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Cosmetics as endocrine disruptors: are they a health risk?

Polyxeni Nicolopoulou-Stamati1 & Luc Hens2 & Annie J. Sasco3

Published online: 29 January 2016 # Springer Science+Business Media New York 2016

Abstract Exposure to chemicals from different sources in everyday life is widespread; one such source is the wide range of products listed under the title Bcosmetics^, including the different types of popular and widely-advertised sunscreens. Women are encouraged through advertising to buy into the myth of everlasting youth, and one of the most alarming con- sequences is in utero exposure to chemicals. The main route of exposure is the skin, but the main endpoint of exposure is endocrine disruption. This is due to many substances in cos- metics and sunscreens that have endocrine active properties which affect reproductive health but which also have other endpoints, such as cancer. Reducing the exposure to endocrine disruptors is framed not only in the context of the reduction of health risks, but is also significant against the background and rise of ethical consumerism, and the responsibility of the cos- metics industry in this respect. Although some plants show endocrine-disrupting activity, the use of well-selected natural products might reduce the use of synthetic chemicals. Instruments dealing with this problem include life-cycle

analysis, eco-design, and green labels; in combination with the committed use of environmental management systems, they contribute to Bcorporate social responsibility .̂

Keywords Endocrine active substances . Endocrine disruptors . Cosmetics . Sunscreens

1 Introduction

Women and men all over the world use large amount of cos- metic products in pursuit of everlasting youth, ignoring the probable health risks. The commercial category of Bcosmetic products^ entails substances or mixtures of substances that are designed mainly for external use, for instance to improve the appearance; clean; perfume; and sometimes protect as in the case of sunscreens [1]. Many cosmetic products such as oils and lipsticks contain UV filters, even though they are not marketed under the term Bsunscreens^ or Bsun lotions^. Cosmetic products contain active substances, preservatives and also the so-called Bfragrances^ or Bperfumes^, the exact composition of which remains a secret under the trade secret standards [2].

Increasing scientific concern exists about the nature and the safety of the ingredients used by the cosmetics industry re- garding their endocrine-disrupting effects. Although numer- ous studies have proved the endocrine-disrupting potential of many ingredients, such as parabens, phthalates and UV filters, and also their ability to cause reproductive impairments [3–6], these substances are still extensively used and characterized as Bsafe^. The main justification is the fact that manufacturers keep the concentrations of the suspected chemical substances low in accordance with the relevant legislation. However, the possibility of combination effects (synergism, additivity, inhi- bition) due to the presence of more than one endocrine

* Polyxeni Nicolopoulou-Stamati [email protected]

1 School of Medicine, Department of Pathology, MSc BEnvironment and Health. Capacity Building for Decision Making^, National and Kapodistrian University of Athens, 75 Mikras Asias Str, 11527 Athens, Greece

2 Vlaamse Instelling voor Technologisch Onderzoek (VITO), Boeretang 200, B2400 Mol, Belgium

3 Epidemiology for Cancer Prevention, Team on HIV, Cancer and Global Health, Inserm U 897 - Epidemiology and Biostatistics, Bordeaux Segalen University, 146 rue Leo Saignat, 33076 Bordeaux cedex, France

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disruptor must be taken into consideration, because theoretically-safe doses of single chemicals cannot be guaran- teed harmless in real-world cases of exposure to chemical mixtures [7]. Moreover, endocrine disruptors often show com- plex dose-effect relationships, impairing extrapolation [8, 9].

Endocrine disruptors change the normal function of the endocrine system, causing serious health problems, and the endpoints of concern include - among others - devel- opmental effects, reproductive impairments and infertility, male and female cancers, neurological disorders, and also effects on the immune system [6, 10–19]. Exposure to endocrine-disrupting chemicals begins in utero, and expo- sure at critical developmental stages (embryo, fetus, peri- natal, juvenile, puberty) is extremely significant in terms of the severity of the health outcome [14, 20–22]. As stated in the literature, a broad range of these endocrine disruptors seems to challenge estrogen receptors, resulting in the development of various diseases [23]. Moreover, in ligand-receptor studies, several of these environmental compounds demonstrated a molecular structure similar to natural ligands, and that makes their binding to nuclear receptors possible, inhibiting or activating their response [24]. These nuclear receptors can serve as targets for en- vironmental contaminants due to the presence of a hydro- phobic pocket that acts as a docking site, which these molecules have a certain affinity for. The majority of these endocrine-disrupting contaminants are not chemical- ly related to natural hormones, making the prediction of their action difficult [23].

