ArticlePDF Available

Sun lotion chemicals as endocrine disruptors

Authors:

Abstract

Ultraviolet solar radiation is a well-known environmental health risk factor and the use of sun lotions is encouraged to achieve protection mainly from skin cancer. Sun lotions are cosmetic commercial products that combine active and inactive ingredients and many of these are associated with health problems, including allergic reactions and endocrine disorders. This review focuses on their ability to cause endocrine and reproductive impairments, with emphasis laid on the active ingredients (common and less common UV filters). In vitro and in vivo studies have demonstrated their ability to show oestrogenic/anti-oestrogenic and androgenic/anti-androgenic activity. Many ingredients affect the oestrous cycle, spermatogenesis, sexual behaviour, fertility and other reproductive parameters in experimental animals. Their presence in aquatic environments may reveal a new emerging environmental hazard.
Sun lotion chemicals as endocrine disruptors
Sotirios Maipas, Polyxeni Nicolopoulou-Stamati
National and Kapodistrian University of Athens, School of Medicine, First Department of Pathology and Cytology Unit,
1st Pathology Laboratory, Athens, Greece
Both authors contributed equally to this work
AbstrAct
Ultraviolet solar radiation is a well-known environmental health risk factor and the use of sun
lotions is encouraged to achieve protection mainly from skin cancer. Sun lotions are cosmetic
commercial products that combine active and inactive ingredients and many of these are
associated with health problems, including allergic reactions and endocrine disorders. This
review focuses on their ability to cause endocrine and reproductive impairments, with empha-
sis laid on the active ingredients (common and less common UV filters). In vitro and in vivo
studies have demonstrated their ability to show oestrogenic/anti-oestrogenic and androgenic/
anti-androgenic activity. Many ingredients affect the oestrous cycle, spermatogenesis, sexual
behaviour, fertility and other reproductive parameters in experimental animals. Their presence
in aquatic environments may reveal a new emerging environmental hazard.
Key words: Active ingredients, Endocrine disruptors, Environmental hazard, Reproductive impair-
ments, Sun creams, Sun lotions, Sunscreens, UV filters
Review
HORMONES 2015, 14(1):32-46
Address for correspondence:
Polyxeni Nicolopoulou-Stamati Professor of Pathology,
Scientific Director of MSc Environment and Health. Capacity
Building for Decision Making, Medical School, National and
Kapodistrian University of Athens, 11527, Greece,
Tel.: +302107462163, Fax:+302106840488,
E-mail: aspis@ath.forthnet.gr
Received: 16-12-2014, Accepted: 30-01-2015
1. INTRODUCTION
Ultraviolet (UV) solar radiation is one of the most
studied environmental health risk factors. The Earth’s
atmosphere functions as a natural shield, but it can-
not protect us completely from the UV radiation that
reaches the surface.
1,2
Skin has its own protective
mechanisms, such as tanning and stratum thicken-
ing, but the level of photoprotection is insufficient to
prevent the harmful effects of UV radiation.3,4
To achieve a better level of protection, the use of
sun lotions and creams, often with a high protection
factor, is advised.
5
However, health issues associ-
ated with their ingredients exist and include, among
others, allergic reactions6-8 as well as endocrine and
reproductive disorders.9,10 Manufacturers of sun lotions
constantly modify the composition of their products
(active and inactive ingredients) to make them more
effective and safer for consumers. Nevertheless, the
safety of these products is relative and questionable.
Sun lotions have become popular commercial prod-
ucts. Furthermore, many cosmetic products (not only
sun lotions and creams) are on the market containing
Sun lotion chemicals as endocrine disruptors 33
some of the active ingredients.
11
Therefore, exposure
to these UV filters does not occur only through tra-
ditional sun protection products. This review article
focuses on the ability of UV filter chemicals to cause
endocrine and/or reproductive impairments.
1.1. UV solar radiation
UV solar radiation is usually divided into three
groups. The most energetic, known as UV-C (100-280
nm), is completely absorbed by atmospheric molecu-
lar oxygen and ozone and does not reach the Earth’s
surface. UV-B (280-315 nm) reaches the surface, its
quantity being determined by stratospheric ozone
concentration since ozone is a strong absorber at
these wavelengths. UV-A (315-400 nm) reaches the
surface without significant losses during its passage
through the atmosphere. Cloudiness impedes both
UV-A and UV-B.
1,12,13
As both UV-B and UV-A cause
negative health effects,
3,14
protection from these forms
of radiation is indicated.
To avoid a possible confusion with the spectral
ranges mentioned above, it is useful to redefine them
according to photobiology. Taking into consideration
the biological effects, the spectrum between 200-290
nm is called UV-C and that between 290 and 320 nm
UV-B, while UV-A covers the 320-400 nm range.12
Exposure to UV radiation causes, inter alia, sunburn,
tanning, photoaging, melanoma and other malignan-
cies, cataracts and immunosuppression.
3,14-16
Although
UV-A penetrates more deeply into the skin,
17
UV-B is
considered to cause more biological effects than UV-
A.
3
Nevertheless, skin exposure to UV-B is necessary
for the cutaneous synthesis of vitamin D.18
1.2. Sun lotions
Sun lotions are cosmetic products that protect
from UV radiation after topical dermal application
due to their active ingredients. These ingredients
absorb or block UV irradiation by reflection and/
or scattering.19,20 Their properties protect their users
from UV-B or both UV-B and UV-A, depending on
their formulation.
Commercial sun lotions are grouped into three
categories. The first includes those products whose
UV filters are organic chemical absorbers.19,21-23 The
second group includes products which contain metal
oxides (inorganic UV filters, e.g. titanium dioxide and/
or zinc oxide).
19-24
The third group includes formula-
tions which combine organic and inorganic agents.
21,24
Manufacturers combine different UV filters (here-
inafter referred to as “active ingredients”) to increase
the sun protection factor (SPF) of their lotions or
creams.
21,25
Simply phrased, SPF is a numerical value
indicating the protection level against sunburn.21
1.3. Endocrine disruptors and reproductive
health
Endocrine disruptors are chemicals that alter the
normal function of the endocrine system, leading to
a variety of health problems, such as reproductive
impairments and female and male cancers as well.26-29
Exposure to endocrine disruptors starts in utero and
never ceases throughout life, since these chemicals
are present in a variety of daily products, including
food, bottled water and cosmetics.30-35 Some of the
ingredients of sun lotions show endocrine altering
and disrupting properties.9,36,37
Possible reproductive impairments are crucial be-
cause they are associated with infertility.26,27,38-41 The
life of all living organisms is strongly connected with
the environment and reproduction is the key factor
for their survival.42 Endocrine disruptors are omni-
present in ecosystems and some of their properties,
including their bioaccumulation potential, should be
taken seriously into account.43
1.4. Sun lotion chemicals and routes
of exposure
Since sun lotions and creams are applied to the
skin, the main route of exposure to them is dermal. The
skin is the body’s largest organ. It has its own defence
mechanisms such as the formation of a protective
barrier.
44
With regard to sun lotions, the effectiveness
of the skin as a barrier against chemicals, biological
agents and radiation depends on many factors such
as the body site of application, the person’s age, the
health status of the skin, the frequency of the appli-
cation, the duration of skin contact with the product
and the possible presence of chemicals that enhance
the penetration of other substances.17,45-47
Furthermore, exposure is also possible through
inhalation. Apart from the fact that some sun lotions
34 S. MAIPAS, P. NICOLOPOULOU-STAMATI
are sprays,
48
many sun lotions contain fragrances
made with endocrine disruptors.49
Finally, exposure through ingestion is also pos-
sible, especially as a result of hand-to-mouth habit.
50
Generally, this behaviour is a noteworthy risk factor
for children.51 Additionally, sunscreen lipsticks con-
tribute to the exposure by ingestion.52,53
2. ORGANIC CHEMICAL ABSORBERS
Since the production of the first sun lotions and
creams, many organic absorbents have been used as
filters. The most common organic chemical absorbers
include the chemicals discussed below.
2.1. Benzophenone compounds
2.1.1. Oxybenzone
Oxybenzone (or 2-hydroxy-4-methoxybenzophe-
none, benzophenone-3, BP3) is a benzophenone (BP)
compound (commonly used as a UV filter) with
known endocrine disrupting characteristics. In vitro
studies (human oestrogen receptor alpha (hERα) and
human androgen receptor (hAR) assays) indicate that
BP3 displays oestrogenic, anti-oestrogenic and anti-
androgenic activity.9
BP3 exhibits anti-oestrogenic and anti-androgenic
activity in vivo in fish. In the brain of adult zebrafish
males, BP3 down-regulates alpha oestrogen receptors
and androgen receptors. The effects mainly occur at an
aquatic concentration of 84 μg/l, but that concentration
is much higher than the highest environmental level
of 10 μg/l, as had been hypothesized by this study.54
Fish exposure to oxybenzone also affects egg produc-
tion and hatching. For instance, exposure of Japanese
medaka to 620 μg/l of BP3 reduces egg production
(temporarily) and the normally expected hatching
percentage. However, effects on these parameters
also occur at lower concentrations (132 μg/l, 16 μg/l).
Significant vitellogenin induction occurs at high doses,
e.g. 620 μg/l in the Japanese medaka (vitellogenin is
a biomarker for oestrogenic results).55,56
Furthermore, oxybenzone increases the uterine
weight of immature rats with a median effective
dose (ED50) in the range of 1000 to 1500 mg/kg/day
(dietary administration). A continuous breeding study
revealed that the exposure of mice to high doses of
BP3 reduces the number and the weight of offspring
and increases the mortality of the lactating dams.
The no observed adverse effect level (NOAEL) for
reproductive toxicity was 1.25% in feed.57 However,
a dermal application of high doses (up to 400 mg/kg/
day) to male mice does not affect reproductive organ
weight or production and quality of sperm.58
In humans, a reduction of birth weight in girls
and an increase in boys may also be associated with
maternal exposure to oxybenzone,59 which has also
been detected in breast milk.60
2.1.2. Benzophenone-1
Benzophenone-1 (2,4-dihydroxybenzophenone,
BP1) is a common metabolite of oxybenzone. BP1
binds to oestrogen receptors obtained from rats’ uteri.
61
Its oestrogenic and anti-androgenic activities have
been confirmed in vitro (hERα and hAR assays).
9
Its
oestrogenic activity has also been confirmed in vivo
in fishes (significant vitellogenin induction at 4.919
mg/l).
