**Table 3.**

#### *Endocrine Disrupting Chemicals in Cosmetics and Personal Care Products and Risk… DOI: http://dx.doi.org/10.5772/intechopen.93091*

first alarmed scientific community about the potential effect of PCPs in breast cancer, suggesting that underarm cosmetic use might increase breast cancer. In fact, they detected a variety of EDCs including PBs in breast tumors, with higher concentrations in those samples from the axilla region, suggesting that their concentrations might be related to the application of deodorant products, body lotions, sprays, moisturizers, and sunscreen products in areas close to the human breast. However, current evidence on the relationship between cosmetic/PCP use and risk of cancer is not very conclusive. In this regard, in a case-control study comprised by 209 cases of breast cancer and 209 healthy controls, Linhart and Talasz [62] reported that the greater use of underarm cosmetic products was associated with increased risk of breast cancer. Contrary, a cohort study did not found any association between use of skincare products and risk of cancer of the breast and endometrium [63]. Another study carried out by McGrath [64] reported that those women with a higher use of antiperspirant products were diagnosed with breast cancer at an earlier age. Furthermore, it has been observed that long-term exposure to body care creams containing ethinyl estradiol may increase the risk of abnormal genital bleeding and breast cancer [65]. Interestingly, a case-report study found that synthetic hormones found in lotions used by the mother were present in very high concentrations in the hair of the girl [66].

However, the variety of products and differences in dosage, patterns of use, and individual susceptibility to specific product formulations pose great difficulties to detect a potential effect of cosmetic and PCP habits on human adverse effects [36, 61, 67–69]. Thus, the use of internal burden of EDCs seems to better reflect the magnitude of cosmetic and PCP use, independently of the type of product used or the dose applied. In this regard, urinary levels of PBs have been related to greater risk for breast cancer [70]. Some studies have also addressed the potential association between exposure to PCP-released EDCs and the origin and development of other female diseases. In this regard, the presence of trace levels of PBs was found in endometrial tissue samples suspected of being related to an increased risk of endometrial carcinoma [71]. Levels of PrP were also related to diminished ovarian reserve in a prospective cohort study of the US women seeking fertility treatment [72]. Regarding the development of sex characteristics during puberty, a recent study observed associations between levels of PBs and earlier development of the breasts and the pubic hair in girls. Moreover, earlier menarche was also related to higher levels of PBs [73].

Regarding BPs, *in vitro* studies have shown that exposure to BPs in rats and mice has been related to feminized sexual behavior and increased uterine weight [39, 74]. Two *in vivo* studies have also demonstrated the disturbance caused by BP in ovarian tissue [75, 76]. Santamaría and Abud [75] found that exposure to BP-1 and BP-3 disrupted early events in ovarian cells, such as germ cell development and disruption of crucial gene expression related to follicular assembly. Similarly, Shin and Go [76] reported the induction of BP-dependent metastasis in an *in vivo* model for ovarian cancer. Moreover, an epidemiological study has reported that urinary BP levels might be associated with blood pressure during pregnancy [77]. Similarly, higher BP levels were related to thyroid hormones and growth factors in pregnant women, as well as to reduced fetal growth [74].

Other hormonally active chemicals widely used in cosmetics are phthalates. Exposure to various congeners has been associated with the appearance of various female diseases. Exposure to di-(2-ethylhexyl) phthalate has been linked to an increased risk of preterm delivery [78–80] and intrauterine growth restriction [81]. Furthermore, it has also been associated with reduced total oocyte yield and a reduced probability of achieving pregnancy and live birth [82]. Other phthalate congeners, such as monoethyl phthalate and dibutyl phthalate, have also been linked to decreased fertility in women [79, 83].

*Endometriosis*

as endometriosis [54, 55].

**3. Potential adverse effects of EDC exposure**

at least in part, EDCs might induce oxidative stress via estrogen receptor-α signaling pathways [52]. Moreover, EDC exposure has also been evidenced to trigger an inflammatory microenvironment [50, 53]. With an intimate relationship, both oxidative and inflammatory responses have also been suggested as crucial mechanisms beyond a variety of chronic diseases, as well as some gynecological conditions such

The consequences of exposure to EDCs seem to be different depending on age and gender (**Table 3**). In the case of men, EDC exposure is suspected to cause alterations in the development of the genitourinary system including cryptorchidism, testicular cancer, and infertility [56, 57]. Among women, the increase in hormone-dependent cancers (either breast or ovarian) [56] as well as uterine fibroids and endometriosis might also be related to inadvertent exposure to EDCs. Moreover, chronic conditions such as metabolic syndrome and its components (obesity, insulin resistance, hypertension, or dyslipidemia), neurobehavioral development disorders, and poor thyroid function are also on the list of possible effects of EDC exposure. In particular, in utero exposure to EDCs is believed to have consequences of such magnitude that they would hardly be suspected in studies of adult individuals. For example, in utero exposure to some EDCs has been linked to increased risk for breast cancer or endometriosis [58, 59]. This association gives maternal exposure some very particular peculiarities and places women of child-

bearing age in the limelight of most studies on endocrine disruption.

