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Exposure to Benzophenone-3 and Reproductive Toxicity: A Systematic Review of Human and Animal Studies
Abstract
Hydroxy-4-methoxybenzophenone, also known as benzophenone-3 (BP-3), is a commonly used ultraviolet filter in skincare and as a food additive. Large concentrations of similar phenolic compounds have been detected in urine, amniotic fluid, and placental tissue, thereby raising questions about its impact on reproduction. The objective of this paper was to investigate the reproductive toxicity of BP-3 in humans and animals. In humans, studies showed that high levels of BP-3 exposure could be linked to an increase in male birth weight but a decline in female birth weight and male gestational age. In fish, BP-3 exposure resulted in a decline in egg production, hatching, and testosterone, along with a down-regulation of steroidogenic genes. In rats, a decrease in epididymal sperm density and a prolonged estrous cycle for females was observed. These positive associations may be attributed to an altered estrogen and testosterone balance as a result of endocrine disrupting effects of BP-3. However, the current body of literature is limited by non-uniform exposure and outcome measurements in studies both across and within species and future studies will need to be conducted in a standardized fashion to allow for a more significant contribution to the literature that allows for better comparison across studies.
... In freshwater environments such as lakes and rivers, varying concentrations of BP-3 were found in different countries, such as 620 ng/L in the Czech Republic (Grabicova et al. 2013), 284-577 ng/L in China (Tsui et al. 2014), 24 ng/L in Switzerland (Poiger et al. 2004), 9-10 ng/L in the United Kingdom (Kasprzyk-Hordern, Dinsdale, and Guwy 2009), 0.5-1258 ng/L in Japan (Tashiro and Kameda 2013), and 10-100 ng/L in Brazil (Silva, Emídio, and Marchi 2013). Further, Geissen et al (2015) noted that these chemicals are not frequently monitored, a paucity of data on global human exposure (Mao et al. 2022), and these compounds may exert adverse effects on aquatic and human life (Gavrila et al. 2023;Ghazipura et al. 2017;Mustieles et al. 2023;Sung et al. 2024). Based upon these observations, benzophenones and NPs used in sunscreens are considered emerging pollutants, resulting from both point and diffuse pollution present in the aquatic environment (Geissen et al. 2015;Juliano and Magrini 2017;Mustieles et al. 2023;Petrie, Barden, and Kasprzyk-Hordern 2015;Tovar-Sánchez et al. 2013). ...
... Zhang et al. 2023). Animal and in vitro studies demonstrated that BP-3 influenced reproduction and sex hormone signaling at concentrations from 16 µg/L (Coronado et al. 2008;Ghazipura et al. 2017;). Previously, dos Santos Almeida et al. (2019 demonstrated that BP-3, at the same concentrations used in this investigation, produced (1) genotoxic and mutagenic effects, (2) initiated circulatory disorders, (3) as well as regressive and immunological changes in the gills of freshwater fish Poecilia reticulata. ...
The increasing use of UV filters, such as benzophenone-3 (BP-3) and titanium dioxide nanoparticles (TiO2 NPs), has raised concerns regarding their ecotoxicological effects on the aquatic environment. The aim of the present study was to examine the embryo-larval toxicity attributed to BP-3 or TiO2 NPs, either alone or in a mixture, utilizing zebrafish (Danio rerio) as a model after exposure to environmentally relevant concentrations of these compounds. Zebrafish embryos were exposed to BP-3 (10, 100, or 1000 ng/L) or TiO2 NPs (1000 ng/L) alone or in a mixture (BP-3 10, 100, or 1000 ng/L plus 1000 ng/L of TiO2 NPs) under static conditions for 144 hr. After exposure, BP-3 levels were determined by high-performance liquid chromatography (HPLC). BP-3 levels increased in the presence of TiO2 NPs, indicating that the BP-3 degradation decreased in the presence of the NPs. In addition, in the presence of zebrafish, BP-3 levels in water decreased, indicating that zebrafish embryos and larvae might absorb BP-3. Data demonstrated that, in general, environmentally relevant concentrations of BP-3 and TiO2 NPs, either alone or in a mixture, did not significantly induce changes in heart and spontaneous contractions frequencies, levels of reactive oxygen species (ROS), morphological and morphometric parameters as well as mortality rates during 144 hr exposure. However, the groups exposed to TiO2 NPs alone and in a mixture with BP-3 at 10 ng/L exhibited an earlier significant hatching rate than the controls. Altogether, the data indicates that a potential ecotoxicological impact on the aquatic environment exists.
... On the other hand, it is known that BPs have a strong harmful effects on terrestrial mammals. The majority of previous studies concerning this issue have been conducted on rodents and have shown that BPs affect blood hormone levels and hematological parameters, have adverse effect on the nervous system, and disrupt the functioning of the female and male reproductive systems [60][61][62]. ...
... Furthermore, the information is inconclusive. Some studies have shown differences in BP-3 metabolism between rats and mice [20, 60,62,86,87], while other research has found that generally BP-3 metabolism in rats and mice is rather similar with only minor differences [88]. ...
Benzophenones (BPs) are substances used in the production of sunscreens, cosmetics, and personal care products. However, there is a lack of knowledge of BPs in wild animals. Therefore, the study aimed to assess the concentration of selected BPs commonly used in the cosmetic industry in guano samples collected from 4 colonies of greater mouse-eared bats (Myotis myotis). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to determine guano concentrations of benzophenone 1 (BP-1), benzophenone 2 (BP-2), benzophenone 3 (BP-3) and benzophenone 8 (BP-8). BP-1 levels above the method quantification limit (MQL) were noted in 97.5% of samples and fluctuated from <0.1 ng/g to 259 ng/g (mean 41.50 ng/g, median 34.8). The second most common was BP-3, which fluctuated from <0.1 ng/g to 19 ng/g (mean 6.67 ng/g, median 5.05), and its levels higher than MQL were observed in 40% of samples. BP-2 and BP-8 concentrations did not exceed the method detection limit (0.04 ng/g) in any analyzed sample. There were visible differences in the BP-1 and BP-3 levels among the studied bat colonies. Mean BP-1 concentration fluctuated from 11.23±13.13 ng/g to 76.71±65.51 ng/g and differed significantly between the colonies. Mean BP-3 concentration fluctuated from 5.03±6.03 ng/g to 9.18±7.65 mg/g, but it did not differ significantly between the colonies. The results show that guano is a suitable matrix for the assessment of wildlife exposure to BPs. This could be particularly advantageous in protected species, where not disturbing and stressing the animals are crucial.
... Among them, endocrine-disrupting chemicals (EDCs) that may mimic and alter the function of hormones, have become a particular concern. Benzophenones (BPs) are one of the EDCs 2,3 which are incautiously used as UV filters in personal care products (PCPs) and plastic packaging 4 . Benzophenones are also applied as flavouring ingredients, for the stabilization of odour, in sleeping tablets as well as in printing factories (IARC 2014) 5 . ...
... Many studies on the biological monitoring of BP metabolites have been performed in different countries, however, studies on pregnant women and their neonates are not extensive. It has been reported that BPs can alter the hormonal balance and interrupt the evolution of the reproductive system of the fetus 4,20,21 . ...
Widespread use of benzophenones (BPs), a group of environmental phenolic compounds, is suspected of interfering with human health. The association of prenatal exposure to benzophenone derivatives with birth outcomes including birth weight and length, head, arm and thoracic circumference, abnormalities, corpulence index and anterior fontanelle diameter (AFD) was investigated. Mother-infant pairs of 166 within PERSIAN cohort population in Isfahan, Iran, in the 1st and 3rd trimesters of pregnancy were assessed. Four common benzophenone metabolites including 2,4-dihydroxy benzophenone (BP-1), 2-hydroxy-4-methoxy benzophenone (BP-3), 4-hydroxy benzophenone (4-OH-BP) and 2,2′-dihydroxy-4-methoxy benzophenone (BP-8) were measured in maternal urine samples. The median concentration of 4-OH-BP, BP-3, BP-1 and BP-8 were 3.15, 16.98, 9.95 and 1.04 µg/g Cr, respectively. In the 1st trimester, 4-OH-BP showed a significant correlation with AFD in total infants, decreasing 0.034 cm AFD per a log unit increase of 4-OH-BP. Within the male neonates, 4-OH-BP in the 1st and BP-8 in the 3rd trimester were significantly associated with head circumference and AFD increase, respectively. Among female neonates in the 3rd trimester, increasing 4-OH-BP and BP-3 concentration was correlated with a decrease in birth weight and AFD, respectively. This study demonstrated that all the target BP derivatives can influence normal fetal growth at any age of the pregnancy, nevertheless, to support these findings further studies are needed in a large and different group population.
... Particularly worrisome are the subtle effects on neurohormonal programing and the abnormalities in all endocrine and metabolic systems showing up in later life. Reports link soluble UV filters to disorders of puberty, infertility, endometriosis [34,35,36], and metabolic disorders and various cancers in both sexes [27,37]. ...
... After 70 years of use there is no evidence of safety or efficacy, perhaps for a simple reason -they are not. Extensive reviews document the diverse adverse effects in humans [37] and wildlife [39]. No BENEFIT only RISK. ...
Review and analysis of the science related to the toxicity of Soluble Organic UV Filters (SOUVF) and the data from global skin cancer statistics and published papers that provide evidence that they do not prevent skin cancer in the general population.
They are all bioavailable to human cells - even those in the fetus and brain. Their potential and proven toxicity are replete in the published literature. We work to advance the imperative that they are contraindicated for use in anyone, particularly in expectant or nursing mothers, young or adolescent children, and couples trying to conceive. We advocate that their continued use is arguably a violation of Medicine's First Rule ( Primum Non Nocere or First Do No Harm) and The Precautionary Principle. For no Benefit- they have polluted humans and the entire global environment
... BP-1 and BP-3 are chemicals with a short half-life (in the order of hours to days) that are rapidly excreted into urine. Both show estrogenic and anti-androgenic activity in vitro, and there is concern about their reproductive toxicity in rodents (Ghazipura et al., 2017;Kim and Choi, 2014). Although benzophenones constitute one of the best-known UV filter families, knowledge gaps still remain. ...
... A possible explanation could be the efficient anti-PGE2 activity shown by BP-3 in humans (Jannesson et al., 2004) that may mediate increased pregnancy length or delayed cervical ripening (Chatterjee et al., 1991), consequently increasing birth weight. Notwithstanding, we are not aware of a mechanism that could explain the opposing association between boys and girls, which could also be explained in terms of altered estrogen-androgen balance (Ghazipura et al., 2017). Comparison with rodent studies is complex, since they are not considered an optimal model for birth outcomes (Ferguson and Chin, 2017). ...
Background
Benzophenone-3 (BP-3) and its major metabolite benzophenone-1 (BP-1) are widely used as UV filters in sunscreens and cosmetics to prevent sunburn and skin damage, or as stabilizers to prevent photodegradation in many commercial products. As a result, their presence is ubiquitous in the environment, wildlife and humans. Based on endocrine disruption concerns, international regulatory agencies are performing a closer evaluation.
Objective
and Methods: This work aimed to comprehensively review the available human relevant evidence for safety issues in MEDLINE/PubMed in order to create a structured database of studies, as well as to conduct an integrative analysis as part of the Human Biomonitoring for Europe (HBM4EU) Initiative.
Results
A total of 1,635 titles and abstracts were screened and 254 references were evaluated and tabulated in detail, and classified in different categories: i) exposure sources and predictors; ii) human biomonitoring (HBM) exposure levels to perform a meta-analysis; iii) toxicokinetic data in both experimental animals and humans; iv) in vitro and in vivo rodent toxicity studies; and v) human data on effect biomarkers and health outcomes. Our integrative analysis showed that internal peak BP-3 concentrations achieved after a single whole-body application of a commercially available sunscreen (4% w/w) may overlap with concentrations eliciting endocrine disrupting effects in vitro, and with internal concentrations causing in vivo adverse female reproductive effects in rodents that were supported by still limited human data. The adverse effects in rodents included prolonged estrous cycle, altered uterine estrogen receptor gene expression, endometrium hyperplasia and altered proliferation and histology of the mammary gland, while human data indicated menstrual cycle hormonal alterations and increased risk of uterine fibroids and endometriosis. Among the modes of action reported (estrogenic, anti-androgenic, thyroid, etc.), BP-3 and especially BP-1 showed estrogenic activity at human-relevant concentrations, in agreement with the observed alterations in female reproductive endpoints. The meta-analysis of HBM studies identified a higher concern for North Americans, showing urinary BP-3 concentrations on average 10 and 20 times higher than European and Asian populations, respectively.