62
Ex vivo assays with testes from mice and rats
revealed that BP1 inhibits testosterone synthesis.63
Moreover, BP1 affects the early life-stage develop-
ment of the marine copepod Acartia Tonsa. Environ-
mental conditions, such as salinity and temperature,
influence the toxic effect. For instance, at 20oC, the
median effective concentration (EC50) was 1.1 mg/l
and at 15oC, 0.49 mg/l.64
Finally, endometriosis in women, which is an
oestrogen-dependent disease, is associated with ex-
posure to benzophenone compounds and especially
with exposure to BP1.65
2.1.3 Other benzophenone compounds
Benzophenone-2 (2,2′,4,4′-tetrahydroxybenzo-
phenone, BP-2) is another sun lotion component of
the benzophenone group. In vitro assays revealed
its ability to display oestrogenic, androgenic and
anti-androgenic activity.9 In addition, in utero expo-
sure of male mice to BP-2 causes hypospadias.66 Its
oestrogenic activity has been confirmed in vivo in
fishes.62,67,68 Exposure of fishes to BP-2 affects the
gonads, the secondary sex characteristics, spawning
activity and fertility with a lowest observed effect
concentration (LOEC) of 1.2 mg/l.67,68
Experiments with zebrafish showed that suliso-
Sun lotion chemicals as endocrine disruptors 35
benzone (Benzophenone-4, BP4) disrupts the normal
endocrine function of the animals (oestrogenic activity)
and induces alterations in the genes related to thyroid
development. The lowest effect concentration (LEC)
was found to be 30 μg/l.69 Furthermore, BP4 shows
oestrogenic/anti-oestrogenic and anti-androgenic
properties in vitro.9
Dioxybenzone (Benzophenone-8, BP8), which
is also a sun lotion benzophenone ingredient, shows
oestrogenic activity in vitro.70 4-hydroxybenzophenone
(or p-hydroxybenzophenone) is another benzophenone
compound with endocrine disrupting properties in
vitro.71 What is more, 4-hydroxybenzophenone dis-
plays endocrine activity in juvenile female rats and
increases the weight of their uterus after subcutaneous
administration.72
2.2. Octyl methoxycinnamate
Octyl methoxycinnamate (ethylhexyl methoxycin-
namate, octinoxate, OMC) is a commonly used UV
filter with known endocrine disrupting properties.9,36
In rats, OMC causes various impairments, in-
cluding the alteration of the normal release of the
luteinizing hormone-releasing hormone (LHRH)
and of the amino acid neurotransmitters from the
hypothalamus.
73
This sunscreen filter can decrease
the normal serum concentrations of the hormones:
thyrotropin (thyroid-stimulating hormone, TSH),
thyroxine (T4) and triiodothyronine (T3) in rats.
This reveals a possible impact on the function of the
hypothalamic-pituitary-thyroid axis.74
OMC exhibits anti-oestrogenic and androgenic/
anti-androgenic activity but no oestrogenic activity in
hERα and hAR assays.
9
Furthermore, a two-generation
study with rats concluded that OMC has no oestrogenic
effect in vivo either. A NOAEL of 450 mg/kg bw/day
(dietary administration) for reproductive disorders
was established and a dose of 1000 mg/kg bw/day
was found to be able to delay the sexual maturation
of the offspring for a few days.75
Exposure to OMC by gavage leads to a decrease
of T4 concentration in female rats (dams) and affects
the reproductive and the neurological development
of their offspring. Exposure to 1000, 750 or 500 mg/
kg bw/day from gestation day 7 to postnatal day 17
negatively affected the sperm counts of the male
offspring.76 OMC also increases the uterine weight
of immature rats with an ED50 of 935 mg/kg/day
(dietary administration).
36
Moreover, the exposure
of the aquatic insect Chironomus riparius to OMC
affects its normal endocrine function.77
Skin absorption of OMC is possible, which ac-
counts for its presence in plasma, urine and human
milk.
60,78
Its presence in human milk leads to neo-natal
exposure, which is of particular concern.
2.3. 4-methylbenzylidene camphor
4-methylbenzylidene camphor (4-MBC, enzaca-
mene) disrupts normal endocrine function in rats,
fishes, aquatic molluscs and insects.37,77,79,80
In vitro assays (hERα and hAR) have revealed
its anti-oestrogenic and anti-androgenic properties.9
Exposure of rats to 4-MBC (dietary administration of
F0 generation and F1 until adulthood) increases the
uterine weight of the female offspring and the thyroid
weight of both sexes in the two generations.
37
4-MBC
delays male puberty and disrupts the normal female
sexual behaviour of the offspring (dietary administra-
tion of F0 generation and F1 until adulthood) with
a NOAEL of 0.7 mg/kg/day and a lowest observed
adverse effect level (LOAEL) of 7 mg/kg/day.10 An
ED50 of 309 mg/kg/day (dietary administration) was
determined in immature rats for increasing uterine
weight.36
2.4. 3-benzylidene camphor
The UV filter 3-benzylidene camphor (3-BC)
exhibits endocrine disrupting activity (oestrogenic,
anti-oestrogenic and anti-androgenic) as demonstrated
using hERα and hAR assays.9 3-BC shows oestrogenic
activity not only in vitro but also in vivo in fish and
aquatic molluscs.62,80
3-BC delays male puberty and disrupts normal
female sexual behaviour and the oestrous cycle of
rat offspring (dietary administration as in the case
of 4-MBC, NOAEL: 0.07 mg/kg/day and LOAEL:
0.24 mg/kg/day).10 Additionally, less heavy rat uteri
are associated with exposure to 3-BC.37
Exposure to 3-BC is also associated with disorders
of the normal reproductive function of fish, produces
feminization of male secondary sex characteristics
and affects the gonads (male and female) and fertility
with a LOEC of 3 μg/l.68
36 S. MAIPAS, P. NICOLOPOULOU-STAMATI
More investigation is also needed to determine a
possible endocrine and reproductive disrupting role
of 2-Ethoxyethyl p-methoxycinnamate (cinoxate),
trolamine salicylate (or triethanolamine salicylate)
and Mexoryl SX (Ecamsule). Lack of evidence as
to endocrine disrupting properties and/or reproduc-
tive impairments characterizes the majority of the
remaining and less common ingredients as well. These
compounds include, among others, Amiloxate (Isoa-
myl p-Methoxycinnamate), Mexoryl SX (Ecamsule),
Uvinul A Plus (diethylamino hydroxybenzoyl hexyl
benzoate), octyl triazone (ethylhexyl triazone, Uvinul
T 150), polysilicone-15 (Parsol SLX) and Methyl
anthranilate (Meradimate).
3. METAL OXIDES
Titanium dioxide (TiO
2
) and zinc oxide (ZnO)
are two metal oxides traditionally known for their
sunblocking properties.20 Sun lotion manufacturers
formerly used the bulk form of these materials, but
nanotechnology advances have made possible the use
of their nanoscale form. The new nanoscale ingredients
are more aesthetic, as they do not produce the charac-
teristic opaque film created by the largescale ones.84
Regarding their possible dermal penetration/ab-
sorption, there are studies that have shown that these
nanoparticles do not penetrate the skin deeper than
the stratum corneum in vitro or do not exhibit skin
penetration in vivo.85 However, Zn from ZnO nano-
particles can be absorbed by a healthy skin and can
be detected in human urine and/or blood samples.86
The parameter “healthy skin” is important because
if the skin has e.g. a disrupted stratum corneum, the
behaviour of these particles may be different.84
Nanoparticle forms of both metal oxides produce
reactive oxygen species (ROS) in the presence of UV
radiation.
84
In general, ZnO nanoparticles are consid-
ered more toxic than TiO2 nanoparticles.87
3.1. Zinc oxide
Zinc is a necessary trace element for normal re-
productive function, such as normal spermatogenesis
and the oestrous cycle.88 However, a study revealed
that high doses of dietary zinc may cause apoptosis
of reproductive tissues in hens.89 Other experiments
have shown that zinc in high doses causes hormonal
problems in rats.90
2.5. PABA, OD-PABA, Et-PABA
PABA (para-aminobenzoic acid, p-aminobenzoic
acid, 4-aminobenzoic acid), OD-PABA (Padimate O,
Octyl-dimethyl PABA, Ethylhexyl dimethyl PABA)
and Et-PABA (Ethyl-4-aminobenzoate) are chemicals
known for their ability to absorb UV radiation.
Regarding likely effects of PABA on the endocrine
and/or the reproductive system, research until now is
limited. A study has demonstrated anti-oestrogenic
activity in a hERα assay,9 but other experiments have
not revealed a noteworthy connection or a negative
effect. For instance, the exposure of pregnant rats
to PABA at 50 mg/kg (intragastric administration)
slightly affects the normal development of the body
mass of rat foetuses, but this effect was characterized
as “insignificant”, as body mass development usually
becomes normal after birth.81
OD-PABA displays oestrogen antagonistic activity
in vitro
70
and shows an endocrine effect in the aquatic
insect Chironomus riparius.
77
Et-PABA is also an
endocrine disrupting agent. Oestrogenic activity in
vitro and in vivo in fishes has been shown.
9
Both
chemicals display anti-androgenic activity in vitro.9
2.6. Other organic filters
The organic UV filters octocrylene (OC), ho-
mosalate (HMS, homomethyl salicylate) and octis-
alate (octyl salicylate, OS or ethylhexyl salicytate,
EHS) show anti-oestrogenic, androgenic and anti-
androgenic activity in hERα and hAR assays.9 The
available data, e.g. for octocylene,82 does not reveal
reproductive risks.
Tinosorb M (methylene bis-benzotriazolyl te-
tramethylbutylphenol, bisoctrizole) and Tinosorb S
(bis-ethylhexyloxyphenol methoxyphenyl triazine,
bemotrizinol) are organic compounds used in sun
lotions. None of these ingredients is expected to have
an endocrine disrupting activity (in vitro assays and
in vivo subcutaneous administration).83 In any case,
both chemicals are relatively new components and
more research is needed on their possible effects on
the endocrine and the reproductive systems.
Avobenzone (butyl-methoxydibenzoylmethane)
is additionally an active compound, regarding which
more investigation is indicated. Limited evidence
suggests that it does not display oestrogenic activity.
36
Sun lotion chemicals as endocrine disruptors 37
In mice, ZnO nanoparticles accumulate in liver
and cause oxidative stress, DNA damage and apo-
ptosis in its cells two weeks after oral exposure to
300 mg/kg.
91
Furthermore, in Cyprinus carpio fishes,
ZnO nanoparticles bioaccumulate more easily and
cause more oxidative damage compared to its bulk
counterparts.92
ZnO nanoparticles are toxic for white sea urchin
embryos with an EC50 of 99.5 μg/l.
93
ZnO nanoparticle
aggregates affect zebrafish and cause delayed embryo
hatching (84 hours EC50 for this study: 23.06 mg/l)
and likely malformations in embryos and larvae.
94
The
aquatic toxicity of ZnO nanoparticles is attributed to
Zn
2+
ions (mainly), or to the nanoparticles themselves,
or to a possible combination of both.94-96
Moreover, a study revealed that the nanoforms
of ZnO can impede normal cocoon production (a
reproductive parameter) of earthworms in artificial
soil conditions, exhibiting greater toxicity attributed
to the dissociation of Zn ions.97
3.2. Titanium dioxide
Nanoparticles of TiO2 present a risk factor for the
male mouse reproductive system, affecting the normal
density and motility of the sperm at high doses of
exposure (500 mg/kg, intraperitoneal injection every
other day).98 The intravenous injection of TiO2 nano-
particles with a diameter of 35 nm disrupts normal
pregnancy progression in already pregnant mice.
99
Chronic exposure (21 days) of the aquatic organism
Dapnia magna to nanoparticles of TiO2 (0.1, 0.5, 1,
5 mg/l) inhibits its reproduction.100
Chronic exposure (13 weeks) of zebrafish to 0.1
mg/l and 1 mg/l of TiO
2
nanoparticles negatively
affects their reproductive system and reduces egg
production.101 Chronic exposure (21 days) to na-
noparticles of TiO2 (length: 50 nm, width: 10nm)
coated with hydrated silica, dimethicone/methicone
copolymer and aluminum hydroxide (T-Lite SF-S)
affects the reproduction of Daphnia magna freshwater
invertebrates in a negative way. A LOEC of 10 mg/l
and a no observed effect concentration (NOEC) of
3 mg/l were defined. The concentration of 10 mg/l
caused a two-day delay in the production of the first
offspring. The EC50 for the reproductive outcomes
was 26.6 mg/l.102
Another known effect related to reproductive tox-
icity issues is the decrease of cocoon production by
earthworms in artificial soil due to exposure to nano
TiO
2
.