Over the years and in parallel with the change in people's habits and lifestyle, numerous evidence has revealed that cosmetics could cause a variety of disease conditions in humans. For instance, women are suspected to have a greater risk for some chronic conditions such as obesity and metabolic syndrome than men [60], and in addition to physiological differences between genders, the greater female consumption of cosmetics and PCPs might also underlie this enhanced risk. Moreover, the consumption of cosmetics and PCPs might also be beyond the development of female-specific diseases such as breast or ovarian cancer. In this regard, Darbre [61]

**3.1 Use of cosmetics and PCPs and feminine diseases**

**32**

**Table 3.**

*Some adverse effects of EDCs in humans.*

#### *Endometriosis*

Several investigations have also suggested the potential association between BPA exposure and adverse outcomes in women. For instance, it has been shown that elevated serum or urine BPA levels are associated with anovulation [84], lower antral follicle counts [85, 86], preterm birth [87]**,** and infertility [88]. Moreover, increasing urinary BPA levels were associated with delayed menarche in adolescent girls [89, 90]. Furthermore, higher BPA levels have been associated with an increased risk of developing polycystic ovary syndrome [84, 91–93], ovarian failure [94], infertility [95]**,** and fibroids [96, 97]. Triclosan, widely present in soaps, detergents, and toothpaste, has also been related to decreased fertility [98], although the currently available evidence is scarce.

#### **3.2 Associations between PCP- and cosmetic-released EDCs and endometriosis**

As mentioned above, detectable levels of PBs and BPs have been detected in endometrial tissue and menstrual blood [29, 71]. Trace levels of intact PBs were predominantly detected in endometrial carcinoma tissues (23%) in contrast to normal endometrium samples (2%), and thus, authors suggested that they might be related to an increased risk of endometrial carcinoma [71]. On the other hand, several PBs and BPs have been detected in menstrual blood samples, a biological sample in intimate contact with the endometrium [29]. Moreover, these menstrual blood concentrations of PBs and BPs were related to the magnitude of use of creams and cosmetics, evidencing that these EDCs from cosmetics and PCPs are capable of reaching a wide variety of biological matrices and thus might orchestrate, or at least contribute, to the development and progression of multiple gynecological diseases such as endometrial cancer and endometriosis.

Concerning endometriosis, the origin of endometriosis still remains unclear. To date, although various theories have been postulated to give a possible explanation for the origin of endometriosis [99–105], none of them consistently explains the onset and progression of the disease in deeper stages. Currently, it is known that it is a multifactorial disease in which genetic, epigenetic, immunological, hormonal, and environmental factors are involved [106]. Due to the suspected increase in the number of cases in the last decades [107], it is suspected that, in addition to the increased awareness among doctors and patients, environmental risk factors are suspected to also contribute to the onset and progression of this disease. This environmental hypothesis of the origin of the disease is also reinforced due to the estrogen-dependent nature of this pathology [53, 108].

Despite the growing public concern about human risks derived from the use of PCPs and cosmetics, there is little evidence on their influence on endometriosis (**Table 4**). To our knowledge, only one study has investigated the relationship between EDCs released from sunscreens and endometriosis. Concentrations of 2-hydroxy-4-methoxybenzophenone, 2,4-dihydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, 2,2′,4,4′-tetrahydroxybenzophenone, and 4-hydroxi-benzophenone were analyzed in urine samples collected from 600 women. The results obtained suggest that exposure to elevated levels of 2,4-dihydroxybenzophenone (BP-3) may be associated with a higher probability of a diagnosis of endometriosis [109]. As authors mentioned, these findings denoted an approximate 65% increase in the odds of an endometriosis diagnosis in women with the highest BP-3 concentration compared to women with lower concentrations.