Discussion
and Conclusions: Our work supports that these benzophenones present endocrine disrupting properties, endorsing recent European regulatory efforts to limit human exposure. The reproducible and comprehensive database generated may constitute a point of departure in future risk assessments to support regulatory initiatives. Meanwhile, individuals should not refrain from sunscreen use. Commercially available formulations using inorganic UV filters that are practically not absorbed into systemic circulation may be recommended to susceptible populations.
... However, BP3 may reduce egg production, hatching, and testosterone levels in fish. 66 In addition, it is recognized as an endocrine disruptor that can produce a number of reproductive adverse effects in humans, including sex-dependent alterations in birth weight and gestational age, as well as decreased epididymal sperm density in male rats and a longer estrous cycle in female rats. 66 Furthermore, BP3 has been linked to mammary gland cancer. ...
... 66 In addition, it is recognized as an endocrine disruptor that can produce a number of reproductive adverse effects in humans, including sex-dependent alterations in birth weight and gestational age, as well as decreased epididymal sperm density in male rats and a longer estrous cycle in female rats. 66 Furthermore, BP3 has been linked to mammary gland cancer. 67 BP and EHS were more frequently detected in kittiwake eggs (BP: 35%; median 1.0 ng/g; mean 1.6 ± 0.2 ng/g; EHS: 20%, median 0.24 ng/g; mean 0.5 ± 0.1 ng/g), compared to fulmar (BP: 9%; EHS: 12%) and murre eggs (BP: 15%; EHS: not detected) (Figure 2). ...
Ultraviolet (UV) absorbents and industrial antioxidants are contaminants of emerging concern (CECs), but little is known about their distribution in Arctic wildlife, as well as how these contaminants vary over time, across regions, and between species. We used archived egg samples to examine the temporal patterns of 26 UV absorbents and industrial antioxidants in three seabird species (black-legged kittiwakes Rissa tridactyla, thick-billed murres Uria lomvia, northern fulmars Fulmarus glacialis) sampled in Arctic Canada between 1975 and 2019. Various synthetic phenolic antioxidants, aromatic secondary amines, benzotriazole UV stabilizers, and organic UV filters were detected in the seabird eggs. Overall, kittiwakes had higher levels of several UV absorbents and industrial antioxidants. Most target contaminants reached their peak concentrations at different points during the 44-year study period or did not vary significantly over time. None of these contaminant concentrations have increased in recent years. The antioxidant 2-6-di-tert-butyl-4-methylphenol (BHT) was the most frequently detected contaminant in seabird eggs, and its level significantly declined over the course of the study period in kittiwake eggs but did not change in the eggs of murres and fulmars. Future research should examine the effects of these CECs on the health of avian species, the sources, and exposure pathways of these contaminants.
... It has been indicated that active ingredients of commercial sunscreens can be toxic to humans and coral reefs [8][9][10][11], which has increased the interest in using phytochemicals in sunscreen formulations [12][13][14][15][16][17]. Phytochemicals are genoprotective and anticancer agents [18,19] that are considered to be non-toxic and pharmacologically safe for human consumption [13]. ...
... As in the previous studies [17,[31][32][33], our data support the use of DNA damage detection assay (in this case, the SOS Chromotest) as an effective complement that improves the efficacy of photoprotection measurement. As we indicated in the Introduction, some organic ingredients of commercial sunscreens can be toxic to humans and coral reefs [8][9][10], with inorganic filters (i.e., titanium dioxide or zinc oxide) being a safer alternative [11]. At photoprotective concentrations, the extracts were relatively less cytotoxic than a commercial sunscreen (Eau Thermale Avène SPF 50+), and its active ingredient (titanium dioxide) was used for comparison. ...
Plants are sources of sunscreen ingredients that prevent cellular mutations involved in skin cancer and aging. This study investigated the sunscreen properties of the extracts from some ornamental plants growing in Colombia. The UV filter capability of the flower extracts obtained from Rosa centifolia L., Posoqueria latifolia (Rudge) Schult, and Ipomoea horsfalliae Hook. was examined. Photoprotection efficacies were evaluated using in vitro indices such as sun protection factor and critical wavelength. UVB antigenotoxicity estimates measured with the SOS Chromotest were also obtained. Extract cytotoxicity and genotoxicity were studied in human fibroblasts using the trypan blue exclusion and Comet assays, respectively. Major compounds of the promising flower extracts were identified by UHPLC-ESI+-Orbitrap-MS. The studied extracts showed high photo-protection efficacy and antigenotoxicity against UVB radiation, but only the P. latifolia extract showed broad-spectrum photoprotection at non-cytotoxic concentrations. The P. latifolia extract appeared to be safer for human fibroblast cells and the R. centifolia extract was shown to be moderately cytotoxic and genotoxic at the highest assayed concentrations. The I. horsfalliae extract was unequivocally cytotoxic and genotoxic. The major constituents of the promising extracts were as follows: chlorogenic acid, ecdysterone 20E, rhamnetin-rutinoside, cis-resveratrol-diglucoside, trans-resvera-trol-diglucoside in P. latifolia; quercetin, quercetin-glucoside, quercetin-3-rhamnoside, kaempferol, kaempferol-3-glucoside, and kaempferol-rhamnoside in R. centifolia. The potential of the ornamental plants as sources of sunscreen ingredients was discussed.
... Several studies have reported that UV filters have endocrine-disrupting effects, including estrogenic, androgenic, and thyroid activities [51][52][53][54]. Ghazipura et al. stated that BP-3 can be absorbed through topical application, and humans often ingest it through water intake [55]. Therefore, Tang et al. investigated reproductive toxicity in pregnant women prenatally exposed to BP-3. ...
Overexposure to ultraviolet radiation mainly leads to skin disorders (erythema, burns, immunosuppression), skin aging, and skin cancer as the most serious side effect. It has been widely accepted that using sunscreen products is an important way to protect against the harmful effects of UV rays. Although commercial sunscreens have constantly changed and improved over time, there are emerging concerns about the safety of conventional, organic, UV filters due to adverse effects on humans (such as photoallergic dermatitis, contact sensitivity, endocrine-disrupting effects, etc.) as well as accumulation in the environment and aquatic organisms. This is why natural compounds are increasingly being investigated and used in cosmetic and pharmaceutical sunscreens. Some of these compounds are widely available, non-toxic, safer for use, and have considerable UV protective properties and less side effects. Plant-based compounds such as flavonoids can absorb UVA and UVB rays and possess antioxidant, anticarcinogenic, and anti-inflammatory effects that contribute to photoprotection. Apart from flavonoids, other natural products such as certain vegetable oils, carotenoids, stilbenes, and ferulic acid also have UV-absorbing properties. Some vitamins might also be beneficial for skin protection due to their antioxidant activity. Therefore, the aim of this research was to gain insight into the potential of natural compounds to replace or reduce the amount of conventional UV filters, based on recent research.
... However, most epidemiological, and experimental observations are limited to BP-3, and the available information is scattered over different experimental models, with a focus on specific toxicological outcomes and with little emphasis on underlying mechanisms. Moreover, knowledge on endocrine disruption is mostly related to sex hormones and reproduction (Ghazipura et al., 2017;Krause et al., 2012). Thyroid hormones (THs) are essential for the proper development and physiological functions of vertebrates (McAninch and Bianco, 2014), and hence the thyroid system is tightly regulated by the hypothalamicpituitary-thyroid (HPT) axis (Fekete and Lechan, 2014). ...
... The active substances for sunscreens that are widely used in the market are avobenzone and benzophenone. However, both compounds can penetrate the skin and thus might be absorbed into the systemic blood flow (Matta et al., 2020), disrupt the hormonal system (Ghazipura et al., 2017), and reduce testosterone quality (Scinicariello & Buser, 2016). Moreover, most sunscreen products have to be re-applied to ensure their activity lasts longer, which makes it less efficient for consumers. ...
3,4-Dimethoxychalcone and rutin, a flavonoid that contains chromophore groups, can absorb UV light and thus can be developed as a sunscreen. The objective of this study was to determine the optimum formula of 3,4-dimethoxychalcone and rutin containing gel, evaluate its physical stability, and activity of 3,4-dimethoxychalcone and rutin gel as a sunscreen through in vitro and in vivo tests. HPMC, CMC-Na, and methylcellulose were formulated into a gel base to obtain good adhesion and a clear appearance gel. Simplex Lattice Design (SLD) with Design Expert software version 10 was utilized to determine the optimum gel formulation. UVA-PF protection, photostability with transpore method, and acute dermal irritation test were performed to evaluate sunscreen activity of 3,4-dimethoxychalcone and rutin gel. The data were analyzed using SPSS version 25. The results showed that the optimum formula for 3,4-dimethoxychalcone-rutin gel consisted of 1.5% HPMC, 1.8% CMC-Na and 0.6% methylcellulose, which showed a pH of 6.96, viscosity of 89.10 dpa.s, and spreadability of 16.30 cm 2. The pH, viscosity, and spreadability of base and 3,4-dimethoxychalcone-rutin gel was stable for 4 weeks of storage. The UVA-PF value is 6.48 which according to the FDA is included in the category of a two star (**) sunscreen label. The sunscreen did not exhibit a shift in wavelength after 6 hours of irradiation. Based on the primary irritation test, 3,4-dimethoxychalcone-rutin sunscreen produced zero (0) erythema and edema index. Thus, it did not cause irritation to the skin of experimental animals. Therefore, the gel containing 3,4-dimethoxychalcone and rutin had potential as a sunscreen product based on in vitro-in vivo tests and was safe on animal skin.
... These concerns encompass its hormone-disrupting properties, potential for photoallergic reactions, and associated environmental risks. [10][11][12][13] White blood cells (WBCs), along with their subtypes such as neutrophils and lymphocytes, have proven to be valuable biomarkers for assessing physiological toxicity of substances and cell damage. 14,15 A recent study in zebrafish revealed the effects of BP-3 on WBC subtypes but not on the total WBC count. ...
Background
Evidence from animal models suggests a role for the organic ultraviolet filter benzophenone‐3′s (BP‐3) on white blood cells (WBCs). However, BP‐3′s effect on WBCs in humans is unknown.
Materials and Methods
We used National Health and Nutrition Examination Survey data from 2003 to 2016. We included participants >6 years with data on urinary BP‐3, urinary creatinine, and WBC count. Quintiles of urinary creatinine‐normalized BP‐3 (CnBP‐3) levels were used in linear regression models adjusting for age, gender, race, body mass index (BMI), smoking status, education level, family income to poverty threshold ratio, survey cycle, and season.
Results
Of the 16 959 participants, 8564 (50.5%) were females, 6602 (38.9%) were White, and 3870 (22.8%) were Black. The mean (standard deviation) age was 37.6 (22.7) years, BMI was 26.8 (7.40) kg/m², WBC count was 7.22 (2.53) × 10⁹/L, neutrophil count was 4.15 (1.86) × 10⁹/L, and lymphocyte count was 2.25 (1.33) × 10⁹/L and median (interquartile range) of CnBP‐3 was 12.1 (44.9) µg/gm. The highest quintile of CnBP‐3 was associated with significantly lower WBC and neutrophil counts compared to the lowest quintile of CnBP‐3 (Δ quintiles = −137 × 10⁶/L, 95% CI: −249 to −24, p = 0.02 and = −177 × 10⁶/L, 95% CI: −323 to −30, p = 0.02, respectively). In contrast, we did not observe a difference in lymphocyte count between the lowest and highest quintiles of CnBP‐3 in unadjusted or adjusted analyses.
Conclusion
We found an inverse relationship between BP‐3 levels and WBC and neutrophil counts, and not with lymphocyte count. Further research is needed to confirm our findings.
... UV filters including AVO have high lipid solubility, and have molecular masses below 500 da, so they can pass through the blood-tissue barrier [6]. Among the UV filters, 3-benzylidene camphor (3-BC) was found in the brain of rats after dermal application [7], Benzophenone-3 (BP-3) was found in human placental samples [8]. Moreover, 2-Hydroxy-4-methoxybenzophenone (HMB) has been detected in urine and semen samples from male volunteers who applied sunscreen containing HMB [9]. ...