97
Furthermore, a possible endocrine role of TiO
2
nanoparticles can be deduced from the induction of
insulin resistance in liver-derived cells.103
The use of nanoparticles raises safety issues. One
of the most important is possible transport through
the placental barrier leading to potential disruption
of normal embryogenesis and to foetal exposure.104
TiO
2
nanoparticles are detected in the male offspring
after subcutaneous administration to pregnant mice
and cause reproductive impairments leading to prob-
lematic spermatogenesis.105
4. SKIN PENETRATION ENHANCERS
Sun lotions can act as penetration enhancers by
favouring the flux of hazardous chemicals through
the skin.106-108 A study had demonstrated that these
products can increase the penetration of benzene
through human skin in vitro, but it did not identify
the culpable components.106 However, a newer study
showed that the active ingredients octyl methoxycin-
namate, oxybenzone, sulisobenzone, OD-PABA,
octisalate, homosalate and the insect repellent DEET
can increase the penetration of 2,4-dichlorophenoxy-
acetic acid through hairless mouse skin in vitro. Only
Octocrylene did not promote the uptake.108
Many of the chemicals that penetrate the skin more
easily show endocrine disrupting activity and/or cause
reproductive impairments. For instance, as mentioned
above, some sun lotions can act as penetration en-
hancers for 2,4-dichlorophenoxyacetic acid.107,108 This
substance, known for its endocrine disrupting role,
109
is a widely used herbicide. 2,4-dichlorophenoxyacetic
acid can affect normal development of the central
nervous system of rats and their spermatogenesis.
110,111
It also disrupts normal rat maternal behaviour.112 Farm-
ers who are exposed to herbicides and daily spend
many hours outside and use sunscreens to protect
themselves from UV radiation face a higher risk for
this kind of penetration.107,108
Therefore, possible endocrine disrupting activity
and/or impairment of the reproductive system caused
by increase of exposure to other chemicals can be
an indirect effect of the use of UV filter chemicals.
38 S. MAIPAS, P. NICOLOPOULOU-STAMATI
5. INACTIVE INGREDIENTS
Sun lotions are formulated using inactive ingre-
dients such as parabens (alkyl esters of p-hydroxy-
benzoic acid). Parabens are common preservatives
of pharmaceutical and cosmetic products. Not all
sun lotions contain parabens and many manufac-
tures have replaced them with other substances. For
instance, during this research, a brand was identified
whose previous formulations contained three parabens
(propylparaben, butylparaben and methylparaben),
but its new ones are paraben-free. Other ingredients
(both inactive and active) also changed, although it
was commercialized as the same product with the
same SPF. Other common inactive ingredients are
dimethicones, phthalates, disodium ethylenediami-
netetraacetate (EDTA), triethanolamine and water.
5.1. Parabens
Parabens show endocrine disrupting activity and
are known to negatively affect the male reproductive
system.
113
Below is a selection of examples that arouse
concern among scientists about their use in cosmetics.
Male rats exposed to propylparaben at four con-
centrations (0.00% (control) and 0.01, 0.1 and 1.0%)
in their diet revealed a dose-dependent decrease of
the testosterone concentration in the serum.114 Bu-
tylparaben shows the same effect in male mice and
inhibits their spermatogenesis.115 Maternal rat expo-
sure to butylparaben affects the development of the
reproductive system of the F1 male offspring after
subcutaneous injections, leading to decreased sperm
count and motility.116
Propylparaben, butylparaben, methylparaben and
ethylparaben display oestrogenic activity in vitro.
However, oral exposure of rats did not result in oes-
trogen activity. On the other hand, subcutaneous
administration of butylparaben resulted in oestrogenic
effects in vivo in rats.117
Parabens have the ability to display 17β-oestradiol-
like effects and bind to the alpha and beta oestrogen
receptors.118 The beta oestrogen receptor (ERβ) may
be engaged in the development of melanoma.119 This
is the basis for major concern regarding the binding
of parabens with oestrogen receptors.117,118 Exposure
to parabens may also cause increased oestradiol con-
centrations in the skin as a result of their ability to
inhibit the oestrogen sulfation mechanism.120
Therefore, the use of endocrine disruptors, such
as parabens, in cosmetic products for cutaneous use
(e.g. sun lotions) poses significant health risks.
113
Fur-
thermore, it should be mentioned that methylbaraben
enhances the negative effect of UV-B radiation on
skin keratinocytes.121
5.2. Dimethicones
Siloxanes are inactive ingredients that are used in
cosmetic products such as sun lotions and creams.
The most commonly used are octamethylcyclotet-
rasiloxane (D4), decamethylcyclopentasiloxane (D5)
and dodecamethylcyclohexasiloxane (D6). The mix-
tures containing mainly these siloxanes are known
as “cyclomethicones”. Sun lotion manufacturers use
polydimethylsiloxane silicone (PDMS) formulations
known as “dimethicones” in which D4 is present in
their final formulation. A dimethicone can be com-
bined with whatever/any form of silica to produce
“simethicone”, which is another inactive ingredient
in sun lotions.122-124
D4 shows endocrine disrupting activity and causes
reproductive disorders. More in particular, D4 exhib-
its weak oestrogenic and anti-oestrogenic activity in
rats.
125
What is more, the daily exposure of rats to
D4 vapour in a variety of concentrations provokes
a longer oestrous cycle and decreases fertility indi-
ces. A NOAEL of 300 ppm for female reproductive
toxicity has been determined, while the NOAEL for
males is 700 ppm.126
5.3. Phthalates
Even though phthalates are not mentioned in the list
of ingredients, they might be part of the formulation
of the ingredient known as “fragrance”, “perfume”
and “parfum” (or other related terms). For manufac-
turers it is not compulsory to reveal the components
of their fragrances because the composition of these
products can be kept secret.49,127 Exposure to phthalates
might also result from their migration from the plastic
packaging into the cosmetic product.128
Numerous papers have been published on the
health effects of phthalates such as diethyl phthalate
(DEP), di-n-butyl phthalate (DBP) and di(2-ethylhexyl
phthalate (DEHP) and of their metabolites such as
mono(2-ethylhexyl) phthalate (MEHP).129-133 This
overview is limited to a few characteristic aspects of
Sun lotion chemicals as endocrine disruptors 39
their effects on the endocrine and the reproductive
system.133,134
Exposure of female rats to DEHP reduces oestra-
diol concentration in serum, prolongs the oestrous
cycle and inhibits ovulation.
135
Further, DEHP shows
anti-androgenic activity of DEHP in rats.136 In utero
and during lactation, DEHP causes abnormalities of
the male reproductive tract in rats and reduces daily
sperm production.
137
An in vitro experiment with
human spermatozoa revealed that the previously
mentioned phthalates and di-n-octyl phthalate (DOP)
affect sperm motility.138
5.4. Other inactive ingredients
Disodium EDTA is commonly used in sun lotions.
The disodium salt of EDTA disturbs the binding of the
Vasoactive Intestinal Peptide (VIP) to the membranes
of the macrophages with a Half-maximal Inhibitory
Concentration (IC50) of 5.4 mM.139
Furthermore, there are other inactive ingredients
which are not harmless. Triethanolamine irritates
the upper respiratory tract of rats with a 90-day no
observed adverse effect concentration (NOAEC) of
4.7 mg/m
3
and produces systemic toxicity at high
doses.140 Moreover, in aquatic organisms chronic ef-
fects cannot be excluded.141 Many other ingredients
induce health problems such as allergic reactions.
142-144
Therefore, there are hidden dangers related to the
inactive ingredients. Some of them show endocrine/
reproductive impairments, but more research is re-
quired to identify and quantify these hazards.
6. SUN LOTIONS AND VITAMIN D
Vitamin D is necessary for the development and
the maintenance of a healthy skeleton.18 Ninety per-
cent of the vitamin D essential for good health is
produced cutaneously.145 More specifically, UV solar
radiation is necessary for the cutaneous synthesis of
previtamin D318 and the wavelengths of the UV-B
region are the most efficient for this synthesis.18,146
The active ingredients in sun lotions reduce exposure
to and absorption of UV-B radiation through the skin.
Consequently, active ingredients inhibit the produc-
tion of the vitamin.147
When the cutaneous synthesis is insufficient, ad-
ditional intake through food or through supplements
is recommended. Vitamin D deficiency has been
associated with skeletal problems, such as rickets in
children and osteomalacia in adults, as well as with
a variety of cancers.148
Vitamin D deficiency impedes the secretion of
insulin from isolated rat pancreas cells
149
and it causes
reproductive and fertility deficiencies in both female
and male rats.150,151
Vitamin D deficiency during human pregnancy is a
significant risk factor for preeclampsia.
152
In addition,
low vitamin D intake during pregnancy is associated
with decreased birth weight.153
7. DISCUSSION
Many active ingredients of sun lotions pose health
risks, while they also negatively affect environmental
quality, and in particular aquatic life.
Commercial sun lotions and creams usually con-
sist of more than one chemical filter to achieve the
desirable level of protection.
21
Consequently, users are
exposed to a cocktail of chemicals. Harmful cocktail
effects might emerge even if the endocrine disrupting
chemicals are present in concentrations lower than
their individual NOEC.
154,155
Sun lotions are a typical
cocktail example because they contain a variety of
substances with documented endocrine disrupting
activity (UV filter mixtures).156
An individual consumer applies a relatively small
amount of a sun protection lotion, which is in the order
of micrograms per cm2,157 but the total quantity used
by all consumers together is thousands of tons. It has
been estimated that annually 4000-6000 tons enter the
aquatic environment in reef areas by washing off.158
Concentrations of organic filters found in natural
waters are of the order of ng/l, while in contaminated
waters they reach the order of μg/l.68,159 Although the
concentrations are still low, it should be noted that
sun lotions and creams persist in the environment for
up to a century and the currently widespread use of
these commercial products may drastically increase
their environmental levels. Nanoparticles such as TiO
2
(which are relatively new ingredients) are measured
in waters in concentrations of μg/l.162
40 S. MAIPAS, P. NICOLOPOULOU-STAMATI
The fate and the properties of these chemicals and
of their degradation products and their possible ability
to produce combination effects determine their final
impact. The current low concentrations in natural
waters are no guarantee for the absence of negative
effects. Furthermore, the properties of the by-products
in swimming pool waters, where the concentration of
UV filters can be of the order of μg/l,163 may conceal
significant threats. For instance, it has been shown that
the chlorination process (chlorine is used to disinfect
swimming pool waters) is able to produce mutagenic
substances if octyl methoxycinnamate is present.164
Consumers use sun lotions to protect themselves
from the harmful effects of solar UV radiation. How-
ever, a possible inadequate application combined
with the ignorance of the real effects of UV radiation
promotes a false sense of safety. What is more, many
sun lotion ingredients are associated with health risks,
including endocrine and reproductive impairments.
Apart from personal use and subsequent exposure
to these agents through skin contact, exposure also
occurs through inhalation and ingestion, especially
during swimming.
165
In crowded swimming areas,
large amounts of sun lotion chemicals end up in the
water and exposure becomes more complex.