Regarding BPA exposure, a recent meta-analysis revealed limited and contradictory epidemiological evidence regarding the contribution of BPA in the risk for endometriosis [110]. Thus, despite few studies have reported an absence of association between urinary levels of BPA and disease [111, 112], others reported increased risk for endometriosis [53, 113–115]. Even more, it has been recently suggested that

**35**

**Table 4.**

*Endocrine Disrupting Chemicals in Cosmetics and Personal Care Products and Risk…*

levels of oxidative stress might act as a mediation effect on the association between exposure to bisphenols and endometriosis risk [53]. Furthermore, exposure to BPA has not only been related to the onset of endometriosis, but it might be also involved in the progression of the disease [112, 114]. Moreover, these findings are supported by different experimental studies. In this sense, recent *in vivo* studies have evidenced in mouse models that exposure to bisphenols in adulthood was related to an increase in the growth of endometrial lesions and the number of atretic oocytes, the interruption of the ovarian steroidogenic pathway, an increase in periglandular fibrosis, and the upregulation of matrix remodeling enzymes [108, 116]. Another *in vivo* study revealed that prenatal exposure to BPA and other bisphenols caused a phenotype similar to endometriosis [117]. These experimental studies suggest that exposure to

*Studies exploring associations between exposure to cosmetics- and PCPs-released EDCs and endometriosis.*

BPA could be related to the development and progression of endometriosis.

*DOI: http://dx.doi.org/10.5772/intechopen.93091*

*Endocrine Disrupting Chemicals in Cosmetics and Personal Care Products and Risk… DOI: http://dx.doi.org/10.5772/intechopen.93091*


#### **Table 4.**

*Endometriosis*

Several investigations have also suggested the potential association between BPA exposure and adverse outcomes in women. For instance, it has been shown that elevated serum or urine BPA levels are associated with anovulation [84], lower antral follicle counts [85, 86], preterm birth [87]**,** and infertility [88]. Moreover, increasing urinary BPA levels were associated with delayed menarche in adolescent girls [89, 90]. Furthermore, higher BPA levels have been associated with an increased risk of developing polycystic ovary syndrome [84, 91–93], ovarian failure [94], infertility [95]**,** and fibroids [96, 97]. Triclosan, widely present in soaps, detergents, and toothpaste, has also been related to decreased fertility [98],

**3.2 Associations between PCP- and cosmetic-released EDCs and endometriosis**

As mentioned above, detectable levels of PBs and BPs have been detected in endometrial tissue and menstrual blood [29, 71]. Trace levels of intact PBs were predominantly detected in endometrial carcinoma tissues (23%) in contrast to normal endometrium samples (2%), and thus, authors suggested that they might be related to an increased risk of endometrial carcinoma [71]. On the other hand, several PBs and BPs have been detected in menstrual blood samples, a biological sample in intimate contact with the endometrium [29]. Moreover, these menstrual blood concentrations of PBs and BPs were related to the magnitude of use of creams and cosmetics, evidencing that these EDCs from cosmetics and PCPs are capable of reaching a wide variety of biological matrices and thus might orchestrate, or at least contribute, to the development and progression of multiple gynecological diseases

Concerning endometriosis, the origin of endometriosis still remains unclear. To date, although various theories have been postulated to give a possible explanation for the origin of endometriosis [99–105], none of them consistently explains the onset and progression of the disease in deeper stages. Currently, it is known that it is a multifactorial disease in which genetic, epigenetic, immunological, hormonal, and environmental factors are involved [106]. Due to the suspected increase in the number of cases in the last decades [107], it is suspected that, in addition to the increased awareness among doctors and patients, environmental risk factors are suspected to also contribute to the onset and progression of this disease. This environmental hypothesis of the origin of the disease is also reinforced due to the

Despite the growing public concern about human risks derived from the use of PCPs and cosmetics, there is little evidence on their influence on endometriosis (**Table 4**). To our knowledge, only one study has investigated the relationship between EDCs released from sunscreens and endometriosis. Concentrations of 2-hydroxy-4-methoxybenzophenone, 2,4-dihydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, 2,2′,4,4′-tetrahydroxybenzophenone, and 4-hydroxi-benzophenone were analyzed in urine samples collected from 600 women. The results obtained suggest that exposure to elevated levels of 2,4-dihydroxybenzophenone (BP-3) may be associated with a higher probability of a diagnosis of endometriosis [109]. As authors mentioned, these findings denoted an approximate 65% increase in the odds of an endometriosis diagnosis in women with the highest BP-3 concentration compared to women with lower concentrations. Regarding BPA exposure, a recent meta-analysis revealed limited and contradictory epidemiological evidence regarding the contribution of BPA in the risk for endometriosis [110]. Thus, despite few studies have reported an absence of association between urinary levels of BPA and disease [111, 112], others reported increased risk for endometriosis [53, 113–115]. Even more, it has been recently suggested that

although the currently available evidence is scarce.

such as endometrial cancer and endometriosis.

estrogen-dependent nature of this pathology [53, 108].