The skin is the main route of exposure, through the appli- cation of body creams, e.g. sunscreens. Absorption of chemicals is possible, and the health of the skin is one deter- mining factor in the effectiveness of the skin barrier [25–27]. Furthermore, exposure is possible through inhalation, as in the case of hairsprays and fragrances that may contain phthalates, and also through ingestion, as in the case of lipsticks [25, 28].

The current review aims at highlighting the probable im- pact of cosmetics as endocrine disruptors. For this purpose, the groups of parabens, phthalates, perfluorinated chemicals, and UV filters will be addressed, together with the commonly- appearing ingredients of Bisphenol A, Triclosan, and alumin- ium salts.

2 Cosmetic ingredients

Cosmetic products contain numerous substances that are not directly related to their desired effects, but are included mainly for their stabilization and preservation properties, and also to enhance the absorption of the product through the skin [29–33]. Herein, the ingredients appearing on the labels of cosmetic products will be covered regarding their probable effects on the endocrine system.

2.1 Parabens

Parabens (p-hydroxybenzoic acid esters) are effective antimi- crobial agents used extensively in many products, including cosmetics such as antiperspirants, body creams and sunscreens [34]. Cosmetic products are the major source of human expo- sure to these preservatives [35]. Furthermore, a recent study with young adults found that the urinary concentration in women was two times greater than that in men [36]. The most common parabens are propylparaben (chemical formula: C10H12O3 [37]), methylparaben (chemical formula: C8H8O3 [37]), ethylparaben (chemical formula: C9H10O3 [37]), and butylparaben (chemical formula: C11H14O3 [37]). Although parabens are usually on the list of ingredients on the product packaging, there are products on the market that contain these agents but do not include them on the list of ingredients [34].

Parabens display endocrine-disrupting activity both in vitro and in vivo, and they have been associated with impairments of the reproductive system of male experimental animals [4, 35, 38, 39]. Evidence exists showing that these endocrine- disrupting chemicals can cause DNA damage and affect the mitochondrial function [40], and there are concerns regarding a possible mitochondrial connection between parabens and male infertility [41]. Parabens have been found intact in hu- man breast tumours [42], and their ability to increase the pro- liferation of human breast cancer cells has been confirmed in vitro [43]. However, current scientific knowledge is insuf- ficient to demonstrate a clear cancer risk due to the topical application of cosmetics containing parabens in the underarm area, and the controversy about the use of parabens and cancer risk is ongoing [35, 43, 44].

2.2 Phthalates

Phthalates are present in many everyday products due to their multi-functionality as they can serve variously as plasticizers, vehicles for fragrances in cosmetic products, lubricants and solvents [45–47]. The term Bfragrance^ or Bparfum^ is written on the labels of the majority of cosmetic products, and the composition of these substances, which may contain phthalates, is a trade secret and it is dealt accordingly [2]. Cosmetics usually use low molecular phthalates such as diethyl phthalate (DEP, chemical formula: C12H14O4 [37]), dimethyl phthalate (DMP, chemical formula: C10H10O4 [37]), and dibutyl phthalate (DBP, chemical formula: C16H22O4 [37]). Many other phthalates such as the di-(2- ethylexhyl) phthalate (DEHP, chemical formula: C24H38O4 [37]) can also be detected in the final products, as a result of a possible migration from the plastic package or due to the manufacturing processes [48].