The proper use of cosmetics, including sun lotions,
is advantageous for health, but special emphasis should
also be given to complementary protection measures,
such as appropriate clothing and avoiding of exposure
during the hours of highest sunlight intensity.5,166
Endocrine and reproductive impairments are known
to be caused in aquatic organisms, such as zebrafish
and Dapnia magna, by some sun lotion agents.69,100
Amongst other effects, sun lotion chemicals also
contribute to the bleaching of coral reefs.
158
Moreover,
the “ubiquity” of these emerging pollutants in aquatic
environments raises bioaccumulation and biomag-
nification issues.167,168 Consequently, the danger for
aquatic life cannot be ignored.
The increasing use of sun lotions, their continuous
washing off from the surface of the human body in
the water and indirect environmental contamination
through waste water treatment plants necessitates
an immediate and appropriate response to this new
emerging hazard.169
There are knowledge gaps concerning the properties
of sun lotion chemicals that should be addressed by
future research. The issues that need special considera-
tion include possible bioaccumulation, the effects that
result from the combination of these chemicals and the
effects of their metabolites and of their degradation
compounds. Furthermore, the likely involvement of
the ERβ in the development of melanoma and topical
treatment with cosmetics containing substances with
oestrogenic activity (e.g. UV filters, parabens) are two
issues that require special attention.113,119
8. CONCLUSIONS
Are sun lotion chemicals endocrine disruptors?
These ingredients do have endocrine disrupting
properties and affect the reproductive system of ex-
perimental animals, revealing a potential danger for
wildlife. The precise in vivo effects on humans are
difficult to measure and the human data are limited.
However, adverse health effects in humans cannot be
excluded and the increasing use of sun lotions may
be an unidentified threat for normal human endocrine
and/or reproductive function.
Formulations of commercial sun lotions are mix-
tures of active and inactive ingredients both of which
are related to health hazards. Different active (and
inactive) ingredients are combined to offer a better
level of UV protection. This makes their composition
more complex, but also increases the possibility of
combination effects. Due to the current widespread
use of sun lotions and to the existing scientifically
documented knowledge, the raising of awareness
of the subject is more important than ever before.
Aquatic toxicity issues require more investigation,
and this new emerging environmental hazard should
not be underestimated.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
1.
Frederick JE, Snell HE, Haywood EK, 1989 Solar
ultraviolet radiation at the Earth’s surface. Photochem
Photobiol 50: 443-450.
2.
McKenzie RL, Björn LO, Bais A, Ilyasd M, 2003 Chang-
Sun lotion chemicals as endocrine disruptors 41
es in biologically active ultraviolet radiation reaching
the Earth’s surface. Photochem Photobiol Sci 2: 5-15.
3.
Diffey BL, 1998 Ultraviolet radiation and human health.
Clin Dermatol 16: 83-89.
4. Sheehan JM, Potten CS, Young AR, 1998 Tanning in
human skin types II and III offers modest photoprotection
against erythema. Photochem Photobiol 68: 588-592.
5. World Health Organization, World Meteorological Or-
ganization, United Nations Environment Programme,
International Commission on Non-Ionizing Radiation
Protection, 2002 Global solar UV index: A practical
guide, World Health Organization, Geneva, Switzerland
http://www.who.int/uv/publications/en/UVIGuide.pdf
(Date last checked: 16/12/2014).
6.
Thune P, 1984 Contact and photocontact allergy to
sunscreens. Photodermatol 1: 5-9.
7.
Ang P, Ng SK, Goh Cl, 1998 Sunscreen allergy in
Singapore. Am J Contact Dermat 9: 42-44.
8. Wong T, Orton D, 2011 Sunscreen allergy and its in-
vestigation. Clin Dermatol 29: 306-310.
9.
Kunz PY, Fent K, 2006 Multiple hormonal activities
of UV filters and comparison of in vivo and in vitro
estrogenic activity of ethyl-4-aminobenzoate in fish.
Aquat Toxicol 79: 305-324.
10.
Schlumpf M, Kypke K, Vökt CC, et al, 2008 Endocrine
active UV filters: Developmental toxicity and exposure
through breast milk. Chimia 62: 345-351.
11.
Manová E, von Goetz N, Hauri U, Bogdal C, Hun-
gerbühler K, 2013 Organic UV filters in personal care
products in Switzerland: A survey of occurrence and
concentrations. Int J Hyg Environ Health 216: 508-514.
12. Lucas R, McMichael T, Smith W, Armstrong B 2006
Solar Ultraviolet Radiation: Global burden of disease
from solar ultraviolet radiation. In: Prüss-Üstün A, Zeeb
H, Mathers C, Repacholi M (eds) Environmental Burden
of Disease Series, No. 13, World Health Organization,
Geneva, Switzerland.
13.
Seckmeyer G, Pissulla D, Glandorf M, et al, 2008
Variability of UV irradiance in Europe. Photochem
Photobiol 84: 172-179.
14. Gallagher RP, Lee TK, 2006 Adverse effects of ultra-
violet radiation: A brief review. Prog Biophys Mol Biol
92: 119-131.
15.
Norval M, 2001 Effects of solar radiation on the human
immune system. J Photochem Photobiol B 63: 28-40.
16. Norval M, 2002 Immunosuppression induced by ultra-
violet radiation: relevance to public health. Bull World
Health Organ 80: 906-907.
17.
Archer CB 2010 Functions of the skin. In: Burns T,
Breathnach S, Cox N, Griffiths C (eds), Rook’s Text-
book of Dermatology, 8th ed, Blackwell Publishing
Ltd, Singapore; pp, 4.1-4.11.
18.
Holick MF, 1994 McCollum Award Lecture, 1994:
Vitamin D – new horizons for the 21st century. Am J
Clin Nutr 60: 619-630.
19.
Wolf R, Wolf D, Morganti P, Ruocco V, 2001 Sunscreens.
Clin Dermatol 19: 452-459.
20. Murphy GM, 1999 Sunblocks: Mechanism of action.
Photodermatol Photoimmunol Photomed 15: 34-36.
21. Gasparro FP, Mitchnick M, Nash JF, 1998 A review of
sunscreen safety and efficacy. Photochem Photobiol
68: 243-256.
22.
Kullavanijaya P, Lim HW, 2005 Photoprotection. J Am
Acad Dermatol 52: 937-958.
23. Sambandan DR, Ratner D, 2011 Sunscreens: An over-
view and update. J Am Acad Dermatol 64: 748-758.
24. Dransfield GP, 2000 Inorganic sunscreens. Radiat Prot
Dosim 91: 271-273.
25.
Lademann J, Schanzer S, Jacobi U, et al, 2005 Synergy
effects between organic and inorganic UV filters in
sunscreens. J Biomed Opt 10: 14008.
26. Nicolopoulou-Stamati P, Pitsos MA, 2001 The impact
of endocrine disrupters on the female reproductive
system. Hum Reprod Update 7: 323-330.
27.
Amaral Mendes JJ, 2002 The endocrine disrupters:
a major medical challenge. Food Chem Toxicol 40:
781-788.
28. Waring RH, Harris RM, 2005 Endocrine disrupters: A
human risk? Mol Cell Endocrinol 244: 2-9.
29.
Wuttke W, Jarry H, Seidlova-Wuttke D, 2010 Definition,
classification and mechanism of action of endocrine
disrupting chemicals. Hormones 9: 9-15.
30.
Colborn T, vom Saal FS, Soto AM, 1993 Developmental
effects of endocrine-disrupting chemicals in wildlife
and humans. Environ Health Perspect 101: 378-384.
31. McLachlan JA, 2001 Environmental signaling: What
embryos and evolution teach us about endocrine dis-
rupting chemicals. Endocrine Reviews 22: 319-341.
32. Norgil Damgaard I, Main KM, Toppari J, Skakkebaek
NE, 2002 Impact of exposure to endocrine disrupters
in utero and in childhood on adult reproduction. Best
Pract Res Cl En Metab 16: 289-309.
33.
Theelen RMC, Liem AKD, Slob W, van Wijnen JH,
1993 Intake of 2, 3, 7, 8 chlorine substituted dioxins,
furans, and planar PCBs from food in the Netherlands:
median and distribution. Chemosphere 27: 1625-1635.
34.
Wagner M, Oehlmann J, 2009 Endocrine disruptors
in bottled mineral water: total estrogenic burden and
migration from plastic bottles. Environ Sci Pollut Res
16: 278-286.
35. Harvey PW, Darbre P, 2004 Endocrine disrupters and
human health: Could oestrogenic chemicals in body
care cosmetics adversely affect breast cancer incidence
in women? A review of evidence and call for further
research. J Appl Toxicol 24: 167-176.
36.
Schlumpf M, Cotton B, Conscience M, Haller V, Stein-
mann B, Lichtensteiger W, 2001 In vitro and in vivo
estrogenicity of UV screens. Environ Health Perspect
109: 239-244.
37.
Schlumpf M, Schmid P, Durrer S, et al, 2004 Endocrine
activity and developmental toxicity of cosmetic UV
filters – an update. Toxicology 205: 113-122.
42 S. MAIPAS, P. NICOLOPOULOU-STAMATI
38.
McLachlan JA, Simpson E, Martin M, 2006 Endocrine
disrupters and female reproductive health. Best Pract
Res Cl En Metab 20: 63-75.
39. Toppari J, Larsen JC, Christiansen P, et al, 1996 Male
reproductive health and environmental xenoestrogens.
Environ Health Perspect 104: Suppl. 4: 741-803.
40.
Dhooge W, Eertmans F, Mahmoud A, Comhaire F 2007
Male reproductive status and its relationship with man-
made, hormone-disrupting substances: studies in Flan-
ders, Belgium. In: Nicolopoulou-Stamati P, Hens L,
Howard CV (eds) Reproductive Health and the Environ-
ment, Springer, Dordrecht, The Netherlands; pp, 75-94.
41.
Corsolini S 2007 Non-pesticide endocrine disrupters
and reproductive health. In: Nicolopoulou-Stamati P,
Hens L, Howard CV (eds) Reproductive Health and the
Environment, Springer, Dordrecht, The Netherlands;
pp, 161-186.
42. Nicolopoulou-Stamati P, Lelos NJ 2007 Introduction:
Environmental impact on reproductive health, recent
trends and developments. In: Nicolopoulou-Stamati P,
Hens L, Howard CV (eds) Reproductive Health and the
Environment, Springer, Dordrecht, The Netherlands;
pp, 1-19.
43.
Health Council of the Netherlands, 1999 Hormone
disruptors in ecosystems, Health Council of the Neth-
erlands, The Hague.
44. McGrath JA, Uitto J 2010 Anatomy and organization
of human skin. In: Burns T, Breathnach S, Cox N,
Griffiths C (eds) Rook’s Textbook of Dermatology, 8th
ed, Blackwell Publishing Ltd, Singapore; pp, 3.1-3.53.
45.
Barrett CW, 1969 Skin penetration. J Soc Cosmet Chem
20: 487-499.
46. Williams AC, Barry BW, 2004 Penetration enhancers,
Adv Drug Deliver Rev 56: 603-618.
47. Loprieno N, 1992 Guidelines for safety evaluation of
cosmetics ingredients in the EC countries. Food Chem
Toxicol 30: 809-815.
48.
Rothe H, Fautz R, Gerber E, et al, 2011 Special aspects
of cosmetic spray safety evaluations: Principles on
inhalation risk assessment. Toxicol Lett 205: 97-104.