**34**

*Studies exploring associations between exposure to cosmetics- and PCPs-released EDCs and endometriosis.*

levels of oxidative stress might act as a mediation effect on the association between exposure to bisphenols and endometriosis risk [53]. Furthermore, exposure to BPA has not only been related to the onset of endometriosis, but it might be also involved in the progression of the disease [112, 114]. Moreover, these findings are supported by different experimental studies. In this sense, recent *in vivo* studies have evidenced in mouse models that exposure to bisphenols in adulthood was related to an increase in the growth of endometrial lesions and the number of atretic oocytes, the interruption of the ovarian steroidogenic pathway, an increase in periglandular fibrosis, and the upregulation of matrix remodeling enzymes [108, 116]. Another *in vivo* study revealed that prenatal exposure to BPA and other bisphenols caused a phenotype similar to endometriosis [117]. These experimental studies suggest that exposure to BPA could be related to the development and progression of endometriosis.

#### *Endometriosis*

Other EDCs found in cosmetics and PCPs are phthalates. Several studies have explored the existing associations between exposure to these chemicals and endometriosis, showing conflicting results. One of the very first investigations reported higher concentrations of phthalates in women with a confirmed diagnosis of endometriosis [118]. Similarly, two studies evidenced an increased risk of endometriosis in women with higher levels of mono (2-ethylhexyl) phthalate [111, 119]. Conversely, few studies did not found any association between levels of urinary levels of any phthalate congener and enhanced risk for endometriosis [112, 120–122].

Currently, there are no studies that have explored the possible contribution of other EDCs released from cosmetics and PCPs (such as parabens, oxycinnamates, camphenes, and dimethicones) and the risk of endometriosis. Moreover, the combined effect of EDCs released from these products on endometriosis has not been addressed yet.

### **4. Conclusions**

To date, there is still very limited evidence on the potential role of EDCs released from cosmetics and PCPs on the origin and development of endometriosis. In general terms, *in vitro*, *in vivo,* and epidemiological evidence is consistent with the endocrine-disrupting hypothesis set out in this chapter, indicating that EDCs might be in the causal pathway that leads to endometriosis. Nevertheless, in all published studies, the particular effect of specific EDCs was measured, without taking into account the possible synergistic or antagonistic effect that these chemicals can exert when they are present in a mixture. Thus, because its diagnosis is difficult and its treatment is mainly symptomatic, it is vitally necessary to establish preventive measures to avoid as far as possible the origin of this disease. Therefore, it is necessary to carry out well-conducted studies, with appropriate sample size and in which the "gold-standard" diagnosis serves to distinguish between cases and controls. Moreover, the combined effect of multiple EDCs on endometriosis should be addressed. These studies are needed to fully elucidate the potential disrupting properties of these PCP-released EDCs in the gynecological tissues. In this way, preventive measures could be established, the chemical composition of PCPs could be modified by other substances that are not endocrine disruptors, or the use of these cosmetics could be reduced as far as possible.

### **Acknowledgements**

This work was supported by a grant from the Spanish Ministry of Health-FEDER (FIS PI17/01743) and the Research Chair "Antonio Chamorro/Alejandro Otero." It was also partly supported by the European Union Commission (the European Human Biomonitoring Initiative H2020-EJP-HBM4EU) and the Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP). The authors are also grateful to the Carlos III Institute of Health (ISCIII) for the predoctoral research contracts (IFI18/00052 and FI17/00316) granted to F.M. Peinado and L.M. Iribarne-Durán, respectively, and the José María Segovia de Arana contract granted to N. Olea (INT18/00060).

**37**

**Author details**

Spain

Spain

*Endocrine Disrupting Chemicals in Cosmetics and Personal Care Products and Risk…*

Francisco M. Peinado1†, Luz M. Iribarne-Durán1†, Olga Ocón-Hernández1,2,

1 Biohealth Research Institute in Granada (ibs.GRANADA), Granada, Spain

4 CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain

5 Nuclear Medicine Unit, "San Cecilio" University Hospital, Granada, Spain

2 Obstetrics and Gynecology Service, San Cecilio University Hospital, Granada,

3 Radiology and Physical Medicine Department, University of Granada, Granada,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Nicolás Olea1,3,4,5 and Francisco Artacho-Cordón1,3,4\*

\*Address all correspondence to: fartacho@ugr.es

† These authors equally contributed to this work.

provided the original work is properly cited.

*DOI: http://dx.doi.org/10.5772/intechopen.93091*

#### **Conflict of interest**

The authors declare no conflict of interest.

*Endocrine Disrupting Chemicals in Cosmetics and Personal Care Products and Risk… DOI: http://dx.doi.org/10.5772/intechopen.93091*