... be available. In a revision, Ghazipura et al. (2017) analyzed the toxicity effects of BP-3 on fish, and the exposure resulted in reduced egg production, hatching rate, and testosterone levels, along with a downregulation of steroidogenic genes. Zebrafish larvae in contact with sediment containing BP-3 (10 μg.g − 1 ) for 96 h presented reduced cardiac frequency and increased standard metabolic rate (Lucas et al., 2021). ...
... The active substances for sunscreens that are widely used in the market are avobenzone and benzophenone. However, both compounds can penetrate the skin and thus might be absorbed into the systemic blood flow (Matta et al., 2020), disrupt the hormonal system (Ghazipura et al., 2017), and reduce testosterone quality (Scinicariello & Buser, 2016). Moreover, most sunscreen products have to be re-applied to ensure their activity lasts longer, which makes it less efficient for consumers. ...
3,4-Dimethoxychalcone and rutin, a flavonoid that contains chromophore groups, can absorb UV light and thus can be developed as a sunscreen. The objective of this study was to determine the optimum formula of 3,4-dimethoxychalcone and rutin containing gel, evaluate its physical stability, and activity of 3,4-dimethoxychalcone and rutin gel as a sunscreen through in vitro and in vivo tests. HPMC, CMC-Na, and methylcellulose were formulated into a gel base to obtain good adhesion and a clear appearance gel. Simplex Lattice Design (SLD) with Design Expert software version 10 was utilized to determine the optimum gel formulation. UVA-PF protection, photostability with transpore method, and acute dermal irritation test were performed to evaluate sunscreen activity of 3,4-dimethoxychalcone and rutin gel. The data were analyzed using SPSS version 25. The results showed that the optimum formula for 3,4-dimethoxychalcone-rutin gel consisted of 1.5% HPMC, 1.8% CMC-Na and 0.6% methylcellulose, which showed a pH of 6.96, viscosity of 89.10 dpa.s, and spreadability of 16.30 cm2. The pH, viscosity, and spreadability of base and 3,4-dimethoxychalcone- rutin gel was stable for 4 weeks of storage. The UVA-PF value is 6.48 which according to the FDA is included in the category of a two star (**) sunscreen label. The sunscreen did not exhibit a shift in wavelength after 6 hours of irradiation. Based on the primary irritation test, 3,4-dimethoxychalcone- rutin sunscreen produced zero (0) erythema and edema index. Thus, it did not cause irritation to the skin of experimental animals. Therefore, the gel containing 3,4-dimethoxychalcone and rutin had potential as a sunscreen product based on in vitro-in vivo tests and was safe on animal skin.
... UVAs have been widely detected in environmental matrices such as water (Castilloux et al., 2022), sediment (Peng et al., 2017b), biota (Peng et al., 2017a), and human tissues including milk (Kim et al., 2019) and placenta (Valle-Sistac et al., 2016). Exposure to UVAs may lead to various adverse effects, such as the disruption of reproductive behavior (Ghazipura et al., 2017;Zhuang et al., 2017), the activation of aryl hydrocarbon receptor-mediated toxicities (Nagayoshi et al., 2015), the perturbation of the thyroid system (Fent et al., 2014;Liang et al., 2017), in fish and mammals. Therefore, UVAs have sparked increasing environmental concern. ...
... Estrogenic and anti-androgenic pathways 115 No rodent data investigating effects on social behavior. One study exposed pregnant mice subcutaneously for 10 d with a moderate BP-3 dose, showing increased neural apoptosis and altered estrogenic signaling in offspring brains, including decreased gene expression and protein levels of ERa and ERb, with a simultaneous increase in GPR30 membrane receptor expression. ...
Background:
Previous studies aiming at relating exposure to phenols and phthalates with child social behavior characterized exposure using one or a few spot urine samples, resulting in substantial exposure misclassification. Moreover, early infancy exposure was rarely studied.
Objectives:
We aimed to examine the associations of phthalates and phenols with child social behavior in a cohort with improved exposure assessment and to a priori identify the chemicals supported by a higher weight of evidence.
Methods:
Among 406 mother-child pairs from the French Assessment of Air Pollution exposure during Pregnancy and Effect on Health (SEPAGES) cohort, 25 phenols/phthalate metabolites were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (∼21 samples/trimester) and at 2 months and 1-year of age (∼7 samples/period). Social behavior was parent-reported at 3 years of age of the child using the Social Responsiveness Scale (SRS). A structured literature review of the animal and human evidence was performed to prioritize the measured phthalates/phenols based on their likelihood to affect social behavior. Both adjusted linear regression and Bayesian Weighted Quantile Sum (BWQS) regression models were fitted. False discovery rate (FDR) correction was applied only to nonprioritized chemicals.
Results:
Prioritized compounds included bisphenol A, bisphenol S, triclosan (TCS), diethyl-hexyl phthalate (ΣDEHP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). With the exception of bisphenols, which showed a mixed pattern of positive and negative associations in pregnant mothers and neonates, few prenatal associations were observed. Most associations were observed with prioritized chemicals measured in 1-y-old infants: Each doubling in urinary TCS (β=0.78; 95% CI: 0.00, 1.55) and MEP (β=0.92; 95% CI: -0.11, 1.96) concentrations were associated with worse total SRS scores, whereas MnBP and ΣDEHP were associated with worse Social Awareness (β=0.25; 95% CI: 0.01, 0.50) and Social Communication (β=0.43; 95% CI: -0.02, 0.89) scores, respectively. BWQS also suggested worse total SRS [Beta 1=1.38; 95% credible interval (CrI): -0.18, 2.97], Social Awareness (Beta 1=0.37; 95% CrI: 0.06, 0.70), and Social Communication (Beta 1=0.91; 95% CrI: 0.31, 1.53) scores per quartile increase in the mixture of prioritized compounds assessed in 1-y-old infants. The few associations observed with nonprioritized chemicals did not remain after FDR correction, with the exception of benzophenone-3 exposure in 1-y-old infants, which was suggestively associated with worse Social Communication scores (corrected p=0.07).
Discussion:
The literature search allowed us to adapt our statistical analysis according to the weight of evidence and create a corpus of experimental and epidemiological knowledge to better interpret our findings. Early infancy appears to be a sensitive exposure window that should be further investigated. https://doi.org/10.1289/EHP11798.
... A premenopausal women. B Postmenopausal women As reviewed by Ghazipura et al. (2017), BP-3 exposure induced reproductive toxicity in animals and humans through alterations of estrogen and testosterone balance. In vitro studies, estrogenic and antiandrogenic activities of BP-3 were confirmed (Balazs et al., 2016). ...
Environmental phenols are well known as emerging endocrine-disrupting chemicals; however, their impacts on sex hormone homeostasis among pre- and postmenopausal women remain unknown. Our objective was to evaluate independent and combined relationships between phenol levels in urine and sex steroid hormones among 323 premenopausal women and 263 postmenopausal women from National Health and Nutrition Examination Survey (NHANES) 2015–2016. A total of 10 phenol concentrations in urine were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum concentrations of estradiol and total testosterone were measured by LC-MS/MS and serum sex hormone-binding globulin (SHBG) concentrations were measured using an immunofluorometric assay. Multivariable linear regression models were conducted to explore associations of individual phenol concentration in urine with natural logarithm-transformed serum hormone levels. Bayesian kernel machine regression (BKMR) model was conducted to evaluate phenol mixtures exposure in association with sex hormones among pre- and postmenopausal women, respectively. Considering both single-chemical models and multiple-chemical models, each doubling of urinary BPS concentration was significantly inversely related to serum SHBG concentration in premenopausal women (percent change: −6.70%, 95% confidence interval, CI: −11.12%, −2.73%; P = 0.002). Moreover, every doubling of urinary BP-3 concentration was significantly positively associated with SHBG level in serum (percent change: 3.53%, 95%CI: 0.70%, 5.70%; P = 0.008). Regarding postmenopausal women, inverse associations between urinary BPS levels and serum estradiol concentrations were observed (percent change: −8.62%, 95% CI: −15.33%, −2.06%; P = 0.012). The results revealed that BPS and BP-3 exposure may adversely disrupt sex hormone homeostasis at the current exposure levels among women in the USA. The findings and their underlying mechanisms are warranted to be confirmed and comprehensively interpreted in further epidemiological and experimental studies.
... In-vivo research studies on BP-3 effect on children's birth weight and gestational age [27] raised concerns about sunscreen's hormonal effects [28]. BP-3 also indicated proliferative effects on MCF-7 breast cancer cells [28]. ...
Sunscreen application is widespread and incorporated into daily life. Although FDA has approved 16 sunscreen ingredients, recent studies suggest a revaluation of their potential adverse effects. This systematic review assesses sunscreens’ percutaneous absorption, toxicity, and their ingredients concentration in urine and plasma. The search was conducted in Medline (PubMed), Scopus, Embase, and Cochrane until 05/08/2021. Data from 21 studies with related inclusion criteria were extracted. 18 studies reported sunscreen complications such as rash, irritation, immune system disorders, stratum corneum DNA damage, and hormonal disruption, 4 articles reported maximum concentration of sunscreen ingredients in plasma, and 4 articles reported urinary concentration of ingredients. In 2016, the FDA suggested a plasma concern level of 0.5 ng/mL for sunscreen ingredients. Sunscreen ingredients including avobenzone, octocrylene, ecamsule, homosalate, octisalate, enzacamene, octinoxate, and oxybenzone were detected more than 0.5 ng/mL after in blood 1-4 daily applications. Sunscreen application reduces the risk of sunlight harmful effects but could have advers effects related to their percutaneous penetration. Taken together, related data provide the impetus for detailed analysis of sunscreen toxicology. Also, highly adsorbed ingredients should be replaced with less adsorbed compounds to minimize body accumulation and the associated risks. Also, life time infant and children sunscreen exposure provide furthur impetus for in-depth toxicologic investigations
... As a traditional UV filter and oil-soluble compound, benzophenone-3 (BP-3) is normally directly mixed with the bulk material and thus are prone to be released to aqueous environment. In connection to some concerns about BP-3 as a chemical UV-filter in cosmetics, studies on acute and reproductive toxicities of BP-3 to human and animals were conducted and it is found that BP-3 generally presents low ecological risks [19][20][21]. Nevertheless, new restriction of using UV filters of BP-3 and octocrylene in cosmetic products has been proposed in amendments to Annex VI of the EU Cosmetics Regulation 1223/2009 in May of 2022 and expected to take effect in last quarter of 2022 [22]. ...
Benzophenone-3 grafted chitosan (CS-BP-3) was successfully synthesized and applied as an antibacterial coating for the first time. The grafting mechanism is based on the reaction between ketone and primary amine to form imine derivatives and the chemical structure of grafted chitosan was studied by Fourier transform infrared (FT-IR) spectroscopy. Water solubility of BP-3 is enhanced after covalently grafted on chitosan and consequently renders the chitosan coating with UV blocking property. Results of thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) further confirmed the thermal stability of BP-3 modified chitosan is enhanced. The CS-BP-3 coating was applied on a variety of substrates of glass, plastics, wood, and metal. The surface features of the coatings such as morphology, water contact angle (WCA), and surface roughness were investigated. The optical and thermal stabilities of the coatings under UV irradiation were studied for 16 h. Antibacterial activity of CS-BP-3 was evaluated against both Gram-negative and Gram-positive bacteria. And the results of bacterial inhibition by CS-BP-3 coating indicate its potential for future application in food packaging.
... On the other hand, some studies and reviews in the international literature show an association between exposure to different substances present in cosmetics (including phthalates, parabens, phenoxyethanol, triclosan, and benzophenone) and the risks of preterm birth, fetal growth restriction, congenital malformations, and neurodevelopmental impairment. 6,[44][45][46][47][48] Some questionnaire-based studies have suggested an association with the risk of congenital malformation in children. ...
We conducted a literature review focusing on the use and health effects of cosmetics, especially among pregnant and lactating women and young children. Based on these data, we propose clinical practice guidelines for health care professionals to use for informing and advising their patients. These include the recommendations that families: (1) reduce the number and the frequency of use (grade B) and the amount applied (expert consensus) of all cosmetic products during the perinatal period and among children; (2) prefer simple, fragrance‐free, and rinsable products, with short ingredient lists (expert consensus); and (3) for children, avoid industrial wipes and prefer water, with suitable soap when necessary.
... The adverse reactions to sunscreens include subjective irritation (stinging, burning), contact dermatitis and comedogenicity. The potential adverse effects induced by UV filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitarythyroid axis (HPT) [81,82]. ...