49. Bridges B, 2002 Fragrance: emerging health and envi-
ronmental concerns. Flavour Frag J 17: 361-371.
50.
van Engelen JGM, Hakkinen PJ, Money C, Rikken
MGJ, Vermeire TG 2007 Human exposure assessment.
In: van Leeuwen CJ, Vermeire TG (eds) Risk assess-
ment of chemicals: An introduction, 2nd ed, Springer,
Dordrecht, The Netherlands; pp, 195-226.
51.
Xue J, Zartarian V, Moya J, et al, 2007 A meta-analysis of
children’s hand-to-mouth frequency data for estimating
nondietary ingestion exposure. Risk Anal 27: 411-420.
52.
Salvador A, Chisvert A, Camarasa A, Pascual-Martí MC,
March JG, 2001 Sequential injection spectrophotometric
determination of oxybenzone in lipsticks. Analyst 126:
1462-1465.
53. Loretz LJ, Api AM, Barraj LM, et al, 2005 Exposure
data for cosmetic products: lipstick, body lotion, and
face cream. Food Chem Toxicol 43: 279-291.
54. Blüthgen N, Zucchi S, Fent K, 2012 Effects of the UV
filter benzophenone-3 (oxybenzone) at low concentra-
tions in zebrafish (Danio rerio). Toxicol Appl Pharmacol
263: 184-194.
55.
Coronado M, De Haro H, Deng X, Rempel MA, Lavado
R, Schlenk D, 2008 Estrogenic activity and reproduc-
tive effects of the UV-filter oxybenzone (2-hydroxy-
4-methoxyphenyl-methanone) in fish. Aquat Toxicol
90: 182-187.
56.
Denslow ND, Chow MC, Kroll KJ, Green L, 1999
Vitellogenin as a biomarker of exposure for estrogen
or estrogen mimics. Ecotoxicology 8: 385-398.
57.
Chapin R, Gulati D, Mounce R, 1997 2-Hydroxy-
4-methoxybenzophenone. Environ Health Perspect
105: Suppl. 1: 313-314.
58. Daston GP, Gettings SD, Carlton BD, et al, 1993 As-
sessment of the reproductive toxic potential of dermally
applied 2-Hydroxy-4-methoxybenzophenone to male
B6C3F1 Mice. Fundam Appl Toxicol 20: 120-124.
59.
Wolff MS, Engel SM, Berkowitz GS, 2008 Prenatal
phenol and phthalate exposures and birth outcomes.
Environ Health Perspect 116: 1092-1097.
60.
Hany J, Nagel R, 1995 Detection of sunscreen agents in
human breast milk, (article in German). Deut Lebensm-
Rundsch 91: 341-345.
61.
Blair RM, Fang H, Branham WS, et al, 2000 The estrogen
receptor relative binding affinities of 188 natural and
xenochemicals: Structural diversity of ligands. Toxicol
Sci 54: 138-153.
62. Kunz PY, Galicia HF, Fent K, 2006 Comparison of in
vitro and in vivo estrogenic activity of UV filters in
fish. Toxicol Sci 90: 349-361.
63.
Nashev LG, Schuster D, Laggner C, et al, 2010 The
UV-filter benzophenone-1 inhibits 17β-hydroxysteroid
dehydrogenase type 3: Virtual screening as a strategy
to identify potential endocrine disrupting chemicals.
Biochem Pharmacol 79: 1189-1199.
64. Kusk KO, Avdolli M, Wollenberger L, 2011 Effect of
2,4-Dihydroxybenzophenone (BP1) on early life-stage
development of the marine copepod Acartia tonsa at
different temperatures and salinities. Environ Toxicol
Chem 30: 959-966.
65. Kunisue T, Chen Z, Buck Louis GM, et al, 2012 Uri-
nary concentrations of benzophenone-type UV filters
in US women and their association with endometriosis.
Environ Sci Technol 46: 4624-4632.
66. Hsieh MH, Grantham EC, Liu B, Macapagal R, Will-
ingham E, Baskin LS, 2007 In utero exposure to ben-
zophenone-2 causes hypospadias through an estrogen
receptor dependent mechanism. J Urology 78: 1637-1642.
67. Weisbrod CJ, Kunz PY, Zenker AK, Fent K, 2007 Ef-
fects of the UV filter benzophenone-2 on reproduction
in fish. Toxicol Appl Pharmacol 225: 255-266.
68.
Fent K, Kunz PY, Gomez E, 2008 UV filters in the
aquatic environment induce hormonal effects and affect
Sun lotion chemicals as endocrine disruptors 43
fertility and reproduction in fish. Chimia 62: 368-375.
69. Zucchi S, Blüthgen N, Ieronimo A, Fent K, 2011 The
UV-absorber benzophenone-4 alters transcripts of genes
involved in hormonal pathways in zebrafish (Danio
rerio) eleuthero-embryos and adult males. Toxicol Appl
Pharmacol 250: 137-146.
70.
Morohoshi K, Yamamoto H, Kamata R, Shiraishi F, Koda
T, Morita M, 2005 Estrogenic activity of 37 components
of commercial sunscreen lotions evaluated by in vitro
assays. Toxicol In Vitro 19: 457-469.
71. Suzuki T, Kitamura S, Khota R, Sugihara K, Fujimoto
N, Ohta S, 2005 Estrogenic and antiandrogenic activities
of 17 benzophenone derivatives used as UV stabilizers
and sunscreens. Toxicol Appl Pharmacol 203: 9-17.
72. Nakagawa Y, Tayama K, 2001 Estrogenic potency of
benzophenone and its metabolites in juvenile female
rats. Arch Toxicol 75: 74-79.
73.
Szwarcfarb B, Carbone S, Reynoso R, et al, 2008 Octyl-
methoxycinnamate (OMC), an ultraviolet (UV) filter,
alters LHRH and amino acid neurotransmitters release
from hypothalamus of immature rats. Exp Clin Endocr
Diab 116: 94-98.
74.
Klammer H, Schlecht C, Wuttke W, et al, 2007 Effects of
a 5-day treatment with the UV-filter octyl-methoxycin-
namate (OMC) on the function of the hypothalamo-pitu-
itary-thyroid function in rats. Toxicology 238: 192-199.
75. Schneider S, Deckardt K, Hellwig J, et al, 2005 Octyl
methoxycinnamate: Two generation reproduction toxic-
ity in Wistar rats by dietary administration. Food Chem
Toxicol 43: 1083-1092.
76.
Axelstad M, Boberg J, Hougaard KS, et al, 2011 Effects
of pre- and postnatal exposure to the UV-filter Octyl
Methoxycinnamate (OMC) on the reproductive, auditory
and neurological development of rat offspring. Toxicol
Appl Pharmacol 250: 278-290.
77.
Ozáez I, Martínez-Guitarte JL, Morcillo G, 2013 Effects
of in vivo exposure to UV filters (4-MBC, OMC, BP-3,
4-HB, OC, OD-PABA) on endocrine signaling genes
in the insect Chironomus riparius. Sci Total Environ
456-457: 120-126.
78. Janjua NR, Mogensen B, Andersson AM, et al, 2004
Systemic absorption of the sunscreens Benzophenone-3,
Octyl-Methoxycinnamate, and 3-(4-Methyl-Benzyli-
dene) Camphor after whole-body topical application
and reproductive hormone levels in humans. J Invest
Dermatol 123: 57-61.
79. Inui M, Adachi T, Takenaka S, et al, 2003 Effect of UV
screens and preservatives on vitellogenin and chorio-
genin production in male medaka (Oryzias latipes).
Toxicology 194: 43-50.
80. Schmitt C, Oetken M, Dittberner O, Wagner M, Oehl-
mann J, 2008 Endocrine modulation and toxic effects of
two commonly used UV screens on the aquatic inver-
tebrates Potamopyrgus antipodarum and Lumbriculus
variegates. Environ Pollut 152: 322-329.
81.
Stroeva OG, Popov VB, 1998 Effect of para-amino-
benzoic acid on the development of rat embryos when
applied to pregnant females, (article in Russian). On-
togenez 29: 444-449.
82.
Odio MR, Azri-Meehan S, Robison SH, Kraus AL,
1994 Evaluation of subchronic (13 week), reproductive,
and in vitro genetic toxicity potential of 2-ethylhexyl-
2-cyano-3,3-diphenyl acrylate (Octocrylene). Fundam
Appl Toxicol 22: 355-368.
83. Ashby J, Tinwell H, Plautz J, Twomey K, Lefevre PA,
2001 Lack of binding to isolated estrogen or androgen
receptors, and inactivity in the immature rat uterotro-
phic assay, of the ultraviolet sunscreen filters Tinosorb
M-active and Tinosorb S. Regul Toxicol Pharmacol
34: 287-291.
84. Newman MD, Stotland M, Ellis JI, 2009 The safety of
nanosized particles in titanium dioxide- and zinc oxide-
based sunscreens. J Am Acad Dermatol 61: 685-692.
85.
Nohynek GJ, Lademann J, Ribaud C, Roberts MS, 2007
Grey goo on the skin? Nanotechnology, cosmetic and
sunscreen safety. Crit Rev Toxicol 37: 251-277.
86.
Gulson B, McCall M, Korsch M, et al, 2010 Small
amounts of zinc from zinc oxide particles in sunscreens
applied outdoors are absorbed through human skin.
Toxicol Sci 118: 140-149.
87. Kahru A, Dubourguier HC, 2010 From ecotoxicology
to nanoecotoxicology. Toxicology 269: 105-119.
88.
Bedwal RS, Bahuguna A, 1994 Zinc, copper and selenium
in reproduction. Experientia 50: 626-640.
89.
Sundaresan NR, Anish D, Sastry KVH, et al, 2008 High
doses of dietary zinc induce cytokines, chemokines, and
apoptosis in reproductive tissues during regression. Cell
Tissue Res 332: 543-554.
90.
Piao F, Yokoyama K, Ma N, Yamauchi T, 2003 Subacute
toxic effects of zinc on various tissues and organs of
rats. Toxicol Lett 145: 28-35.
91.
Sharma V, Singh P, Pandey AK, Dhawan A, 2012 Induc-
tion of oxidative stress, DNA damage and apoptosis in
mouse liver after sub-acute oral exposure to zinc oxide
nanoparticles. Mutat Res 745: 84-91.
92.
Hao L, Chen L, Hao J, Zhong N, 2013 Bioaccumulation
and sub-acute toxicity of zinc oxide nanoparticles in ju-
venile carp (Cyprinus carpio): A comparative study with
its bulk counterparts. Ecotox Environ Safety 91: 52-60.
93.
Fairbairn EA, Keller AA, Mädler L, Zhou D, Pokhrel S,
Cherr GN, 2011 Metal oxide nanomaterials in seawater:
Linking physicochemical characteristics with biological
response in sea urchin development. J Hazard Mater
192: 1565-1571.
94. Zhu X, Wang J, Zhang X, Chang Y, Chen Y, 2009 The
impact of ZnO nanoparticle aggregates on the embryonic
development of zebrafish (Danio rerio). Nanotechnol-
ogy 20: 195103.
95.
Wong SWY, Leung PTY, Djurišić AB, Leung KMY, 2010
Toxicities of nano zinc oxide to five marine organisms:
Influences of aggregate size and ion solubility. Anal
Bioanal Chem 396: 609-618.
44 S. MAIPAS, P. NICOLOPOULOU-STAMATI
96.