Phthalates are known for their endocrine-disrupting poten- tial, their ability to cause oxidative stress, embryonic develop- mental problems, reproductive impairments, and

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neurobehavioral effects in experimental animals [46, 49–53]. Regarding human exposure to phthalates and their metabo- lites, there is evidence that prenatal and infant exposure, e.g. through breast milk [54], may be associated with cognitive, mental and behavioral effects such as lower IQ indices, preg- nancy loss, hyperactivity, attention problems, problematic so- cial communication, as well as with negative effects on the normal development of the reproductive system [46, 47, 54–57]. Furthermore, male infants are likely to be more vul- nerable to phthalates and their metabolites than female infants [54–56]. Evidence points to a possible association between phthalate exposure and low sperm quality, decreased concen- trations of sex and thyroid hormones, precocious puberty, obesity, breast cancer, and also effects on adult remembering condition [5, 46, 58–60]. Moreover, it should be noted that an in vitro study has revealed the ability of phthalate mixtures to induce increases in the proliferation of colorectal adenocarci- noma cells [61].

2.3 Perfluorinated chemicals

Perfluorinated Chemicals (PFCs) are water, grease, stain and dirt repellents used in a great variety of everyday products, including cosmetics such as lotions and nail polishes. Two of the most common PFCs are perfluorooctanoic acid (PFOA, chemical formula: C8HF15O2 [37]) and perfluorooctane sulfo- nate (PFOS, chemical formula: C8HF17O3S [37]), the health risks of which may have been largely underestimated [62].

These ubiquitous chemicals have been detected in human breast milk samples and also in umbilical cord blood samples [63]. PFCs in vitro interfere with the function of sex hormone receptors [64], and can also enter thyroid cells [65]. It has been shown that the in utero exposure to PFOS is negatively corre- lated with the birth weight of human female infants [66], and a possible connection between human sub-fecundity and PFCs has been suggested [67]. Furthermore, there is increased sci- entific concern about the effects of PFCs on normal human thyroid function and on concentrations of thyroid hormones [63, 68, 69]. There is also evidence that PFOA may have carcinogenic potential [63, 70].

2.4 Aluminium salts

Aluminium salts are the antiperspirant agents in underarm cos- metics that are applied onto the skin very frequently, leading to continuous dermal exposure [71–74]. Aluminium (Al) is a metalloestrogen [71, 72, 74], and it has neurotoxic potential [75, 76]. Furthermore, a recent in vitro study demonstrated that Al can inhibit human acetylcholinesterase, an enzyme partici- pating in cholinergic neurotransmission [77]. There are con- cerns that Al may play a role in the neuropathology of Alzheimer’s disease, and the probable connection between chronic exposure to Al and Alzheimer’s disease is a matter of

ongoing controversy [76, 78, 79]. There is also evidence of the ability of Al to cause problems to the osseous system, bone pain and fatigue [75, 80]. Aluminium has been detected in both normal breast tissue and malignant lesions [81, 82], and there are studies that suggest that the long-term use of aluminium- based cosmetics applied topically near the breasts may be a risk factor in the etiopathology of breast cancer [71, 74].

2.5 Triclosan

Triclosan (5-Chloro-2-(2,4-dichlorophenoxy)phenol, chemi- cal formula: C12H7Cl3O2 [37]) is a common antimicrobial agent that may act as thyroid agonist [83]. It is used in per- sonal care products, deodorants, toothpastes, hand soaps, dishwashing detergents, plastics and fabrics and other prod- ucts [84]. Its ubiquity can be confirmed by its presence in household dust [85], and also in human plasma and breast milk samples [86].

In humans, exposure to triclosan has been associated with earlier breast development [83]. Furthermore, its endocrine- disrupting activity has been confirmed in vivo in experimental animals [87, 88] and in vitro in human breast cancer cells [89]. Furthermore, it has been proven that triclosan can affect the concentration of thyroid hormones in juvenile male rats [90]. Another worrying factor is dioxin formation after photodegradation of Triclosan in wastewater, freshwater and also seawater [91, 92] which constitutes a potential hazard to aquatic life.

2.6 Bisphenol a (BPA)

Bisphenol A (BPA, chemical formula: C15H16O2 [37]) is a well-known endocrine disruptor used mainly in the plastics industry, for example in the production of soft plastic toys [93–95]. In cosmetics, it serves as an antioxidant agent [95]. BPA can migrate from plastic packaging and contaminate the contents [96, 97], and in Europe, the use of BPA in infant feeding bottles and cosmetics is forbidden [1, 98].