Due to the rapid growth of the cosmetic industry in recent years, the development of new, reliable, cost-effective, ease of use and rapid methods to assay cosmetics’ quality is of particular importance. Modern electrochemistry provides powerful analytical techniques with excellent sensitivity, instrumental simplicity and portability, providing reliable alternatives to conventional analytical methods. This review aims to give readers a clear view of advances in areas of electrode modification, successful strategies for signal amplification, and miniaturization techniques used in electroanalytical devices for cosmetics control and safety. We have summarized recent trends in the nonenzymatic electrochemical sensor systems applied in the analysis of cosmetic products revealing that there are a variety of efficient sensors for whitening agents, preservatives, UV filters, heavy metals, etc. In conclusion, current challenges related to the sensors design and future perspectives are outlined.
... Concentrated amount of fragrance inside the body can induce organ toxicity, hormonal disorder, reproductive disorder and cancer. 88,89 ...
Cosmetics are the products that are used to apply to our skin, face and hair every day and its uses are increasing around the world. The substance which are used to improve the appearance are comes under the category of cosmetics. In day-to-day life people are exposed to a great range of harmful chemicals in the form of cosmetics, from the various daily used products like dermal products, beauty products and hair products. These products are used to enhance the appearance or to maintain personal hygiene. Cosmetic products may contain various ingredients. Such substances improve the quality and shelf life of the products but may be toxic to human health. This review paper discusses the composition of various cosmetic products, their role, adverse effects and also highlights about the replacements of some of the harmful ingredients caused by cosmetic products based on the various scientific literature review.
... Triclosan is used as an antibacterial ingredient in soaps, cosmetics, toothpastes and other personal care products (Dann and Hontela, 2011). Benzophenone-3 is an ultraviolet radiation filter added to sunscreens, cosmetics and plastics since the 1970s (Dann and Hontela, 2011;Kim and Choi, 2014;Ghazipura et al., 2017). 2,4dichlorophenol is a metabolite of the common herbicide 2,4-dichlorophenoxyacetic acid, which has been in use since the 1940s (Kutz et al., 1992). ...
STUDY QUESTION
Are urinary phenol concentrations of methylparaben, propylparaben, butylparaben, triclosan, benzophenone-3, 2,4-dichlorophenol or 2,5-dichlorophenol associated with fecundability and early pregnancy loss?
SUMMARY ANSWER
2,5-dichlorophenol concentrations were associated with an increased odds of early pregnancy loss, and higher concentrations of butylparaben and triclosan were associated with an increase in fecundability.
WHAT IS KNOWN ALREADY
Phenols are chemicals with endocrine-disrupting potential found in everyday products. Despite plausible mechanisms of phenol reproductive toxicity, there are inconsistent results across few epidemiologic studies examining phenol exposure and reproductive function in non-fertility treatment populations.
STUDY DESIGN, SIZE, DURATION
Specimens and data were from the North Carolina Early Pregnancy Study prospective cohort of 221 women attempting to conceive naturally from 1982 to 1986. This analysis includes data from 221 participants across 706 menstrual cycles, with 135 live births, 15 clinical miscarriages and 48 early pregnancy losses (before 42 days after the last menstrual period).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Participants collected daily first-morning urine specimens. For each menstrual cycle, aliquots from three daily specimens across the cycle were pooled within individuals and analyzed for phenol concentrations. To assess sample repeatability, we calculated intraclass correlation coefficients (ICCs) for each phenol. We evaluated associations between phenol concentrations from pooled samples and time to pregnancy using discrete-time logistic regression and generalized estimating equations (GEE), and early pregnancy loss using multivariable logistic regression and GEE.
MAIN RESULTS AND THE ROLE OF CHANCE
ICCs for within-person variability across menstrual cycles in pooled phenol concentrations ranged from 0.42 to 0.75. There was an increased odds of early pregnancy loss with 2,5-dichlorophenol concentrations although the CIs were wide (5th vs 1st quintile odds ratio (OR): 4.79; 95% CI: 1.06, 21.59). There was an increased per-cycle odds of conception at higher concentrations of butylparaben (OR: 1.62; 95% CI: 1.08, 2.44) and triclosan (OR: 1.49; 95% CI: 0.99, 2.26) compared to non-detectable concentrations. No associations were observed between these endpoints and concentrations of other phenols examined.
LIMITATIONS, REASONS FOR CAUTION
Limitations include the absence of phenol measurements for male partners and a limited sample size, especially for the outcome of early pregnancy loss, which reduced our power to detect associations.
WIDER IMPLICATIONS OF THE FINDINGS
This study is the first to use repeated pooled measures to summarize phenol exposure and the first to investigate associations with fecundability and early pregnancy loss. Within-person phenol concentration variability underscores the importance of collecting repeated samples for future studies. Exposure misclassification could contribute to differences between the findings of this study and those of other studies, all of which used one urine sample to assess phenol exposure. This study also contributes to the limited literature probing potential associations between environmental exposures and early pregnancy loss, which is a challenging outcome to study as it typically occurs before a pregnancy is clinically recognized.
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (award number F31ES030594), the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project numbers ES103333 and ES103086) and a doctoral fellowship at the Yale School of Public Health. The authors declare they have no competing interests to disclose.
TRIAL REGISTRATION NUMBER
N/A.
... In our previous study (Cahova et al., 2021b), toxic effects of octinoxate on rainbow trout (Oncorhychus mykiss) were observed, including impaired antioxidant defence, changes in white blood cell counts, adverse effects on various metabolic pathways, and even histopathological changes, especially in liver cells. The ability of UVs to disrupt the hormonal system is also a current topic (Ghazipura et al., 2017;Zhou et al., 2019). Moreover, octinoxate is considered as an endocrine disruptor and listed in "The Watch List" of contaminants of emerging concern (CECs). ...
Ultraviolet filters are commonly used in various cosmetic products. Due to their huge consumption ultraviolet filters become a part of the environment. Octinoxate is a commonly used ultraviolet filter that is widely detected in the aquatic environment. In our study, we investigated whether this ultraviolet filter is able to disrupt thyroid hormone regulation after six weeks of exposure in rainbow trout (Oncorhynchus mykiss). Thyroid hormones play crucial role in development and regulation of the organism and its disruption could cause the whole-body imbalance. Our study includes a compilation of in vivo and in vitro tests. The results of the in vivo experiment revealed a significant increase in thyroxine hormone in plasma for the highest tested dose of octinoxate (i.e. 395.6 μg/kg). We examined selected tissues (liver and cranial kidney) to determine the mRNA expression of genes involved in thyroid hormones regulation. The analysis confirmed downregulation of deiodinase 2 mRNA expression for the highest tested dose (i.e. 395.6 μg/kg) and downregulation of paired box 8 mRNA for medium (96 μg/kg) and the highest octinoxate dose (395.6 μg/kg.) only in cranial kidney. In vitro analysis indicated that octinoxate does not elicit (anti-)thyroid activity via thrβ and does not behave as a transthyretin ligand. Based on our results, octinoxate has a potential to act as a thyroid hormone disruptor, but further research required to better understand the entire regulatory mechanism.
Endocrine disruptor chemicals (EDCs) are natural and synthetic compounds found ubiquitously in the environment that interfere with the hormonal-immune axis, potentially impacting human health and reproduction. Exposure to EDCs has been associated with numerous health risks, such as neurodevelopmental disorders, metabolic syndrome, thyroid dysfunction, infertility, and cancers. Nevertheless, the current approach to establishing causality between EDCs and disease outcomes has limitations. Epidemiological and experimental research on EDCs faces challenges in accurately assessing chemical exposure and interpreting non-monotonic dose response curves. In addition, most studies have focused on single chemicals or simple mixtures, overlooking complex real-life exposures and EDC mechanistic insights, in particular regarding their impact on the immune system. The ENDOMIX project, funded by the EU’s Horizon Health Program, addresses these challenges by integrating epidemiological, risk assessment, and immunotoxicology methodologies. This systemic approach comprises the triangulation of human cohort, in vitro, and in vivo data to determine the combined effects of EDC mixtures. The present review presents and discusses current literature regarding human reproduction in the context of immunotolerance and EDC mode of action. It further underscores the ENDOMIX perspective to elucidate the impact of EDCs on immune-reproductive health.
Endocrine-disrupting compounds (EDCs) are ubiquitous in soil, posing serious risks to soil biota, especially earthworms, which have been found to be affected by these compounds, despite not being their typical target organisms. Earthworms are essential for sustaining soil health and quality, by promoting soil aeration, organic matter decomposition and nutrient cycling, among other functions. This review synthesizes available literature evidencing the negative impact of EDC exposure, through traditional endocrine pathways and other toxicological mechanisms, on histopathological, biochemical, molecular and reproductive endpoints of earthworms. The compounds described, in the consulted literature, to induce histopathological, biochemical, genotoxicity and molecular and reproductive alterations include antibiotics, antimicrobial additives, flame retardants, fragrances, fungicides, herbicides, hormones, inorganic ions, insecticides, organic UV filters, parabens, perfluoroalkyl substances, pesticides, petroleum derivatives, plasticizers and polychlorinated biphenyls. These compounds reach soil through direct application or via contaminated organic amendments and water derived from potentially polluted sources. The findings gather in the present review highlight the vulnerability of earthworms to a broad spectrum of chemicals with endocrine disrupting capacity. Additionally, these studies emphasize the physiological disruptions caused by EDC exposure, underscoring the critical need to protect biodiversity, including earthworms, to ensure soil quality and ecosystem sustainability. Ongoing research has provided insights into molecular mechanisms responsive to EDCs in earthworms, including the identification of putative hormone receptors that exhibit functional similarity to those present in vertebrates. In conclusion, this review emphasizes the impact of EDCs in earthworms, especially through non-hormonal mediated pathways, and addresses the need for strong regulatory frameworks to mitigate the detrimental effects of EDCs on soil invertebrates in order to safeguard soil ecosystems.
Graphical abstract
This review aimed at summarizing some of the key points that were discussed during the photoprotection session at the International Forum of Dermatology in 2022. This international conference was designed to address prominent topics of clinical dermatology in a holistic way, allowing to articulate multiple viewpoints. Therefore, this review does not claim to be exhaustive, but is instead intended to give an overview of recent developments and ongoing controversies in the field of photoprotection. Cumulative ultraviolet radiation (UVR) exposure is the major aetiological factor in the development of photoageing, photoimunosuppression and photocarcinogenesis. UVA (320–400 nm) penetrates into the dermis and damages DNA and other intracellular and acellular targets primarily by generating reactive oxygen species (ROS). It is the major contributor to photoageing, characterized by fine and coarse wrinkles, dyspigmentation and loss of elasticity. UVB (290–320 nm) is responsible for sunburns through direct damage to DNA by the formation of 6–4 cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6–4 pyrimidone photoproducts. Both UVA and UVB exposure increase the risk of basal cell carcinoma, squamous cell carcinoma and melanoma. In recent years, visible light (VL; 400–700 nm) has also been implicated in the exacerbation of conditions aggravated by sun exposure such as hyperpigmentation and melasma. Photoprotection is a critical health strategy to reduce the deleterious effects of UVR and VL. Comprehensive photoprotection strategies include staying in the shade when outdoors, wearing photoprotective clothing including a wide‐brimmed hat, and sunglasses, and the use of sunscreen. Due to the absorption of UV filters, the safety of sunscreens has been questioned. Newer sunscreens are becoming available with filters with absorption even beyond the UV spectrum, offering enhanced protection compared with older products. Prevention of photocarcinogenesis, sun‐induced or sunlight‐exacerbated hyperpigmentary conditions and drug‐induced photosensitivity is an important reason for adopting comprehensive photoprotection strategies.