Reed RB, Ladner DA, Higgins CP, Westerhoff P,
Ranville JF, 2012 Solubility of nano-zinc oxide in
environmentally and biologically important matrices.
Environ Toxicol Chem 31: 93-99.
97. Cañas JE, Qi B, Li S, 2011 Acute and reproductive
toxicity of nano-sized metal oxides (ZnO and TiO2)
to earthworms (Eisenia fetida). J Environ Monitor
13: 3351-3357.
98.
Guo LL, Liu XH, Qin DX, et al, 2009 Effects of
nanosized titanium dioxide on the reproductive system
of male mice, (article in Chinese). Zhonghua Nak Ke
Xue 15: 517-522.
99. Yamashita K, Yoshioka Y, Higashisaka K, et al, 2011
Silica and titanium dioxide nanoparticles cause preg-
nancy complications in mice. Nat Nanotechnol 6:
321-328.
100. Zhu X, Chang Y, Chen Y, 2010 Toxicity and bioaccu-
mulation of TiO2 nanoparticle aggregates in Daphnia
magna. Chemosphere 78: 209-215.
101. Wang J, Zhu X, Zhang X, et al, 2011 Disruption of
zebrafish (Danio rerio) reproduction upon chronic
exposure to TiO
2
nanoparticles. Chemosphere 83:
461-467.
102. Wiench K, Wohlleben W, Hisgen V, et al, 2009 Acute
and chronic effects of nano- and non-nano-scale TiO
2
and ZnO particles on mobility and reproduction of the
freshwater invertebrate Daphnia magna. Chemosphere
76: 1356-1365.
103.
Gurevitch D, Shuster-Meiseles T, Nov O, Zick Y, Rudich
A, Rudich Y, 2012 TiO2 nanoparticles induce insulin
resistance in liver-derived cells both directly and via
macrophage activation. Nanotoxicology 6: 804-812.
104.
Kulvietis V, Zalgeviciene V, Didziapetriene J, Rotom-
skis R, 2011 Transport of nanoparticles through the
placental barrier. Tohoku J Exp Med 225: 225-234.
105.
Takeda K, Suzuki K, Ishihara A, et al, 2009 Nanopar-
ticles transferred from pregnant mice to their offspring
can damage the genital and cranial nerve systems. J
Health Sci 55: 95-102.
106.
Nakai JS, Chu I, Li-Muller A, Aucoin R, 1997 Ef-
fect of environmental conditions on the penetration
of benzene through human skin. J Toxicol Environ
Health 51: 447-462.
107. Brand RM, Spalding M, Mueller C, 2002 Sunscreens
can increase dermal penetration of 2,4-dichlorophen-
oxyacetic acid. J Toxicol Clin Toxicol 40: 827-832.
108.
Pont AR, Charron AR, Brand RM, 2004 Active ingre-
dients in sunscreens act as topical penetration enhanc-
ers for the herbicide 2,4-dichlorophenoxyacetic acid.
Toxicol Appl Pharmacol 195: 348-354.
109. Kim HJ, Park YI, Dong MS, 2005 Effects of 2,4-D
and DCP on the DHT-induced androgenic action in
human prostate cancer cells. Toxicol Sci 88: 52-59.
110.
Rosso SB, Di Paolo OA, Evangelista de Duffard AM,
Duffard R, 1997 Effects of 2,4-dichlorophenoxyacetic
acid on central nervous system of developmental rats.
Associated changes in ganglioside pattern. Brain Res
769: 163-167.
111. Alves MG, Neuhaus-Oliveira A, Moreira PI, Socorro
S, Oliveira PF, 2013 Exposure to 2,4-dichlorophen-
oxyacetic acid alters glucose metabolism in immature
rat Sertoli cells. Reprod Toxicol 38: 81-88.
112.
Stürtz N, Deis RP, Jahn GA, Duffard R, Evangelista de
Duffard AM, 2008 Effect of 2,4-dichlorophenoxyacetic
acid on rat maternal behaviour. Toxicology 247: 73-79.
113.
Darbre PD, Harvey PW, 2008 Paraben esters: Review
of recent studies of endocrine toxicity, absorption,
esterase and human exposure, and discussion of po-
tential human health risks. J Appl Toxicol 28: 561-578.
114.
Oishi S, 2002 Effects of propyl paraben on the male re-
productive system. Food Chem Toxicol 40: 1807-1813.
115. Oishi S, 2002 Effects of butyl paraben on the male
reproductive system in mice. Arch Toxicol 76: 423-429.
116.
Kang KS, Che JH, Ryu DY, Kim TW, Li GX, Lee
YS, 2002 Decreased sperm number and motile activ-
ity on the F1 offspring maternally exposed to butyl
p-hydroxybenzoic acid (butyl paraben). J Vet Med
Sci 64: 227-235.
117.
Routledge EJ, Parker J, Odum J, Ashby J, Sumpter
JP, 1998 Some alkyl hydroxy benzoate preservatives
(parabens) are estrogenic. Toxicol Appl Pharmacol
153: 12-19.
118. Okubo T, Yokoyama Y, Kano K, Kano I, 2001 ER-
dependent estrogenic activity of parabens assessed
by proliferation of human breast cancer MCF-7 cells
and expression of ERα and PR. Food Chem Toxicol
39: 1225-1232.
119.
Schmidt AN, Nanney LB, Boyd AS, King LE Jr, Ellis
DL, 2006 Oestrogen receptor-β expression in melano-
cytic lesions. Exp Dermatol 15: 971-980.
120. Prusakiewicz JJ, Harville HM, Zhang Y, Ackermann
C, Voorman RL, 2007 Parabens inhibit human skin
estrogen sulfotransferase activity: Possible link to
paraben estrogenic effects. Toxicology 232: 248-256.
121.
Handa O, Kokura S, Adachi S, et al, 2006 Meth-
ylparaben potentiates UV-induced damage of skin
keratinocytes. Toxicology 227: 62-72.
122. Environment Canada, Health Canada, 2008 Screen-
ing assessment for the challenge Octamethylcyclo-
tetrasiloxane (D4), Environment Canada and Health
Canada, Government of Canada https://www.ec.gc.
ca/ese-ees/2481B508-1760-4878-9B8A-270EEE8B-
7DA4/batch2_556-67-2_en.pdf (Date last checked:
16/12/2014).
123.
Environment Canada, Health Canada, 2011 Risk
management scope for [Trisiloxane, octamethyl-]
(Octamethyltrisiloxane) (MDM), Environment Canada
and Health Canada, Government of Canada http://
www.ec.gc.ca/ese-ees/9B3AF91C-71D1-4C5F-ACC1-
DB946930072E/B12%20107-51-7%20RM%20
Scope%20_EN.pdf (Date last checked: 16/12/2014).
124.
International Pharmaceutical Excipients Council
Sun lotion chemicals as endocrine disruptors 45
(IPEC) of the Americas, 2011 Inactive ingredient da-
tabase issues with ANDAs, Backgrounder Document
(IPEC – FDA OGD Meeting – December 9, 2011),
IPEC Americas http://www.fda.gov/downloads/Drugs/
DevelopmentApprovalProcess/HowDrugsareDevel-
opedandApproved/ApprovalApplications/Abbreviat-
edNewDrugApplicationANDAGenerics/UCM291010.
pdf (Date last checked: 16/12/2014).
125.
McKim JM Jr, Wilga PC, Breslin WJ, Plotzke KP,
Gallavan RH, Meeks RG, 2001 Potential estrogenic
and antiestrogenic activity of the cyclic siloxane octa-
methylcyclotetrasiloxane (D4) and the linear siloxane
hexamethyldisiloxane (HMDS) in immature rats using
the uterotrophic assay. Toxicol Sci 63: 37-46.
126.
Siddiqui WH, Stump DG, Plotzke KP, Holson JF,
Meeks RG, 2007 A two generation reproductive tox-
icity study of octamethylcyclotetrasiloxane (D4) in
rats exposed by whole-body vapor inhalation. Reprod
Toxicol 23: 202-215.
127.
Steinemann AC, 2009 Fragranced consumer products
and undisclosed ingredients. Environ Impact Assess
Rev 29: 32-38.
128.
Gimeno P, Maggio AF, Bousquet C, Quoirez A, Civade
C, Bonnet PA, 2012 Analytical method for the identifi-
cation and assay of 12 phthalates in cosmetic products:
Application of the ISO 12787 international standard
“Cosmetics-Analytical methods-Validation criteria for
analytical results using chromatographic techniques”.
J Chromatogr A 1253: 144-153.
129.
Api AM, 2001 Toxicological profile of diethyl phthal-
ate: a vehicle for fragrance and cosmetic ingredients.
Food Chem Toxicol 39: 97-108.
130. Hauser R, Calafat AM, 2005 Phthalates and human
health. Occup Environ Med 62: 806-818.
131. Rastogi SK, Kesavachandran C, Mahdi F, Pandey A,
2006 Phthalate exposure and health outcomes. Indian
J Occup Environ Med 10: 111-115.
132.
Sathyanarayana S, 2008 Phthalates and children’s
health. Curr Probl Pediatr Adolesc Health Care 38:
34-49.
133. Martino-Andrade AJ, Chahoud I, 2010 Reproductive
toxicity of phthalate esters. Mol Nutr Food Res 54:
148-157.
134.
Harris CA, Sumpter JP 2001 The endocrine disrupting
potential of phthalates. In: Metzler M (ed) Endocrine
Disruptors, Part I, The Handbook of Environmental
Chemistry, Vol. 3, Part L, Springer-Verlag Berlin Hei-
delberg, Germany; pp, 169-201.
135.
Davis BJ, Maronpot RR, Heindel JJ, 1994 Di-(2-
ethylhexyl) Phthalate suppresses estradiol and ovulation
in cycling rats. Toxicol Appl Pharmacol 128: 216-223.
136.
Stroheker T, Cabaton N, Nourdin G, Régnier JF,
Lhuguenot JC, Chagnon MC, 2005 Evaluation of
anti-androgenic activity of di-(2-ethylhexyl)phthalate.
Toxicology 208: 115-121.
137. Andrade AJM, Grande SW, Talsness CE, et al, 2006
A dose response study following in utero and lacta-
tional exposure to di-(2-ethylhexyl) phthalate (DEHP):
Reproductive effects on adult male offspring rats.
Toxicology 228: 85-97.
138. Fredricsson B, Möller L, Pousette Å, Westerholm R,
1993 Human sperm motility is affected by plasticiz-
ers and diesel particle extracts. Pharmacol Toxicol
72: 128-133.
139.
Segura JJ, Calvo JR, Guerrero JM, Sampedro C,
Jimenez A, Llamas R, 1996 The disodium salt of EDTA
inhibits the binding of vasoactive intestinal peptide to
macrophage membranes: Endodontic implications. J
Endodont 22: 337-340.
140. Gamer AO, Rossbacher R, Kaufmann W, van Raven-
zwaay B, 2008 The inhalation toxicity of di- and
triethanolamine upon repeated exposure. Food Chem
Toxicol 46: 2173-2183.
141.
Libralato G, Volpi Ghirardini A, Avezzú F, 2010 Seawa-
ter ecotoxicity of monoethanolamine, diethanolamine
and triethanolamine. J Hazard Mater 176: 535-539.
142.
Ortiz KJ, Yiannias JA, 2004 Contact dermatitis to
cosmetics, fragrances, and botanicals. Dermatol Ther
17: 264-271.