In vivo studies with experimental animals showed that BPA may be associated with reproductive impairments, such as morphological changes and problematic spermatogenesis, neurological effects, alterations on the normal body weight, and carcinogenic effects [93, 99–101]. Regarding exposure to BPA and probable human health outcomes, there is evidence for serious health impairments that requires more investiga- tion and confirmation. For instance, there are concerns about probable association between BPA and male infertility, cancer of the reproductive system, polycystic ovarian syndrome, di- abetes, and problematic behaviour in children [94, 96, 100, 101]. It should be mentioned that a study has suggested that exposure to BPA during gestation tended to affect the behav- ioural and emotional parameters of female rather than male children observed in the third year of life [102].

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2.7 UV filters

Sunscreens and other cosmetics such as makeup products and lipsticks contain UV filters that either absorb or block solar UV radiation (respectively, organic chemical absorbers and inorganic UV filters, i.e. the nanoparticles of the metal oxides TiO2 and ZnO) [103–105]. In vivo and in vitro studies have demonstrated the ability of many organic chemical absorbers to display endocrine-disrupting activity and cause reproduc- tive impairments, and there is also evidence that the nanopar- ticles of the metal oxides may display similar activity [6, 106].

2.7.1 Organic UV filters

Common organic chemical absorbers are benzophenone com- pound oxybenzone (2-hydroxy-4-methoxybenzophenone, benzophenone-3, chemical formula: C14H12O3 [37]), octyl methoxycinnamate (ethylhexyl methoxycinnamate, octinoxate, chemical formula: C18H26O3 [37]), 4- methylbenzylidene camphor (enzacamene, chemical formula: C18H22O [37]), and 3-benzylidene camphor (chemical formu- la: C17H20O [37]). The endocrine-disrupting activity of these organic filters has been confirmed in vitro in human estrogen receptor alpha and androgen receptor assays [107].

Oxybenzone is present in human breast milk samples [108], and maternal exposure has been associated with an increase in birth weight in boys and a decrease in birth weight in girls [109], and also with delayed breast development in girls [83]. Furthermore, it has been confirmed in vivo in fish that oxybenzone can down-regulate alpha estrogen receptors and androgen receptors [110], affect egg production and hatching percentage [111]; it can also cause an increase in uterine weight in immature rats [112], reductions in weight in mice offspring and increases in the mortality rates of lactat- ing dams [113].

Octyl methoxycinnamate is another organic UV filter which has been confirmed present in human breast milk [108]. In vivo studies in experimental animals have revealed probable impacts on the normal function of the hypothalamic- pituitary-thyroid axis leading to decreases in concentrations of various hormones [114], reproductive disorders such as delays in offspring sexual maturation [115], increases in uterine weight [112], and also neurological disorders [116].

Furthermore, the in vivo ability of 4-methylbenzylidene camphor to disrupt the endocrine function has been confirmed in rats, in aquatic organisms [117–119], and also in insects [120]. Exposure of rats to this sunscreen filter can increase uterine and thyroid weight [118], delay male puberty and af- fect sexual behaviour in female offspring [121].

The ability of the UV filter 3-benzylidene camphor to cause endocrine and reproductive impairments has been demonstrat- ed in rats [118, 121], in fish [122, 123], and in aquatic mol- luscs [119]. Exposure in rats affects male puberty, female

sexual behaviour, oestrous cycles and uterine weight [118, 121]. Furthermore, exposure of fish to 3-benzylidene camphor has been associated with reproductive impairments, feminiza- tion of male sex characteristics and fertility issues [123].

There are limited data on other organic UV filters regarding their potential to cause endocrine and reproductive impair- ments. For instance, there is evidence that exposure of preg- nant rats to the filter PABA (4-Aminobenzoic acid, chemical formula: C7H7NO2 [37]) may slightly affect body mass devel- opment in rat foetuses [124]. Limited evidence may suggest that other organic UV filters do not act as endocrine disruptors, but the limited data cannot guarantee safety and more investigation is needed to identify possible health risks.