Few earlier reviews on emerging organic contaminants (EOCs) in drinking water systems (DWS) focused on their detection, behaviour, removal and fate. Reviews on multiple exposure pathways, human intake estimates, and health risks including toxicokinetics, and toxicodynamics of EOCs in DWS are scarce. This review presents recent advances in human intake and health risks of EOCs in DWS. First, an overview of the evidence showing that DWS harbours a wide range of EOCs is presented. Multiple human exposure to EOCs occurs via ingestion of drinking water and beverages, inhalation and dermal pathways are discussed. A potential novel exposure may occur via the intravenous route in dialysis fluids. Analysis of global data on pharmaceutical pollution in rivers showed that the cumulative concentrations (µg L-1) of pharmaceuticals (mean ± standard error of the mean) were statistically more than two times significantly higher (p=0.011) in South America (11.68±5.29), Asia (9.97±3.33), Africa (9.48±2.81) and East Europe (8.09±4.35) than in high-income regions (2.58±0.48). Maximum cumulative concentrations of pharmaceuticals (µg/L) decreased in the order; Asia (70.7) had the highest value followed by South America (68.8), Africa (51.3), East Europe (32.0) and high-income regions (17.1) had the least concentration. The corresponding human intake via ingestion of untreated river water was also significantly higher in low- and middle-income regions than in their high-income counterparts. For each region, the daily intake of pharmaceuticals was highest in infants, followed by children and then adults. A critique of the human health hazards, including toxicokinetics and toxicodynamics of EOCs is presented. Emerging health hazards of EOCs in DWS include; (1) long-term latent and intergenerational effects, (2) the interactive health effects of EOC mixtures and the challenges of multifinality and equifinality, and (3) the Developmental Origins of Health and Disease hypothesis. Finally, research needs on human health hazards of EOCs in DWS are presented.
Benzophenone ultraviolet light filters (BPs) are high-production-volume chemicals extensively used in personal care products, leading to widespread human exposure. Given their estrogenic properties, the potential health risks associated with exposure to BPs have become a public health concern. This review aims to summarize sources and pathways of exposure to BPs and associated health risks. Dermal exposure, primarily through the use of sunscreens, constitutes a major pathway for BP exposure. At a recommended application rate, dermal exposure of BP-3 via the application of sunscreens may reach or exceed the suggested reference dose. Other exposure pathways to BPs, such as drinking water, seafood, and packaged foods, contribute minimal to the overall dose. Inhalation is a minor pathway of exposure; however, its contribution cannot be ignored. Human exposure to BPs is an order of magnitude higher in North America than in Asia and Europe. Studies conducted on laboratory animals and cells have consistently demonstrated the toxic effects of BP exposure. BPs are estrogenic and elicit reproductive and developmental toxicities. Furthermore, neurotoxicity, hepatotoxicity, nephrotoxicity, and carcinogenicity have been reported from chronic BP exposure. In addition to animal and cell studies, epidemiological investigations have identified associations between BPs and couples' fecundity and other reproductive disorders, as well as adverse birth outcomes. Further studies are urgently needed to understand the risks posed by BPs on human health.
Background:
Gestational phthalate and phenol exposure disrupts adipogenesis, contributing to obesity in mice. Whether gestational phthalate or phenol exposure is associated with infant body composition has not been investigated in humans.
Objective:
We examined associations between biomarkers of phthalate and phenol exposure in midpregnancy and infant size and body composition at birth and at 5 months of age.
Methods:
Analyses were conducted among 438 infants from the Healthy Start prospective pregnancy cohort. Sixteen phthalate and phenol biomarkers were quantified in spot urine samples collected at 24-28 wk of gestation. Infant outcomes measured at birth and at 5 months of age included size [weight (in grams)] and body composition [fat and lean masses (in grams); percentage fat mass]. Single- (linear) and multipollutant (quantile g-computation) models were used to estimate associations of phthalate and phenol biomarkers with infant outcomes at birth and at 5 months of age. Models were adjusted for sociodemographics, sample collection timing, and lifestyle factors and used to examine for effect modification by infant sex.
Results:
In single-pollutant models, mono-benzyl phthalate and di-n-butyl phthalate were inversely associated with percentage fat mass [β: -0.49 (95% CI: -0.91, -0.08) and -0.51 (95% CI: -1.02, 0.01), respectively] in male but not female infants at birth. Similar, but less precise, associations were observed at 5 months of age. In multipollutant models, a 1-quartile increase in the phthalate and phenol biomarker mixture was inversely associated with percentage fat mass at birth [-1.06 (95% CI: -2.21, 0.1)] and at 5 months of age [-2.14 (95% CI: -3.88, -0.39)] among males, but associations were null among females [0.48 (95% CI: -0.78, 1.75) and -0.64 (95% CI: -2.68, 1.41), respectively]. Similar associations were observed with infant weight.
Conclusion:
In this U.S.-based prospective cohort, gestational phthalate and phenol biomarkers were inversely associated with infant weight and fat mass, particularly in males. https://doi.org/10.1289/EHP12500.
Sunscreens are an important means of protection against sunburns, dyspigmentation, photoaging, and photocarcinogenesis. Sunscreens come in a variety of formulations that can protect against ultraviolet B (UVB) radiation, both UVB and ultraviolet A (UVA) radiation (broad-spectrum sunscreens), and UVB, UVA, and visible light (tinted broad-spectrum sunscreens). In the USA, there is currently a paucity of FDA-approved broad-spectrum filters on the market. Studies have identified the presence of multiple UV filters in water sources globally. Many laboratory studies have implicated the potential impact of UV filters on coral reef bleaching, the food chain, and human health. However, many of these studies are performed at concentrations that are much higher than those present in the natural environment. With increasing discussion surrounding the role of organic and inorganic UV filters as potential environmental pollutants over the past decade, approval of additional broad-spectrum filters would be an important means of alleviating the use of more controversial filters. The aim of this article is to review the effects of UV filters on health and the environment and explore potential adjunctive agents for photoprotection.Graphical abstract
Emerging organic contaminants (EOCs) of anthropogenic origins are ubiquitous in environmental compartments, including aquatic systems. Thus, EOCs have attracted considerable research and public attention due to their potential human and ecological health risks. However, compared to other aquatic environments such as wastewater systems, comprehensive reviews focussing on the occurrence and human health risks of EOCs in drinking water systems are still lacking. Therefore, to address this knowledge gap, the current review posits that drinking water systems harbour a cocktail of toxic EOCs, which pose public health risks via multiple exposure routes. In the present review, global evidence is examined to track EOCs along the source-pathway-receptor-impact-mitigation (SPRIM) continuum. Evidence shows that, various groups of EOCs, including pharmaceuticals and personal care products, solvents, plasticizers, endocrine disrupting compounds, gasoline additives, per- and polyfluoroalkyl substances (PFAS), food colourants, artificial sweeteners, and musks and fragrances, have been detected in drinking water systems. The anthropogenic sources of EOCs detected in drinking water systems, including wastewater systems and industrial emissions, are summarized. Further, the behaviour and fate of EOCs in the drinking water systems, including removal processes are discussed. Once in drinking water systems, human exposure to EOCs may occur via ingestion of contaminated drinking water and cooked foods, and possibly dermal contact and inhalation. The high-risk environments, and risk factors and behaviours predisposing humans to EOC exposure are discussed. Evidence on the human health risks of the various EOCs and a critique of the data are presented. Notably, besides inferential data, quantitative epidemiological evidence directly relating the occurrence of EOCs in drinking water systems to specific adverse human health outcomes is still scarce. Lastly, future research directions, including the need for quantitative public health risk assessment, and the application of emerging detection tools are discussed.
Mycosporine-like amino acids (MAAs) are promising natural sunscreens mainly produced in marine organisms. Until now, metabolic engineering efforts to produce MAAs in heterologous hosts have mainly focused on shinorine production, and the low production levels are still not suitable for industrial applications. In this study, we successfully developed Saccharomyces cerevisiae strains that can efficiently produce various disubstituted MAAs, including shinorine, porphyra-334, and mycosporine-2-glycine (M2G), which are formed by conjugating serine, threonine, and glycine to mycosporine-glycine (MG), respectively. We first generated an MG-producing strain by multiple integration of the biosynthetic genes from cyanobacteria and applying metabolic engineering strategies to increase sedopheptulose-7-phosphate pool, a substrate for MG production. Next, five mysD genes from cyanobacteria, which encode D-Ala-D-Ala ligase homologues that conjugate an amino acid to MG, were introduced into the MG-producing strain to determine the substrate preference of each MysD enzyme. MysDs from Lyngbya sp., N. linckia, and Euhalothece sp. Showed high specificity toward serine, threonine, and glycine, resulting in efficient production of shinorine, porphyra-334, and M2G, respectively. This is the first report on the production of porphyra-334 and M2G in S. cerevisiae. Furthermore, we identified that the substrate specificity of MysD was determined by the omega loop region of 43-45 amino acids predicted based on its structural homology to a D-Ala-D-Ala ligase from Thermus thermophiles involved in peptidoglycan biosynthesis. The substrate specificities of two MysD enzymes were interchangeable by swapping the omega loop region. Using the engineered strain expressing mysD from Lyngbya sp. Or N. linckia up to 1.53 g/L shinorine or 1.21 g/L porphyra-334 was produced by fed-batch fermentation in a 5-L bioreactor, the highest titer reported so far. These results suggest that S. cerevisiae is a promising host for industrial production of different types of MAAs, providing a sustainable and eco-friendly alternative for the development of natural sunscreens.
Consumer products containing benzophenone-type ultraviolet (UV) filters (BPs) have been widely accepted by the public, resulting in the widely existence of various BPs in the human body and environment. In recent years, more and more evidences show that BPs are endocrine disruptors. In view of the continuous exposure risk of BPs and their endocrine disrupting characteristics, the carcinogenicity of BPs and their effects on reproduction and development are of particular concern. However, due to the wide varieties of BPs and the scattered toxicity studies on BPs, people have a limited understanding on the safety of BPs. Therefore, this paper systematically reviews the carcinogenicity, reproductive and developmental toxicity of BPs in order to expand people's knowledge on the health risks of BPs and screen for more safe BPs. Although existing toxicological studies are insufficient, it can be determined that BPs have different potentials for carcinogenicity, and reproductive and developmental toxicity. Among those BPs, 2-hydroxyl-4-methoxyl benzophenone needs to be used with caution due to its adverse effects on cancer cell proliferation and migration, reproductive ability, sex differentiation, neurodevelopment, and so on. It is worth noting that functional group substitutions significantly affect the interaction between BPs and biomolecules such as DNA, cancer cells, and seminal fluid, resulting in different levels of toxicity. In short, it is very necessary to evaluate the carcinogenicity, reproductive and developmental toxicity of BPs, which is of great significance for establishing reasonable BPs content standards in cosmetics, water quality treatment standards for BPs, and so on.
Background: Plastics have conveyed great benefits to humanity and made possible some of the most significant advances of modern civilization in fields as diverse as medicine, electronics, aerospace, construction, food packaging, and sports. It is now clear, however, that plastics are also responsible for significant harms to human health, the economy, and the earth’s environment. These harms occur at every stage of the plastic life cycle, from extraction of the coal, oil, and gas that are its main feedstocks through to ultimate disposal into the environment. The extent of these harms not been systematically assessed, their magnitude not fully quantified, and their economic costs not comprehensively counted.
Goals: The goals of this Minderoo-Monaco Commission on Plastics and Human Health are to comprehensively examine plastics’ impacts across their life cycle on: (1) human health and well-being; (2) the global environment, especially the ocean; (3) the economy; and (4) vulnerable populations—the poor, minorities, and the world’s children. On the basis of this examination, the Commission offers science-based recommendations designed to support development of a Global Plastics Treaty, protect human health, and save lives.
Conclusions: It is now clear that current patterns of plastic production, use, and disposal are not sustainable and are responsible for significant harms to human health, the environment, and the economy as well as for deep societal injustices.
The main driver of these worsening harms is an almost exponential and still accelerating increase in global plastic production. Plastics’ harms are further magnified by low rates of recovery and recycling and by the long persistence of plastic waste in the environment. The thousands of chemicals in plastics—monomers, additives, processing agents, and non-intentionally added substances—include amongst their number known human carcinogens, endocrine disruptors, neurotoxicants, and persistent organic pollutants. These chemicals are responsible for many of plastics’ known harms to human and planetary health. The chemicals leach out of plastics, enter the environment, cause pollution, and result in human exposure and disease. All efforts to reduce plastics’ hazards must address the hazards of plastic-associated chemicals.
The occurrence of chemical compounds specific to individual plastic polymers allowed the determination of components in compost feedstock (urban greenery and bio bins of households). The total concentration of plastic polymers is 431 mg/kg. The main identified polymers are polystyrene, polyethylene terephthalate, polyethylene, polycarbonate, and polypropylene. Additives used to modify the properties of plastics are present in the concentration of 195 mg/kg. Twelve compounds used as additives in the production of plastics in both the feedstock and the compost were identified. A statistically significant relationship was found between the decrease of concentration of organic matter and concentrations of compounds that identify plastic polymers (polyethylene terephthalate and polystyrene). The decrease of concentrations of compounds specific to polymers after three months was observed in the range between 33 and 84%, while the decrease for additives was 68%. After 18 months, the loss was higher than 82% except for polypropylene (only 70%). Compound leachability after three months of composting decreased to one-quarter for most polymers (except polypropylene and polyethylene), and to one-third for additives.