143.
Orton DI, Wilkinson JD, 2004 Cosmetic allergy:
Incidence, diagnosis, and management. Am J Clin
Dermatol 5: 327-337.
144. Laguna C, de la Cuadra J, Martín-González B, et al,
2009 Allergic contact dermatitis to cosmetics. Actas
Dermosifiliogr 100: 53-60.
145.
Reichrath J, 2006 The challenge resulting from positive
and negative effects of sunlight: How much solar UV
exposure is appropriate to balance between risks of
vitamin D deficiency and skin cancer? Prog Biophys
Mol Biol 92: 9-16.
146. Fioletov VE, McArthur LJB, Mathews TW, Marrett
L, 2009 On the relationship between erythemal and
vitamin D action spectrum weighted ultraviolet radia-
tion. J Photochem Photobiol B 95: 9-16.
147. Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA,
Holick MF, 1987 Sunscreens suppress cutaneous
vitamin D
3
synthesis. J Clin Endocrinol Metab 64:
1165-1168.
148. Holick MF, Chen TC, 2008 Vitamin D deficiency: a
worldwide problem with health consequences. Am J
Clin Nutr 87: Suppl: 1080-1086.
149.
Norman AW, Frankel JB, Heldt AM, Grodsky GM,
1980 Vitamin D deficiency inhibits pancreatic secre-
tion of insulin. Science 209: 823-825.
150. Halloran BP, DeLuca HF, 1980 Effect of vitamin D
deficiency on fertility and reproductive capacity in
the female rat. J Nutr 110: 1573-1580.
151.
Kwiecinski GG, Petrie GI, DeLuca HF, 1989 Vitamin
D is necessary for reproductive functions of the male
rat. J Nutr 119: 741-744.
152.
Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers
RW, Roberts JM, 2007 Maternal Vitamin D deficiency
46 S. MAIPAS, P. NICOLOPOULOU-STAMATI
increases the risk of preeclampsia. J Clin Endocrinol
Metab 92: 3517-3522.
153. Mannion CA, Gray-Donald K, Koski KG, 2006 As-
sociation of low intake of milk and vitamin D during
pregnancy with decreased birth weight. Can Med
Assoc J 174: 1273-1277.
154.
Rajapakse N, Silva E, Kortenkamp A, 2002 Combining
xenoestrogens at levels below individual No-Observed-
Effect Concentrations dramatically enhances steroid
hormone action. Environ Health Perspect 110: 917-921.
155.
Kortenkamp A, 2007 Ten years of mixing cocktails: A
review of combination effects of endocrine-disrupting
chemicals. Environ Health Perspect 115: Suppl 1:
98-105.
156.
Kunz PY, Fent K, 2006 Estrogenic activity of UV
filter mixtures. Toxicol Appl Pharmacol 217: 86-99.
157. Wulf HC 2010 Sunscreens. In: Jemec GBE, Kemény
L, Miech D (eds) Non-surgical treatment of keratino-
cyte skin cancer, Springer-Verlag Berlin Heidelberg;
pp, 167-176.
158. Danovaro R, Bongiorni L, Corinaldesi C, et al, 2008
Sunscreens cause coral bleaching by promoting viral
infections. Environ Health Perspect 116: 441-447.
159.
Díaz-Cruz MS, Barcel D, 2009 Chemical analysis
and ecotoxicological effects of organic UV-absorbing
compounds in aquatic ecosystems. Trends Anal Chem
28: 708-717.
160. Urbach F, 2001 The historical aspects of sunscreens.
J Photochem Photobiol B 64: 99-104.
161. Skolnick A, Saladi RN, Fox JL, 2007 An Update on
Sunscreens. JAOCD 8: 23-29.
162. Mueller NC, Nowack B, 2008 Exposure modeling of
engineered nanoparticles in the environment. Environ
Sci Technol 42: 4447-4453.
163. Zwiener C, Richardson SD, DeMarini DM, Grummt
T, Glauner T, Frimmel FH, 2007 Drowning in disin-
fection byproducts? Assessing swimming pool water.
Environ Sci Technol 41: 363-372.
164.
Nakajima M, Kawakami T, Niino T, Takahashi Y,
Onodera S, 2009 Aquatic fate of sunscreen agents
octyl-4-methoxycinnamate and octyl-4-dimethylamino-
benzoate in model swimming pools and the mutagenic
assays of their chlorination byproducts. J Health Sci
55: 363-372.
165.
Moya J, Bearer CF, Etzel RA, 2004 Children’s be-
havior and physiology and how it affects exposure to
environmental contaminants. Pediatrics 113: Suppl
3: 996-1006.
166. Diffey B, 2001 Sunscreen isn’t enough. J Photochem
Photobiol B 64: 105-108.
167. Fent K, Zenker A, Rapp M, 2010 Widespread occur-
rence of estrogenic UV-filters in aquatic ecosystems
in Switzerland. Environ Pollut 158: 1817-1824.
168.
Tovar-Sánchez A, Sánchez-Quiles D, Basterretxea G,
et al, 2013 Sunscreen products as emerging pollutants
to coastal waters. PLOS ONE 8: e65451.
169. Gago-Ferrero P, Díaz-Cruz MS, Barceló D, 2012 An
overview of UV-absorbing compounds (organic UV
filters) in aquatic biota. Anal Bioanal Chem 404:
2597-2610.
... Reports to date, emphasize how chemical and mineral filters reach coastal waters and through bioaccumulation and biomagnification issues affect marine organisms (Fent et al., 2010;Wood, 2018). Another concern that has been object of a fierce debate is the health safety of the chemical filters, since there are studies where ingredients of this group are described as penetration enhancers and others present endocrine disruption characteristics (Coronado et al., 2008;Maipas and Nicolopoulou-Stamati, 2015). These sustainability aspects of UV filters increased interest in natural compounds derived from renewable sources that may exhibit a filtering activity, as the so-called UV absorbing phytochemicals (i.e., polyphenols, carotenoids, vitamins and anthocyanidins) (Beerling, 2014;Tampucci et al., 2017). ...
Article
In recent years, sustainability on the cosmetics industry has received growing interest from consumers, cosmetics industries and organizations, as well as academics from various disciplinary fields. Increasing concerns about cosmetics safety, environmental impacts as deforestation and social impacts as those resulting from unfair trade have intensified attention given to such topic. While sustainability impacts occur through all phases of the cosmetic product life cycle, selection of raw materials is deserving of greater attention as information on this topic remains scattered and diffuse. Formulating with alternative ingredients considered more sustainable can be quite challenging due to possible lack of performance, instability and aesthetic limitations normally associated with their use. This paper discusses the relation between sustainability and the cosmetics industry, the factors stimulating the developments on this field, the need to assess those and the available tools, alongside with the sustainability impacts produced during all the product life cycle. The analysis reveals cosmetics sustainability as a complex and multifaceted issue that cannot be evaluated considering single aspects, but using an integrated assessment about the environmental, social and economical dimensions and about the final product quality and performance.
Article
Full-text available
Sunscreen and sunblock are crucial skincare products to prevent photoaging and photo-carcinogenesis through the addition of chemical filters to absorb or block ultraviolet (UV) radiation. However, several sunscreen and sunblock ingredients, mostly UV filters, have been associated with human and environmental safety concerns. Therefore, the exploration and discovery of promising novel sources of efficient and safer compounds with photoprotection-related activities are currently required. Marine invertebrates, particularly their associated microbiota, are promising providers of specialized metabolites with valuable biotechnological applications. Nevertheless, despite Actinobacteria members being a well-known source of bioactive metabolites, their photoprotective potential has been poorly explored so far. Hence, a set of methanolic extracts obtained from Cliona varians-derived actinomycetes was screened regarding their antioxidant and UV-absorbing capacities (i.e., photoprotection-related activities). The active extract-producing strains were identified and classified within genera Streptomyces, Micrococcus, Gordonia, and Promicromonospora. This is the first report of the isolation of these microorganisms from C. varians (an ecologically important Caribbean coral reef-boring sponge). The in vitro cytotoxicity on dermal fibroblasts of oxybenzone and the selected active extracts revealed that oxybenzone exerted a cytotoxic effect, whereas no cytotoxic effect of test extracts was observed. Accordingly, the most active (SPFi > 5, radical scavenging > 50%) and nontoxic (cell viability > 75%) extracts were obtained from Streptomyces strains. Finally, LC-MS-based characterization suggested a broad chemical space within the test strains and agreed with the reported streptomycetes' chemodiversity. The respective metabolite profiling exposed a strain-specific metabolite occurrence, leading to the recognition of potential hits. These findings suggest that marine Streptomyces produce photoprotectants ought to be further explored in skincare applications.
Article
Full-text available
Marine-derived fungi proved to be a rich source of biologically active compounds. The genus Penicillium has been extensively studied regarding their secondary metabolites and biological applications. However, the photoprotective effects of these metabolites remain underexplored. Herein, the photoprotective potential of Penicillium echinulatum, an Antarctic alga-associated fungus, was assessed by UV absorption, photostability study, and protection from UVA-induced ROS generation assay on human immortalized keratinocytes (HaCaT) and reconstructed human skin (RHS). The photosafety was evaluated by the photoreactivity (OECD TG 495) and phototoxicity assays, performed by 3T3 neutral red uptake (3T3 NRU PT, OECD TG 432) and by the RHS model. Through a bio-guided purification approach, four known alkaloids, (-)-cyclopenin (1), dehydrocyclopeptine (2), viridicatin (3), and viridicatol (4), were isolated. Compounds 3 and 4 presented absorption in UVB and UVA-II regions and were considered photostable after UVA irradiation. Despite compounds 3 and 4 showed phototoxic potential in 3T3 NRU PT, no phototoxicity was observed in the RHS model (reduction of cell viability < 30%), which indicates their very low acute photoirritation and high photosafety potential in humans. Viridicatin was considered weakly photoreactive, while viridicatol showed no photoreactivity; both compounds inhibited UVA-induced ROS generation in HaCaT cells, although viridicatol was not able to protect the RHS model against UVA-induced ROS production. Thus, the results highlighted the photoprotective and antioxidant potential of metabolites produced by P. echinulatum which can be considered a new class of molecules for photoprotection, since their photosafety and non-cytotoxicity were predicted using recommended in vitro methods for topical use.
Article
Full-text available
Faced with the ban of some organic UV filters such as octinoxate or avobenzone, especially in Hawaii, it became essential to offer new alternatives that are both renewable and safe for humans and the environment. In this context, a class of bio-based molecules displaying interesting UV filter properties and great (photo)stability has been developed from Meldrum's acid and bio-based and synthetic p-hydroxycinnamic acids, furans and pyrroles. Moreover, p-hydroxycinnamic acid-based Meldrum's derivatives possess valuable secondary activities sought by the cosmetic industry such as antioxidant and anti-tyrosinase properties. The evaluation of the properties of mixture of judiciously chosen Meldrum's acid derivatives highlighted the possibility to modulate secondary activity while maintaining excellent UV protection. Meldrum's acid derivatives are not only competitive when benchmarked against organic filters currently on the market (i.e., avobenzone), but they also do not exhibit any endocrine disruption activity.
