, OMC
was shown to decrease serum testosterone levels in
rodents. Some UV filters affect the HPT axis. Fur-
ther studies are needed to determine their mecha-
nism of action and other possible adverse effects.20
Human exposure to UV filters is primarily by
a dermal route. Exposure of aquatic organisms and
their environments (such as rivers, lakes, seas, etc.)
are also a serious matter of concern. Their muta-
genic, pseudopersistent, bioaccumulative, and endo-
crine-disruptive properties can also cause significant
effects to aqualife and disrupt habitats.
In conclusion, we suggest that although a large
number of in vivo and in vitro studies suggested that
UV filters exhibit endocrine-disrupting effects and
Journal of Environmental Pathology, Toxicology and Oncology
Endocrine-Disrupting Properties of Organic UV Filters211
cytotoxicity, more human studies are needed to un-
derstand individual toxic effects of the compounds
as well as harmful effects of their mixtures. Both
experimental and population studies will shed light
on the compounds’ mechanism of action.
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