The presence of microplastics in various abiotic and biotic matrices has sought the attention of researchers across the globe. Despite being subsurface, groundwater is also reported to be contaminated with microplastics. However, there is paucity of information regarding the major pathways responsible for microplastic contami�nation in groundwater. Further, information is altogether lacking about the assessment methodologies for microplastics’ contamination in the subsurface zone. Therefore, in this review paper, we aim to provide insights into various interaction pathways among the surface and subsurface sources through which groundwater gets contaminated. The novel feature of the review is that it also attempts to establish a conceptual framework for modelling the microplastic contamination in groundwater, where the extent of contamination was ascertained by combining the movement of microplastic particles and the movement of associated additives/plasticizers. As groundwater is one of the important sources for drinking as well as irrigation, potential impacts of microplastics’
contamination onto the human health and soil ecology is also discussed. Possible management strategies have also been summarized. Thus, this review will provide a complete depiction and consequences of the micro�plastics’ contamination in groundwater and therefore serve as a starting point for future researchers in the area of
groundwater microplastics.
Background
Phenolic compounds with potential adverse health effects are gradually being replaced. Little is known about the potential health risks of BPA, BP3, and TCS exposure in children and adolescents aged 6–19 years in the United States.
Objectives
To determine trends and rates of change in hazard indices (HI) for three phenolics in U.S. children and adolescents for BPA, BP3, TCS, and to assess changes in gender, race/ethnicity, age, and potential health risks.
Methods
Metabolic biomonitoring data from field-collected urine samples from the National Health and Nutrition Examination Survey (NHANES) were utilized. Daily intake of three phenols (bisphenol A, benzophenone-3, and triclosan) between 2005 and 2016 in children and adolescents were obtained. Cumulative risk indicators, including hazard quotient (HQ), hazard index (HI), and maximum cumulative ratio (MCR), were used for the health risk assessment of the three phenols.
Results
During this period, the change in LSGM HI was −2.9% per cycle [95% Cl: (−3.7%, −2.2%)], and the percentage of participants with HI > 0.1 decreased from 15.6% to 10.5%. Children (6–11 years) had higher mean HI values than adolescents (12–19 years), while female had higher LSGM HI values than male. MCR values were generally low and negatively correlated with HI. However, the average value of MCR increased from 1.722 to 2.107 during this period.
Conclusion
Exposure to phenolics among U.S. children and adolescents has changed in recent decades. However, gaps in data limit the interpretation of trends but legislative activity and advocacy campaigns by nongovernmental organizations may play a role in changing trends. Moreover, there are growing concerns about the potential health risks associated with exposure to multiple phenols in children and adolescents.
The placenta is a temporary endocrine organ that facilitates gas, nutrient, and waste exchange between maternal and fetal compartments, partially shielding the fetus from potentially hazardous environmental toxicants. However, rather than being “opaque”, the placenta is translucent or even transparent to some potential fetal developmental hazards, including toxic trace elements (TEs), perfluoroalkyl and polyfluoroalkyl substances (PFAS), and environmental phenols (EPs) to which people with pregnancy are frequently exposed. These agents are both passively and actively transferred to the fetal compartment, where endocrine disruption, oxidative stress, and epigenetic changes may occur. These pathologies may directly impact the fetus, or deposit and accumulate in the placenta to indirectly impact fetal development. Thus, it is critical for clinicians to understand the potential placental toxicity and transfer of widely distributed environmental agents ubiquitous during pregnancy. With such knowledge, targeted interventions and clinical recommendations can be developed to limit those risks.
Introduction: UV radiation is related to skin cancers, skin photoaging and sunburn. It can be harmful for human skin, so it is crucial to have a protection against sun rays. Substances protecting people from sun are sunscreens, that block and absorb UV radiation. The first sunscreen was discovered in 1928 and, since then, there have been many concerns about its safety, efectiveness and impant on the environment. Types of accessible sunscreens are physical sunscreens, chemical sunscreens and a combination. This study review is performed to assess possible risks of using sunscreens and evaluate if there are more positive or negative effects of their action.
The aim of the study: To evaluate positive and negative effects of sunscreens action.
Materials and methods: We searched Pubmed and ResearchGate in order to find relevant studies about sunscreens and their impact on human skin, human health and environment.
Results: There seem to be some adverse effects of sunblockers for the environment, such as destroying coral reefs, bioaccumulating in fish tissue and water sources. In some studies there was mentioned a negative impact of sunscreens on hormonal systems and pregnancy, as well as on human skin. On the other hand, many studies display that sunblockers inhibit the carcinogenic effect of sun rays, preventing people from developing skin cancers.
Conclusions: Althought sunscreens can have some negative effects, studies showed that there are more positive effects of their action. They can be harmful for the environment, but at the same time they can be a protection. Sunscreens protect skin from developing skin cancer and also delay skin aging. However, the protection against sun is complex.
Objectives
To explore the association of endocrine-disrupting chemicals (EDCs) with insulin resistance (IR) in children as well as whether obesity played a mediation role between EDCs and IR.
Methods
In this cross-sectional study, the data of 878 subjects were included, and divided into the non-IR group (n=501) and IR group (n=377). The associations of EDC and IR, obesity, abdominal obesity were shown by restricted cubic spline (RCS). Univariate and multivariable logistic analysis were applied to explore the associations between EDCs and IR as well as EDCs and obesity, respectively. Bootstrap coefficient product was used to analyze the medication effect of obesity on EDCs and IR.
Results
RCS showed that increase of benzophenone-3 (BP-3) level was associated with increased risk of IR, obesity and abdominal obesity. After adjusting for confounders, BP-3>100 ng/mL was a risk factor for IR (OR=1.42, 95%CI: 1.11–1.81). In the adjusted model, we found BP-3>100 ng/mL was a risk factor for both obesity (OR=1.52, 95%CI: 1.13–2.04) and abdominal obesity (OR=1.68, 95%CI: 1.11–2.54). The indirect effect of obesity as a mediator on the relationship between BP-3 and IR was 0.038 (95%CI: 0.016–0.090) and the direct effect of obesity as a mediator on the relationship between BP-3 and IR was 0.077 (95%CI: 0.001–0.160). As for abdominal obesity, the indirect effect of it on the relationship between BP-3 and IR was 0.039 (95%CI: 0.007–0.070).
Conclusions
BP-3 level might be a risk factor for IR and obesity in children, and obesity was a mediator on the relationship between BP-3 and IR in children.
BACKGROUND2-Hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential.METHODS
To determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23.RESULTS AND CONCLUSION
Exposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats
Carlijn Hooijmans and colleagues discuss developments that might improve the quality and translation of animal research, focusing on the importance of systematic reviews, the role of an international register of animal studies, and cooperation across the scientific community.
Please see later in the article for the Editors' Summary
As a consequence of growing public concern about UV radiation effects on human health chemical and physical UV filters are increasingly used in personal care and other products. The release of these lipophilic and often persistent compounds into surface waters may pose a risk for aquatic organisms. The aim of the study was to determine effects of four frequently used UV filters on primary aquatic producers and consumers, the green alga Desmodesmus subspicatus and the crustacean Daphnia magna. Exposure to benzophenone 3 (BP3), ethylhexyl methoxycinnamate (EHMC), 3-benzylidene camphor (3-BC) and 3-(4'-methylbenzylidene)-camphor (4-MBC) resulted in growth inhibition of D. subspicatus with 72 h IC(10) values of 0.56 mg/L (BP 3), 0.24 mg/L (EHMC), 0.27 mg/L (3-BC) and 0.21 mg/L (4-MBC). EC(50) concentrations in the acute test with D. magna were 1.67, 0.57, 3.61 and 0.80 mg/L for BP3, EHMC, 3-BC and 4-MBC, respectively. Chronic exposure of D. magna resulted in NOECs of 0.04 mg/L (EHMC) and 0.1 mg/L (3-BC and 4-MBC). BP 3 showed no effects on neonate production or the length of adults. Rapid dissipation of these substances from the water phase was observed indicating the need for more frequent test medium renewal in chronic tests or the use of flow-through test systems.
Data concerning the effects of prenatal exposures to phthalates and phenols on fetal growth are limited in humans. Previous findings suggest possible effects of some phenols on male birth weight.
Our aim was to assess the relationships between prenatal exposures to phthalates and phenols and fetal growth among male newborns.
We conducted a case-control study on male malformations of the genitalia nested in two French mother-child cohorts with recruitment between 2002 and 2006. We measured, in maternal urinary samples collected between 6 and 30 gestational weeks, the concentrations (micrograms per liter) of 9 phenol (n = 191 pregnant women) and 11 phthalate metabolites (n = 287). Weight, length, and head circumference at birth were collected from maternity records. Statistical analyses were corrected for the oversampling of malformation cases.
Adjusted birth weight decreased by 77 g [95% confidence interval (CI): -129, -25] and by 49 g (95% CI: -86, -13) in association with a 1-unit increase in ln-transformed 2,4-dichlorophenol (DCP) and 2,5-DCP urinary concentrations, respectively. Benzophenone-3 (BP3) ln-transformed concentrations were positively associated with weight (26 g; 95% CI: -2, 54) and head circumference at birth (0.1 cm; 95% CI: 0.0, 0.2). Head circumference increased by 0.3 cm (95% CI: 0.0, 0.7) in association with a 1-unit increase in ln-transformed BPA concentration. For phthalate metabolites there was no evidence of monotonic associations with birth weight.
Consistent with findings of a previous study, we observed evidence of an inverse association of 2,5-DCP and a positive association of BP3 with male birth weight.
The capability of benzophenone-3 (BP-3) to absorb and dissipate ultraviolet radiation facilitates its use as a sunscreen agent. BP-3 has other uses in many consumer products (e.g., as fragrance and flavor enhancer, photoinitiator, ultraviolet curing agent, polymerization inhibitor).
Our goal was to assess exposure to BP-3 in a representative sample of the U.S. general population > or = 6 years of age.
Using automated solid-phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry, we analyzed 2,517 urine samples collected as part of the 2003--2004 National Health and Nutrition Examination Survey.
We detected BP-3 in 96.8% of the samples. The geometric mean and 95th percentile concentrations were 22.9 microg/L (22.2 microg/g creatinine) and 1,040 microg/L (1,070 microg/g creatinine), respectively. Least-square geometric mean (LSGM) concentrations were significantly higher (p < or = 0.04) for females than for males, regardless of age. LSGM concentrations were significantly higher for non-Hispanic whites than for non-Hispanic blacks (p < or = 0.01), regardless of age. Females were more likely than males [adjusted odds ratio (OR) = 3.5; 95% confidence interval (95% CI), 1.9-6.5], and non-Hispanic whites were more likely than non-Hispanic blacks (adjusted OR = 6.8; 95% CI, 2.9-16.2) to have concentrations above the 95th percentile.
Exposure to BP-3 was prevalent in the general U.S. population during 2003--2004. Differences by sex and race/ethnicity probably reflect differences in use of personal care products containing BP-3.
Many phthalates and phenols are hormonally active and are suspected to alter the course of development.
We investigated prenatal exposures to phthalate and phenol metabolites and their associations with body size measures of the infants at birth.
We measured 5 phenol and 10 phthalate urinary metabolites in a multiethnic cohort of 404 women in New York City during their third trimester of pregnancy and recorded size of infants at birth.
Median urinary concentrations were > 10 microg/L for 2 of 5 phenols and 6 of 10 phthalate monoester metabolites. Concentrations of low-molecular-weight phthalate monoesters (low-MWP) were approximately 5-fold greater than those of high-molecular-weight metabolites. Low-MWP metabolites had a positive association with gestational age [0.97 day gestational age per ln-biomarker; 95% confidence interval (CI), 0.07-1.9 days, multivariate adjusted] and with head circumference. Higher prenatal exposures to 2,5-dichlorophenol (2,5-DCP) predicted lower birth weight in boys (-210 g average birth weight difference between the third tertile and first tertile of 2,5-DCP; 95% CI, 71-348 g). Higher maternal benzophenone-3 (BP3) concentrations were associated with a similar decrease in birth weight among girls but with greater birth weight in boys.