2.7.2 Nanoparticles of metal oxides

The nanoparticles of titanium dioxide (TiO2) and zinc oxide (ZnO) have replaced the large-scale forms that produced a less aesthetically-acceptable result when applied to the skin [125]. Oxidative stress and their probable transport through the pla- cental barrier leading to foetal exposure are two health issues that have been associated with their use [126, 127]. Since nanoparticles do not belong to a particular homogenous chem- ical group, the health risk assessment of these cosmetic ingre- dients may have to be based on case-by-case testing [128].

ZnO nanoparticle aggregates can affect reproduction in fish [129]. An in vivo study with fish has also demonstrated that ZnO nanoparticles can more easily bio-accumulate as com- pared to the large-scale forms [130]. In vivo studies have also revealed that the exposure of experimental animals to TiO2 nanoparticles can disrupt pregnancy progression [131], affect reproductive parameters such as sperm characteristics [131, 132], and the genital and cranial nervous systems [133].

3 Discussion

Cosmetics have been used for centuries and not always with safe ingredients. In antiquity, even though the substances used in cosmetics were natural and not man-made, such as mercury and lead, some were toxic [134, 135], and there was under- standable ignorance of their toxic effects, in contrast with today. Ancient Greek civilization admired the classic beauty of the Venus de Milo, and it is obvious that she never used cosmetics (Fig. 1).

There is ample evidence that correlates exposure to endo- crine disruptors with impairments of the reproductive system, metabolic disorders, neurological problems, disturbance of the hypophysal-thyroid-genital axis, effects on the fetus, cancer, and other endpoints of endocrine disruption [14, 15, 18, 136–138]. The cosmetic industry uses many barely- regulated chemical substances in cosmetic products, of which a significant number are associated with endocrine disruption.

376 Rev Endocr Metab Disord (2015) 16:373–383

It is recognized that cosmetics constitute a significant part of our exposure to chemicals. Even though there are efforts, based on databases of chemical substances used in cosmetic products, to inform the consumers, such as certain websites (for instance: Skin Deep – Cosmetics Database: http://www. ewg.org/skindeep/, and Clean Makeup: http://web.colby.edu/ cleanmakeup/) and the application FoxTox for smartphones (http://www.edc-free-europe.org/smart-fox-toxfox-app-helps- consumers-detect-edcs-in-cosmetics/), the information does not reach all consumers, raising the serious issue of unintentional exposure and the subsequent ethical questions.

The impact of endocrine disruptors on health is a subject that requires improved testing and deeper knowledge for the identification of endocrine-acting chemicals as, certainly, there are knowledge gaps requiring supporting environments for creative innovation and disease prevention. Of course, reduc- ing exposure would alleviate adverse health effects resulting from the use of cosmetic products. However, current lifestyles preclude this, and the need for safer chemicals is urgent. As a result of scientific uncertainty regarding the subject [15, 139], consensus statements have been published [140]. An issue of paramount importance is the exposure of pregnant women,

foetuses and embryos to endocrine-disrupting chemicals. The results of early-life exposure to endocrine disruptors can ap- pear later in life, as in the case of testicular dysgenesis syn- drome [141–143]. Other concerns include the possible in- creased risk of Polycystic Ovary Syndrome development [142, 144]. The effects on future generations starting even before their birth need to be thoroughly addressed.

Cosmetic ingredients are emerging pollutants; their envi- ronmental monitoring is at a very early stage. However, it is known that they reach the environment in multiple ways, often through water, posing health risks to marine and freshwater ecosystems and to humans, e.g. through the contamination of drinking water sources and the food chain [145–148]. The environmental metabolic pathways are multiple and complex. Wastewater treatment plants are unable to remove endocrine disruptors totally [146], and barely alleviate the problem of their distribution throughout the environmental compart- ments, or of the exposure to them, taking into account that endocrine-disrupting chemicals display non-monotonic dose responses [9, 149, 150]. Endocrine disruptors end up in natu- ral ecosystems, for instance through wastewater treatments plants, water used to rinse the human body, and also landfill leachate as may occur with the residues inside cosmetic prod- ucts’ packaging [145, 146, 151]. The organic contaminants (many of them have confirmed endocrine-disrupting ability), their metabolites and their degradation compounds have dif- ferent physicochemical properties that affect their fate, behav- iour and transport in natural ecosystems. For instance they can undergo hydrolysis, and photolysis induced by sunlight, as in the case of Triclosan, of which the photolytic degradation leads to dioxin formation [3, 91, 92]. Furthermore, their pos- sible ability to bio-accumulate in the fatty tissues of fish [145], and the presence of cosmetic ingredients in marine mussels [152], and the ability of the UV filters to cause coral bleaching [153] are important factors that reveal an emerging environ- mental hazard which is incompletely understood.