Article
Sunscreens are widely prescribed and used to prevent skin cancer; however, they have been reported to contain various chemicals which mimic hormones and disrupt hormonal functioning in humans. The aim of this study was to develop topical nanogel for skin cancer prevention using an antioxidant compound quercetin (Qu) and inorganic titanium dioxide (TiO2). Two formulations of Qu nanocrystals were optimized with low and high concentration of drug using the Box-Behnken design with the quadratic response surface model and further homogenized with TiO2. Qu nanocrystal (0.08% and 0.12%) formulations showed a particle size of 249.65 ± 2.84 nm and 352.48 ± 3.56 nm with zeta potential of − 14.7 ± 0.41 mV and − 19.6 ± 0.37 mV and drug content of 89.27 ± 1.39% and 90.38 ± 1.81% respectively. Scanning electron microscopy (SEM) images showed rod-shaped nanocrystals with a particle size below 400 nm. Qu (0.08%), Qu (0.12%), Qu (0.12%) + TiO2 (5%), and Qu (0.12%) + TiO2 (15%) nanogels showed over 70% drug release with significantly (p < 0.001) enhanced skin deposition of Qu as compare with Qu suspension within 24 h. The average numbers of tumor, tumor volume, and percentage of animals with tumors at onset in the Qu (0.12%) + TiO2 (15%) nanogel-pretreated group was found to be significantly (p < 0.05) less as compared with the UV only exposed group. Further, Qu (0.12%) + TiO2 (15%) nanogel significantly (p < 0.001) downregulated COX-2, EP3, EP4, PCNA, and cyclin D1 expressions in contrast to Qu and TiO2 only pretreated groups. Therefore, novel combination of Qu (0.12%) + TiO2 (15%) with enhanced skin deposition can be used as a chemopreventive strategy in UVB-induced skin photocarcinogenesis.
Article
Full-text available
Background Premature skin aging results from exposure to a range of environmental factors, primarily ultraviolet radiation, but also high‐energy visible light in the blue spectrum, infrared radiation, and environmental pollution. These extrinsic factors result in the generation of reactive oxygen species which promote photoaging and DNA damage resulting in skin cancers. Aims To formulate skincare products utilizing a new coating applied to zinc oxide and titanium dioxide particles and complimentary skincare ingredients to provide broad protection against a range of environmental insults. Methods A cross‐polymer, multifunctional coating of silicate, polyalkylsilsesquioxane, and polydimethylsiloxane moieties increases the photostability and decreases the reactivity of mineral sunscreen agents when interacting with energy sources. These products are also formulated with antioxidants to minimize free radical propagation. Additionally, this coating improves the esthetic feel of mineral sunscreens, while the appearance is enhanced by formulating products with a blend of iron oxides. Results A series of in vitro and ex vivo studies demonstrated the ability of mineral‐based products formulated with the new multifunctional coating to provide protection against ultraviolet radiation, high‐energy visible light, infrared radiation, and environmental pollution. Conclusion Newly formulated mineral‐based skincare products provide environmental protection, are ecologically safe, and can replace chemical‐based sunscreen ingredients.
Article
Full-text available
Ultraviolet (UV) filters are chemicals widely used in personal care products (PCPs). Due to their effect as endocrine disruptor compounds (EDCs), the toxicity of UV filters is a current concern for human health. EDC exposure may be correlated to cardiovascular diseases (CVD), but to our knowledge, no studies assessed the UV filters effects as human EDCs at the vascular level. Octylmethoxycinnamate (OMC) is the world’s most widely used UV-B filter, present in more than 90% of PCPs. Due to its demonstrated multiple hormonal activities in animal models, this substance is also suspected to be a human EDC. The purpose of this study was to assess the rapid/short-term effects of OMC on arterial tonus and analyse its mode of action (MOA). Using human umbilical arteries, the endocrine effects of OMC were evaluated in in vitro (cellular and organ) experiments by planar cell surface area (PCSA) and organ bath, respectively. Our data show that OMC induces a rapid/short-term smooth muscle relaxation acting through an endothelium-independent MOA, which seems to be shared with oestrogens, involving an activation of soluble guanylyl cyclase (sGC) that increases the cyclic guanosine monophosphate (cGMP) intracellular levels and an inhibition of L-type voltage-operated Ca2+ channels (L-Type VOCC).
Article
Sunscreens are the most popular way of protection against sunburn. Other possible indications are reduction of the risks of extrinsic aging and skin cancer. Inorganic and organic filters are used. Organic filters, such as PABA derivatives, cinnamates, benzophenones, and octocrylene may possess the risk of unwanted adverse events such as photo-allergy or negative environmental impact. All sunscreens that are used according to the manufacturers advice will reduce vitamin-D synthesis.
Article
Full-text available
Marine ecosystems are increasingly threatened by the release of personal care products. Among them, sunscreens are causing concern either for the effects on skin protection from UV radiation and for the potential impacts on marine life. Here, we assessed the UVA protective efficacy of three sunscreens on human dermal fibroblasts, including two common products in Europe and USA, and an eco-friendly product. The sunscreens’ effects were also tested on Paracentrotus lividus, a marine species possibly threatened by these contaminants. We found that all tested sunscreens had similar efficacy in protecting human fibroblasts from UVA radiation. Conversely, the sunscreens’ effects on embryo-larval development of P. lividus were dependent on the product tested. In particular, the USA sunscreen, containing benzophenone-3, homosalate and preservatives, caused the strongest impact on the sea urchin development, whereas the eco-friendly sunscreen determined the weakest effects. These results suggest that although the tested products protected human skin cells from UVA-induced damage, they might severely affect the success of recruitment and survival of the sea urchin. Our findings underline the importance of developing eco-friendly sunscreens for minimising or avoiding the impact on marine life while protecting human skin from UV damage.
Article
Full-text available
Background: To investigate the associations of genetic polymorphism with high-density lipoprotein-cholesterol (HDL-C) levels in Iranian adolescents. Methods: This multicentre study was conducted on 10 - 18 year-old students from 27 provinces in Iran. Logic regression approach was used to determine the main effects and interactions of polymorphisms related to HDL-C levels. Results: The rs708272 polymorphism was significantly related to HDL-C levels. Moreover, rs708272 increased HDL-C levels and had a protective effect on HDL-C. The interaction of rs2230808 and rs5880 polymorphisms as well as the interaction of rs320 and rs708272 polymorphisms were associated with lower HDL-C levels. Furthermore, the interaction of rs320 and rs1801177 polymorphisms was associated with lower HDL-C levels. Conclusions: We found that not only single SNPs, but also interactions of several SNPs affect HDL-C levels. Given the high prevalence of low HDL-C in Middle Eastern populations, further genetic studies are required for detailed analysis.
Article
Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for most humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy either a child's or an adult's vitamin D requirement. Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A circulating level of 25-hydroxyvitamin D of >75 nmol/L, or 30 ng/mL, is required to maximize vitamin D's beneficial effects for health. In the absence of adequate sun exposure, at least 800–1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given in physiologic concentrations.
Article
We report the epidemiology of sunscreen allergy over a period of 5 years at the National Skin Centre. A total of 61 patients with suspected allergy to sunscreen underwent patch or photopatch testing to our sunscreen series from 1992 to 1996. The results were retrospectively analysed and evaluated. Out of these 61 patients, 5 were found to have positive patch test reactions to sunscreens. 2 were photoallergic, and 3 were allergic to active ingredients in sunscreens. The main causative allergens were 2-ethylhexyl-4-methoxycinnamate (Parsol MCX) and 2-hydroxy-4-methoxybenzophenone (oxybenzone). We conclude that sunscreen contact allergy is uncommon in our practice. (C) 1998 Decker Publishing Inc.
Article
The biological efficacy (erythema action) of the radiation is dependent on wavelength. The unit SED (standard erythema dose) is a direct measure of the erythema action of radiation. The skin by itself absorbs UV radiation depending on the thickness of stratum corneum and the degree of pigmentation. When testing SPF of a sunscreen in humans 2 mg/cm2 is applied, in real life much less sunscreen is used 0.5 mg/cm2. It has been suggested that the protection is reduced exponentially when a thinner layer is used. The number of sunburn cells, cutaneous DNA damage, conversion of urocanic acid, and immu-nosuppression are diminished by sunscreen use. Human studies have indicated that the number of actinic keratoses as well as squamous cell carcinomas can be reduced if sunscreens are used regularly.
Chapter
Components of normal human skinEmbryologyEpidermisThe dermal-epidermal junctionDermisLangerhans' cellsMast cellsBasophilsNerves and sense organsMerkel cellsBlood vesselsLymphatic systemRegional variation
Article
Evaluation of Subchronic (13 Week), Reproductive, and in Vitro Genetic Toxicity Potential of 2-Ethylhexyl-2-cyano-3,3-diphenyl Acrylate (Octocrylene). Odio, M. R., Azri-Meehan, S., Robison, S. H., and Kraus, A. L. (1994). Fundam. Appl. Toxicol. 22, 355-368. Use of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene) in commercial sunscreen products has increased considerably in recent years. To support larger scale human exposure to this compound, additional toxicological information was needed in several key areas. The present studies evaluated subchronic toxicity, developmental toxicity, and in vitro genotoxic potential of Octocrylene. In the subchronic study, male and female New Zealand white (NZW) rabbits treated topically with concentrations of octocrylene up to 534 mg/kg/day for 13 weeks showed slight to moderate dose-dependent skin irritation that correlated positively with a mild depression in body weight gain. Lack of associated histopathologic or clinical hematology abnormalities suggested that the body weight effect probably reflected a nonspecific response to topical irritation. In percutaneous developmental toxicity studies, NZW does were treated topically with Octocrylene at levels up to 267 mg/kg/day on Days 6 through 18 of gestation. Body weight gain, food consumption, and all maternal, reproductive, and offspring parameters evaluated were comparable between Octocrylene-treated and control animals. In the oral developmental toxicity assay, female CD-1 mice received oral doses of Octocrylene up to 1000 mg/kg/day on Days 8-12 of gestation. No evidence of maternal or developmental toxicity was seen at any dose tested. Genotoxicity was evaluated in vitro using the Chinese hamster ovary cell assay to assess clastogenicity and the mouse lymphoma cell assay to assess forward gene mutations. Octocrylene did not induce any significant increase in genotoxicity. This evaluation of toxicological potential supports the use of Octocrylene as a human photoprotectant.
Article
Assessment of the Reproductive Toxic Potential of Dermally Applied 2-Hydroxy-4-methoxybenzophenone to Male B6C3FI Mice. Daston, G. P., Gettings, S. D., Carlton, B. D., Chudkowski, M., Davis, R. A., Kraus, A. L., Luke, C. F., Ouellette, R. E., Re, T. A., Hoberman, A. M., and Sambuco, C. P. (1993). Fundam. Appl. Toxicol. 20, 120-124. The potential of 2-hydroxy-4-methoxybenzophenone (HMB) to cause male reproductive toxicity was assessed in B6C3FI mice. HMB was administered topically for 13 weeks (5 days/week) to groups of 10 mice each at dosages of 0, 10, 20, 100, or 400 mg/kg/day. Additional high dosage and control mice were also included and euthanized at interim time points to characterize the time course of any effects. After 91 days (or at interim periods) mice were euthanized and reproductive organ weights, cauda epididymal sperm concentration and proportion of motile and abnormal sperm, and testicular spermatid concentration were determined. Testicular histology was evaluated in fixed tissue. HMB treatment had no effect on body weight gain or any of the male reproductive parameters assessed at any time point. These results indicate that topically applied HMB has no reproductive toxic potential in male B6C3FI mice at dosages as high as 400 mg/kg/day.