We observed a range of phthalate and phenol exposures during pregnancy in our population, but few were associated with birth size. The association of 2,5-DCP and BP3 with reduced or increased birth weight could be important in very early or small-size births. In addition, positive associations of urinary metabolites with some outcomes may be attributable partly to unresolved confounding with maternal anthropometric factors.
Ultraviolet (UV) screens are increasingly used as a result of growing concern about UV radiation and skin cancer; they are also added to cosmetics and other products for light stability. Recent data on bioaccumulation in wildlife and humans point to a need for in-depth analyses of systemic toxicology, in particular with respect to reproduction and ontogeny. We examined six frequently used UVA and UVB screens for estrogenicity in vitro and in vivo. In MCF-7 breast cancer cells, five out of six chemicals, that is, benzophenone-3 (Bp-3), homosalate (HMS), 4-methyl-benzylidene camphor (4-MBC), octyl-methoxycinnamate (OMC), and octyl-dimethyl-PABA (OD-PABA), increased cell proliferation with median effective concentrations (EC(50)) values between 1.56 and 3.73 microM, whereas butyl-methoxydibenzoylmethane (B-MDM) was inactive. Further evidence for estrogenic activity was the induction of pS2 protein in MCF-7 cells and the blockade of the proliferative effect of 4-MBC by the estrogen antagonist ICI 182,780. In the uterotrophic assay using immature Long-Evans rats that received the chemicals for 4 days in powdered feed, uterine weight was dose-dependently increased by 4-MBC (ED(50 )309mg/kg/day), OMC (ED(50) 935 mg/kg/day), and weakly by Bp-3 (active at 1,525 mg/kg/day). Three compounds were inactive by the oral route in the doses tested. Dermal application of 4-MBC to immature hairless (hr/hr) rats also increased uterine weight at concentrations of 5 and 7.5% in olive oil. Our findings indicate that UV screens should be tested for endocrine activity, in view of possible long-term effects in humans and wildlife.
Although pesticide use is widespread, little is known about potential adverse health effects of in utero exposure. We investigated the effects of organophosphate pesticide exposure during pregnancy on fetal growth and gestational duration in a cohort of low-income, Latina women living in an agricultural community in the Salinas Valley, California. We measured nonspecific metabolites of organophosphate pesticides (dimethyl and diethyl phosphates) and metabolites specific to malathion (malathion dicarboxylic acid), chlorpyrifos [O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl) phosphoro-thioate], and parathion (4-nitrophenol) in maternal urine collected twice during pregnancy. We also measured levels of cholinesterase in whole blood and butyryl cholinesterase in plasma in maternal and umbilical cord blood. We failed to demonstrate an adverse relationship between fetal growth and any measure of in utero organophosphate pesticide exposure. In fact, we found increases in body length and head circumference associated with some exposure measures. However, we did find decreases in gestational duration associated with two measures of in utero pesticide exposure: urinary dimethyl phosphate metabolites [beta(adjusted) = -0.41 weeks per log10 unit increase; 95% confidence interval (CI), -0.75 -- -0.02; p = 0.02], which reflect exposure to dimethyl organophosphate compounds such as malathion, and umbilical cord cholinesterase (beta(adjusted) = 0.34 weeks per unit increase; 95% CI, 0.13-0.55; p = 0.001). Shortened gestational duration was most clearly related to increasing exposure levels in the latter part of pregnancy. These associations with gestational age may be biologically plausible given that organophosphate pesticides depress cholinesterase and acetylcholine stimulates contraction of the uterus. However, despite these observed associations, the rate of preterm delivery in this population (6.4%) was lower than in a U.S. reference population.
Ultraviolet (UV) filters are commonly used compounds in personal care products and polymer based materials, as they can absorb solar energy in the UVA and UVB spectrum. However, they are able to bind to hormone receptors and have several and different types of hormonal activities determined by in vitro assays. One of the aims of this work was to measure the hormonal and cytotoxic activities of four frequently used UV filters using bioluminescence based yeast test organisms. Using Saccharomyces cerevisiae BLYES and BLYAS strains allowed the rapid and reliable detection of agonist and antagonist hormonal activities, whereas BLYR strain served to measure cytotoxicity. Results confirmed that all tested UV filters show multiple hormonal activities. Cytotoxicity is detected only in the case of benzophenone-3. Research data on the toxic effects of benzophenone-3, especially on aquatic organisms are scarce, so further investigations were carried out regarding its cytotoxic and teratogenic effects on bacteria and zebrafish (Danio rerio) embryos, respectively. Results revealed the cytotoxicity of benzophenone-3 not only to yeasts but to bacteria, as well as its ability to influence zebrafish embryo hatching and development.
The chemical UV filter benzophenone-3 (BP-3) is suspected to be an endocrine disruptor based on results from in vitro and in vivo testing. However, studies including endpoints of endocrine adversity are lacking. The present study investigated the potential endocrine disrupting effects of BP-3 in zebrafish (Danio rerio) in the Fish Sexual Development Test (OECD TG 234) and a 12 day adult male zebrafish study. In TG 234, exposure from 0 to 60 d post hatch caused a monotone dose dependent skewing of the phenotypic sex ratio towards less males and more female zebrafish (NOEC: 191 µg/L, LOEC: 388 µg/L). Besides, gonad maturation was affected in both female fish (NOEC 191 µg/L, LOEC 388 µg/L) and male fish (NOEC 388 µg/L, LOEC 470 µg/L). Exposure to BP-3 did not affect the vitellogenin concentration in TG 234. After 12 d exposure of adult male zebrafish, a slight but yet significant increase in the vitellogenin concentration was observed at 268 µg/L but not at 63 µg/L and 437 µg/l BP-3. Skewing of the sex ratio is a marker of an endocrine mediated mechanism as well as a marker of adversity and therefore the conclusion of the investigation is that BP-3 is an endocrine disrupting chemical in accordance with the WHO definition. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
To assess benzophenone-type ultraviolet (UV) filter concentrations, chemicals used in sunscreen and personal care products, and semen endpoints.
Cohort.
Sixteen counties in Michigan and Texas.
A total of 413 men provided semen and urine samples, 2005-2009. Five UV filters were quantified (ng/mL) in urine using liquid chromatography-triple quadrupole mass spectrometry: BP-1 (2,4-dihydroxybenzophenone), BP-2 (2,2',4,4'-tetrahydroxybenzophenone), BP-3 (2-hydroxy-4-methoxybenzophenone), BP-8 (2,2'-dihydroxy-4-methoxybenzophenone), and 4-OH-BP (4-hydroxybenzophenone). Using linear regression, β-coefficients (β) and 95% confidence intervals (CIs) for each chemical dichotomized at the 75th percentile and Box-Cox transformed semen endpoint were estimated, after adjusting for age, body mass index, cotinine, season, and site.
None.
Thirty-five semen endpoints.
BP-2 was associated with diminished sperm concentration (β = -0.74; 95% CI -1.41, -0.08), straight (β = -4.57; 95% CI -8.95, -0.18) and linear movement (β = -3.15; 95% CI -6.01, -0.30), more immature sperm (β = 0.38; 95% CI 0.15, 0.62), and a decreased percentage of other tail abnormalities (β = -0.16; 95% CI -0.31, -0.01). BP-8 was associated with decreased hypo-osmotic swelling (β = -2.57; 95% CI -4.86, -0.29) and higher acrosome area (β = 1.14; 95% CI 0.01, 2.26). No associations were observed for BP-1, BP-3, or 4OH-BP.
The findings suggest that specific UV filters may be associated with some aspects of semen endpoints, but await future corroboration.
Published by Elsevier Inc.
Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4-diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes.
Copyright © 2014. Published by Elsevier Inc.
Benzophenone-3 (BP-3) has been widely used in sunscreens and many other consumer products, including cosmetics. The widespread use of BP-3 has resulted in its release into the water environment, and hence its potential impact on aquatic ecosystem is of concern. To better understand the risk associated with BP-3 in aquatic ecosystems, we conducted a thorough review of available articles regarding the physicochemical properties, toxicokinetics, environmental occurrence, and toxic effects of BP-3 and its suspected metabolites. BP-3 is lipophilic, photostable, and bioaccumulative, and can be rapidly absorbed via oral and dermal routes. BP-3 is reported to be transformed into three major metabolites in vivo, i.e., benzophenone-1 (BP-1), benzophenone-8 (BP-8), and 2,3,4-trihydroxybenzophenone (THB). BP-1 has a longer biological half-life than its parent compound and exhibits greater estrogenic potency in vitro. BP-3 has been detected in water, soil, sediments, sludge, and biota. The maximum detected level in ambient freshwater and seawater is 125ng/L and 577.5ng/L, respectively, and in wastewater influent is 10,400ng/L. The major sources of BP-3 are reported to be human recreational activities and wastewater treatment plant (WWTP) effluents. BP-3 and its derivatives have been also detected in fish lipid. In humans, BP-3 has been detected in urine, serum, and breast milk samples worldwide. BP-1 has also been detected in placental tissues of delivering women. While sunscreens and cosmetics are known to be major sources of exposure, the fact that BP-3 has been detected frequently among young children and men suggests other sources. An increasing number of in vitro studies have indicated the endocrine disrupting capacity of BP-3. Based on a receptor binding assay, BP-3 has shown strong anti-androgenic and weak estrogenic activities but at the same time BP-3 displays anti-estrogenic activity as well. Predicted no effect concentration (PNEC) for BP-3 was derived at 1.32μg/L. The levels observed in ambient water are generally an order of magnitude lower than the PNEC, but in wastewater influents, hazard quotients (HQs) greater than 1 were noted. Considering limited ecotoxicological information and significant seasonal and spatial variations of BP-3 in water, further studies on environmental monitoring and potential consequences of long-term exposure in aquatic ecosystem are warranted.
Widespread use of phenols has led to ubiquitous exposure to phenols. In experimental animals, phenols increased resorptions, reduced live litter size and fetal body weights. However, there are limited epidemiological evidences of the relationships between exposure to phenols and pregnancy outcomes. We evaluated the associations between parental urinary levels of various phenols and spontaneous abortion in a Chinese population residing in the middle and lower reaches of the Yangtze River. A case-control study was conducted that included 70 case couples with medically unexplained spontaneous abortion and 180 control couples who did not have a history of spontaneous abortion and had at least one living child. Both parental urinary phenols were measured by ultra-high performance liquid chromatography-tandem mass spectrometry including bisphenol A (BPA), benzophenone-3 (BP-3), 2,3,4-trichlorophenol (2,3,4-TCP), pentachlorophenol (PCP), 4-n-octylphenol (4-n-OP) and 4-n-nonylphenol (4-n-NP). Compared with the low exposure group, there was an increased risk of spontaneous abortion with high paternal urinary PCP concentration [odds ratio (OR)=2.09, 95% Confidence Interval (CI), 1.05-4.14], and maternal exposure to 4-n-OP and alkylphenol(s) also significantly increased the risk of spontaneous abortion (OR=2.21, 95% CI, 1.02-4.80; OR=2.81, 95% CI, 1.39-5.65, respectively). Our study firstly provides the evidence that paternal PCP exposure, maternal 4-n-OP and alkylphenol(s) exposure are associated with spontaneous abortion in humans.
Many phenols are known to mimic or antagonize hormonal activities and may adversely affect fetal growth. A study of 567 pregnant women was conducted to investigate the relationship between prenatal phenol exposure and birth outcomes, including birth weight, length, and gestational age. We measured the concentrations of bisphenol A, benzophenone-3, 4-n-octylphenol and 4-n-nonylphenol in maternal urine and examine their association with birth outcomes. Categories of urinary benzophenone-3 concentration were associated with decreased gestational age in all infants (p for trend = 0.03). Between middle and low exposure groups, we also found bisphenol A was negatively associated with gestational duration (βadjusted = -0.48 week; 95% confidence interval: -0.91, -0.05). After stratification by gender, we found the consistent results in infant boys with those in all infants, but we did not observe significant association for girls. In conclusion, we found prenatal phenol exposure was sex-specifically related to birth outcomes.