The health effects of endocrine-disrupting chemicals in cosmetics and their impact on public health in particular are currently incompletely understood. Only some of the chemicals used in the industry have been tested for their effects on the endocrine system. Human metabolic and en- vironmental pathways are known to exist, but have only been partially defined. Information on dose-effect relation- ships in this context is scant, and the human-wildlife health nexus is incompletely understood. In spite of these uncer- tainties, it is well known that a healthy endocrine system is essential for the reproduction of humans and wildlife. Moreover, its impairment affects a cascade of related func- tions. Concern is raised about the high incidence and the increasing trends of endocrine-related disorders in humans and wildlife. The combination of these most significant, par- tially irreversible health effects and the attendant uncertainty calls for a precautionary approach. In addition, calculating

Fig. 1 Cosmetics that Venus de Milo never used

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the costs of the health effects of endocrine-disrupting chemicals in cosmetics is not an exact science [154]. Furthermore, the use of alternatives of natural origin should not be considered totally safe. Many of these substances have estrogenic activity, and also act as endocrine disruptors [72, 155–157]. However, the use of natural alternatives might alleviate the use of synthetic chemicals.

We live in a challenging world in which we have to make choices. Being prudent and informed is an attitude that so- ciety is obliged to adopt. Nevertheless, one must not forget the continuous development of new substances replacing the old, hopefully with less adverse effects, but without ade- quate research on their safety. Life-cycle analysis contributes to eco-design and green labels. Rigorously-applied environ- mental management systems in the cosmetics industry con- tribute to its corporate social responsibility. The more gen- eralized application of these instruments will contribute to the safer use of cosmetic products. Along with the industry, public authorities have a pivotal role in precaution. The re- lease of new cosmetics should be more thoroughly regulat- ed. We should be less sensitive to marketing-driven strate- gies, usually organized by powerful lobbying machines. Furthermore, we should register, combine and evaluate all the relevant public and environmental evidence concerning new cosmetics. Awareness-raising campaigns with the active participation of the health sector might increase our knowl- edge on a likely underestimated environmental health prob- lem [10, 158, 159].

4 Conclusions

It is extremely difficult to design studies in societies that will give a clear indication whether chemicals included in cos- metics are acting as endocrine disruptors in all exposed human beings. Even though we have studies addressing the subject in vitro and in vivo in experimental animals, extrapolation the results to humans always needs special attention, as it is diffi- cult to incorporate both the different personal exposure pattern of each cosmetics user, and also the genetic predisposition of each individual [160, 161]. Therefore, the study of endocrine- disrupting activity, especially after the Delaney Clause and the banning of animal testing [1, 162–164], rests on population- based data collection, and as such, any relevant information will take a long time before it reaches the interested party. Despite the knowledge gaps and the complexity of the issue, it seems that there is enough evidence that exposure to cos- metics is a matter of concern, and citizens should be informed. As cosmetics are a significant part of the body chemical bur- den [35, 165, 166], there is a strong need for safer industrial technologies, transparent information for the safe use of the products, and consumer awareness in the frame of the precau- tionary principle [8, 167].

Acknowledgments We wish to thank Sotirios Maipas for his help in the editing and careful reading of the text, Bart Hens for his advice, and Craig Morrison for his contribution to the final editing of the manuscript.

Compliance with ethical standards

Conflict of interest The authors declare no conflict of interest. The manuscript was not supported by any grant or sponsorship.

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