Today, topical application of sunscreens, containing ultraviolet-filters (UV-filters), is preferred protection against adverse effects of ultraviolet radiation. Evidently, use of sunscreens is effective in prevention of sunburns in various models. However, evidence for their protective effects against melanoma skin cancer is less conclusive. Three important observations prompted us to review the animal data and human studies on possible side effects of selected chemical UV-filters in cosmetics. (1) the utilization of sunscreens with UV-filters is increasing worldwide; (2) the incidence of the malignant disorder for which sunscreens should protect, malignant melanoma, is rapidly increasing and (3) an increasing number of experimental studies indicating that several UV-filters might have endocrine disruptive effects. The selected UV-filters we review in this article are benzophenone-3 (BP-3), 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), Homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) and 4-aminobenzoic acid (PABA). The potential adverse effects induced by UV-filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitary-thyroid axis (HPT). Few human studies have investigated potential side effects of UV-filters, although human exposure is high as UV-filters in sunscreens are rapidly absorbed from the skin. One of the UV-filters, BP-3, has been found in 96% of urine samples in the US and several UV-filters in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV-filters contribute to possible adverse effects on the developing organs of foetuses and children.
Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR)=2.97; 95% CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31, 1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as ≤ 10 years (OR=1.41 95% CI=0.97, 2.03) than defined as ≤ 11 years (OR=1.16; 95% CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.
Previous studies in extracts of sediments surrounding municipal outfalls off the coast of California, USA and effluents of New York City, NY, USA indicated the UV-filtering agent, oxybenzone (CAS# 131-57-7; benzophenone-3) as a potential estrogen. The effects of oxybenzone on estrogenic activity and reproduction were evaluated using a 14-day juvenile rainbow trout assay for plasma vitellogenin and a subsequent 21-day Japanese medaka reproduction assay. Significant induction of vitellogenin was observed in the rainbow trout at the 1000 microg/L nominal concentration (749 microg/L median measured value) of oxybenzone which was approximately 75 times greater than the concentrations observed in previous wastewater effluent. Vitellogenin induction was also observed in the 1000 microg/L nominal concentration (620 microg/L median measured) of oxybenzone in male Japanese medaka (Oryzias latipes) after 21 days of exposure. The number of eggs produced per female per day exposed to the same concentration (620 microg/L) were significantly lower after 7 days, but returned to control values after 21 days. Fertilized eggs were then monitored for 20 days to assess hatching success. The overall percentage of fertilized eggs collected during the 21-day exposure that hatched was significantly lower in the 620 microg/L oxybenzone concentration. There was also a temporal effect at this concentration as egg viability (percentage of fertilized eggs that hatched) was diminished 13-15 days after eggs were collected. All three oxybenzone concentrations (16, 132, and 620 microg/L) and the 50 ng/L estradiol positive control showed reduced hatching of eggs at day 15, and the 132 and 620 microg/L oxybenzone concentrations diminished the percentage of eggs that hatched on days 13-15. These data indicate that the UV-filter oxybenzone alters endocrine or reproduction endpoints in two fish species, but at concentrations significantly higher than those measured in the environment.
Conventional tests of reproductive toxicity may fail to detect the effects of some agents altering reproductive functions in the male or female. A valid study of reproductive toxicity must be based on a sound understanding of the underlying reproductive physiology, use of sensitive and precise analytical methods, a powerful experimental design, and evaluation of multiple criteria in both the male and female. Potential sites and mechanisms of action of an agent affecting reproduction were considered together with approaches for tests that might be used. Development of new in vitro tests, based on procedures used for probing reproductive physiology, would be desirable. Procedures for detecting alterations in male reproductive function using animal models were considered in detail. For example, spermatogenesis is a long process and a toxic agent may alter functionality of a testicular cell type several days or weeks before this toxicity is detectable as a change in spermatogenesis. Several weeks or months may pass before a detectable change in semen occurs. Therefore, tests utilizing appropriate animal models should have a duration that is six times the duration of one cycle of the seminiferous epithelium. Evaluations of male reproductive function would be enhanced by including determinations of testicular spermatid reserves, selected simple but precise and meaningful quantitative evaluations of testicular histology, determination of the number of sperm within the distal half of the epididymis, evaluation of the progressive motility and morphology of sperm from the distal end of the epididymis, and measurement of the concentration of follicle stimulating hormone in blood. For rabbits, longitudinal analyses of seminal quality are important.
The potential of 2-hydroxy-4-methoxybenzophenone (HMB) to cause male reproductive toxicity was assessed in B6C3F1 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
B6C3F1 mice at dosages as high as 400 mg/kg/day.
2-Hydroxy-4-methoxybenzophenone (HMB) occurs naturally in flower pigments and is synthesized for use in sunscreens, as a UV stabilizer in various cosmetic products, and in plastic surface coatings and polymers. Toxicity studies of HMB were performed in F344/N rats and B6C3F1 mice, by administering HMB in feed and by topical application, in studies of 2 weeks' (5 animals/sex, dose and species) and 13 weeks' (10 animals/sex, dose and species) duration. Assessments included hematology, clinical chemistry, urinalysis, reproductive toxicity, and histopathologic evaluations. In both 2- and 13-week dosed feed studies, rats received diets containing 0, 3125, 6250, 12500, 25000, or 50000 ppm HMB. One high-dose female rat died during the 2-week study. Body weight gains of high-dose male and female rats were reduced in the 13-week study. Liver and kidney weights were increased in dosed rats in both studies. In the 2-week studies, enlarged livers were associated with a marked hepatocyte cytoplasmic vacuolization in rats receiving diets containing concentrations of 6250 ppm HMB or higher; renal lesions, consisting of dilated tubules and regeneration of tubular epithelial cells, were found primarily in high-dose rats. In the 13-week studies, kidney lesions progressed to include papillary degeneration, or necrosis, and inflammation, while the liver lesion appeared to regress; liver enzymes in serum remained elevated. Rats receiving a diet with 50000 ppm HMB showed markedly lower epididymal sperm density and an increase in the length of the estrous cycle at the end of the 13-week studies. In 2-week dermal studies, rats received topical applications of 1.25 to 20 mg of HMB in an acetone or lotion vehicle. The only effects noted were small and variable increases in liver and kidney weights, reaching statistical significance primarily in the higher dose groups. In 13-week studies, rats received topical doses from 12.5 to 200 mg/kg HMB in acetone. Kidney weights were elevated in dosed groups of female rats. No other findings were attributed to HMB treatment. In 2- and 13-week dosed feed studies, mice received feed containing 0, 3125, 6250, 12500, 25000, or 50000 ppm HMB. A dose- related increase in liver weight associated with hepatocyte cytoplasmic vacuolization was the only finding in mice in the 2- week studies. Decreased body weight gains were dose-related in mice in the 13-week studies; mild increases in liver weights were seen in dosed mice of both sexes. Kidney weights were increased variably in dosed females. Microscopic lesions were noted only in the kidneys of males receiving 50000 ppm HMB; these included eosinophilic protein casts in dilated renal tubules and a mild inflammation associated with the dilated tubules. Mice in the highest dose group exhibited a decrease in epididymal sperm density and an increase in length of the estrous cycle. In 2-week dermal studies, mice received topical applications from 0.5 to 8 mg HMB in an acetone or lotion vehicle. The only effects noted were minimal, variable increases in liver and kidney weights, primarily in the higher dose groups. In 13-week studies, mice received topical doses of 22.75 to 364 mg/kg in acetone. Kidney weights were increased variably in dosed male mice. Epididymal sperm density was decreased at all 3 dose levels evaluated (22.75, 91, and 200 mg/kg). The genetic toxicity of HMB also was evaluated in mutagenicity studies with Salmonella typhimurium, in cytogenetic studies with Chinese hamster ovary (CHO) cells, and by evaluation of micronucleated erythrocytes in peripheral blood smears from mice in the 13-week studies. HMB was weakly mutagenic in Salmonella with metabolic activation, and induced sister-chromatid exchanges and chromosomal aberrations in CHO cells in the presence of a metabolic activation system. There was no increase in the frequency of micronucleated erythrocytes in the blood of mice receiving HMB. In summary, HMB produced generally similar effects following topical and oral administration to rats and mice. Consistent findings included decreases in epididymal sperm density, lengthened estrous cycle, and increased liver and kidney weights. Mice in the dosed feed studies exhibited microscopic changes in the kidneys, comprising tubular dilatation with eosinophilic protein casts. Dilatation, tubular regeneration, papillary degeneration, and inflammation were noted in the kidneys of rats; and liver lesions consisting of an apparently reversible hepatocyte cytoplasmic vacuolization occurred in both rats and mice. A no-observed-adverse-effect level (NOAEL) for microscopic lesions was 6250 ppm HMB in the diet for rats and mice. A NOAEL was not reached for decreased epididymal sperm density in the 13- week dermal study in mice (<23 mg/kg/day). Synonyms: Oxybenzone; 4-Methoxy-2-hydroxy-benzophenone; Cyasorb UV; Uvinul M 40; (2-hydroxy-4-methoxyphenyl)phenyl-methanone; NSC-7778; Spectra-sorb UV; Syntase 62; UF 3; USAF CY-9; NCI-C60957.
Benzophenone-3 (BZ-3) is a commonly used, chemical UV-absorber. It has been used for many years to protect against UV-radiation. Previous studies have shown that BZ-3 penetrates the skin, and it can be found in urine, faeces, and blood. In this study we examined the percutaneous absorption of BZ-3. The amount of BZ-3 absorbed was measured in urine, as experimental studies in the rat have shown that urine is the major route of excretion. Eleven volunteers applied the recommended amount of a commercially available sunscreen and urine samples were collected during a 48-h period after application. The average total amount excreted was 11 mg, median 9.8 mg, which is approximately 0.4% of the applied amount of BZ-3. Some of the volunteers still excreted BZ-3 48 h after application. It is evident that BZ-3 undergoes conjugation in the body to make it water soluble. However, we do not know at what age the ability to conjugate is fully developed, and therefore for children physical filters such as titanium dioxide and/or zinc oxide might still be considered a more appropriate sunscreen component.
The purpose of the present study was to develop a reverse-phase high-performance liquid chromatographic (HPLC) assay for quantifying four common sunscreen agents, namely 2-hydroxy-4-methoxybenzophenone, 2-ethylhexyl-p-methoxycinnamate, 2-ethylhexylsalicylate (octylsalicylate) and salicylic acid 3,3,5-trimethcyclohexyl ester (homosalate) in a range of biological matrices. This assay was further applied to study the skin penetration and systemic absorption of sunscreen filters after topical application to human volunteers. Separation was achieved utilizing a Symmetry C(18) column with methanol-water as the mobile phase. The assay permits analysis of the sunscreen agents in biological fluids, including bovine serum albumin (BSA) solution, plasma and urine, and in human epidermis. The assay was linear (r2 > 0.99) with minimum detectable limits of 0.8 ng for oxybenzone, 0.3 ng for octylmethoxycinnamate, and 2 ng for homosalate and octylsalicylate. The inter- and intra-day variation for the four sunscreens was less than 3% at the upper end of the linear range and less than 6% at the lower end. Recoveries of sunscreens from plasma, 4% (w/v) BSA solution and epidermal membranes were within the range of 91-104%. Recoveries from urine of the four sunscreens, and oxybenzone with its metabolites were more than 86%. Up to approximately 1% of the applied dose of oxybenzone and its metabolites was detected in the urine. Appreciable amounts were also detected in the stratum corneum through tape stripping. The HPLC assay and extraction procedures developed are sensitive, simple, rapid, accurate and reproducible. Results from the preliminary clinical study demonstrate significant penetration of all sunscreen agents into the skin, and oxybenzone and metabolites across the skin.
Recent in vitro and animal studies have reported estrogen-like activity of chemicals used in sunscreen preparations. We investigated whether the three sunscreens benzophenone-3 (BP-3), octyl-methoxycinnamate (OMC), and 3-(4-methylbenzylidene) camphor (4-MBC) were absorbed and influenced endogenous reproductive hormone levels in humans after topical application. In this 2-wk single-blinded study 32 healthy volunteers, 15 young males and 17 postmenopausal females, were assigned to daily whole-body topical application of 2 mg per cm(2) of basic cream formulation without (week 1) and with (week 2) the three sunscreens at 10% (wt/wt) of each. Maximum plasma concentrations were 200 ng per mL BP-3, 20 ng per mL 4-MBC, and 10 ng per mL OMC for females and 300 ng per mL BP-3, 20 ng per mL 4-MBC, and 20 ng per mL OMC for men. All three sunscreens were detectable in urine. The reproductive hormones FSH, LH were unchanged but minor differences in testosterone levels were observed between the 2 wk. A minor difference in serum estradiol and inhibin B levels were observed in men only. These differences in hormone levels were not related to sunscreen exposure.