ArticleLiterature Review

Exposure to Benzophenone-3 and Reproductive Toxicity: A Systematic Review of Human and Animal Studies

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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.

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... Numerous studies have shown the negative effects of OBZ on the reproductive system, where it acts as an endocrine disrupting chemical (EDC) [11][12][13]. In fish, OBZ exposure caused a reduction in egg production and induced egg protein production in males and juveniles [14,15]. ...
... One prior study by Balazs et al. (2016) showed that OBZ exposure increased mortality and developmental disorders in zebrafish embryos [16]. In rodents, OBZ reduced body weight and uterine weight, increased abnormal sperm levels, decreased epididymal sperm density, altered gland morphology and function, prolonged the estrous cycle, and induced idiopathic sudden death in lactating mothers [6,11,17,18]. A recent in vitro study showed that exposure to OBZ (5.8 nM) decreased the total number of oocytes, the number of nests per ovary and the early primary follicle population, indicating that OBZ perturbed the early events of germ cell development in rat whole ovary cultures [19]. ...
... OBZ, an organic UV filter, is widely used in sunscreens, personal care products, and food product packaging, and it is found almost everywhere in the environment [11]. Furthermore, OBZ is small enough to allow it to penetrate through skin and be detected in urine, breast milk, and blood [8]. ...
Article
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Oxybenzone (OBZ), an ultraviolet light filter that is widely used in sunscreens and cosmetics, is an emerging contaminant found in humans and the environment. Recent studies have shown that OBZ has been detected in women's plasma, urine, and breast milk. However, the effects of OBZ exposure on oocyte meiosis have not been addressed. In this study, we investigated the detrimental effects of OBZ on oocyte maturation and the protective roles of melatonin (MT) in OBZ-exposed mouse models. Our in vitro and in vivo results showed that OBZ suppressed oocyte maturation, while MT attenuated the meiotic defects induced by OBZ. In addition, OBZ facilitated H3K4 demethylation by increasing the expression of the Kdm5 family of genes, elevating ROS levels, decreasing GSH, impairing mitochondrial quality, and disrupting spindle configuration in oocytes. However, MT treatment resulted in significant protection against OBZ-induced damage during oocyte maturation and improved oocyte quality. The mechanisms underlying the beneficial roles of MT involved reduction of oxidative stress, inhibition of apoptosis, restoration of abnormal spindle assembly and up-regulation of H3K4me3. Collectively, our results suggest that MT protects against defects induced by OBZ during mouse oocyte maturation in vitro and in vivo.
... BP-3 is among the most commonly used ultraviolet light absorbing components in medicine, cosmetics, skin, and hair products. Health concerns arose when in vivo and in vitro animal studies showed associations between BP-3 exposure and levels of sex hormones such as estrogen and testosterone [6,[18][19][20][21][22][23][24][25]. It has been shown in rats and humans that BP-3 can be metabolized to metabolites such as 2,4-dihydroxybenzophenone or benzophenone-1 (BP-1) and 2,2′,4,4′-tetrahydroxybenzophenone or benzophenone-2 (BP-2) [26][27][28]. ...
... Antiandrogenic activity of BP-1 has been also observed in vitro studies [29]. Epidemiologic studies have shown an association between BP-3 (and its metabolites) and endometriosis [30], shorter pregnancy time, and possible decrease in fetal growth [25,[31][32][33]. Based on current regulations in the USA, BP-3 can be present at up to 6 weight percent (% w/w) of sunscreen products and 0.5% w/w of other personal care products [34]. ...
Article
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Background Fugacity, the driving force for transdermal uptake of chemicals, can be difficult to predict based only on the composition of complex, non-ideal mixtures such as personal care products. Objective Compare the predicted transdermal uptake of benzophenone-3 (BP-3) from sunscreen lotions, based on direct measurements of BP-3 fugacity in those products, to results of human subject experiments. Methods We measured fugacity relative to pure BP-3, for commercial sunscreens and laboratory mixtures, using a previously developed/solid-phase microextraction (SPME) method. The measured fugacity was combined with a transdermal uptake model to simulate urinary excretion rates of BP-3 resulting from sunscreen use. The model simulations were based on the reported conditions of four previously published human subject studies, accounting for area applied, time applied, showering and other factors. Results The fugacities of commercial lotions containing 3–6% w/w BP-3 were ~20% of the supercooled liquid vapor pressure. Simulated dermal uptake, based on these fugacities, are within a factor of 3 of the mean results reported from two human-subject studies. However, the model significantly underpredicts total excreted mass from two other human-subject studies. This discrepancy may be due to limitations in model inputs, such as fugacity of BP-3 in lotions used in those studies. Significance The results suggest that combining measured fugacity with such a model may provide order-of-magnitude accurate predictions of transdermal uptake of BP-3 from daily application of sunscreen products.
... Des données de faible qualité ont soulevé la question de possibles effets oestrogéniques et antiandrogéniques des écrans solaires chimiques. Même si une récente méta-analyse a fait état d'un lien entre l'oxybenzone et des effets négatifs sur l'appareil reproducteur des poissons, la littérature résumée était hétérogène et par conséquent, les résultats étaient peu concluants 50 . Chez des sujets humains, une étude prospective a mentionné une baisse de la fertilité chez des hommes ayant été exposés à la benzophénone-2 et à la 4-hydroxybenzophénone, mais ces observations pourraient être dues à des variables de confusion propres à l'étude 51 . ...
... Chez des sujets humains, une étude prospective a mentionné une baisse de la fertilité chez des hommes ayant été exposés à la benzophénone-2 et à la 4-hydroxybenzophénone, mais ces observations pourraient être dues à des variables de confusion propres à l'étude 51 . Une revue systématique qui évaluait des études chez l'animal et chez l'humain, a mentionné que des taux élevés d'exposition à l'oxybenzone durant la grossesse étaient associés à une diminution de l'âge gestationnel chez les nouveau-nés de sexe masculin et à des poids à la naissance plus bas chez les nouveau-nés de sexe féminin 50 . Une forte hétérogénéité a toutefois limité l'utilité de cette étude 50 . ...
... Phenols are widely used in food packaging materials, personal care products, and numerous other consumer products (16)(17)(18)(19)(20), resulting in ubiquitous exposure (21,22). Bisphenols, benzophenones, triclosan, and parabens are among the most studied phenols because of concerns about their endocrine active properties and their widespread population exposure (17,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). ...
... BPS and several parabens have been shown to induce oxidative stress and impair hormonal signaling in female reproductive tissues (89)(90)(91) and are linked to oxidative stress markers in pregnant women (92,93). Although benzophenone-3 is also suspected of interfering with steroid hormone regulation (25), and triclosan may interact with the thyroid axis (30), limited experimental data exist in relation to perinatal outcomes. The observed sex differences may be because of the differences in the expression of endocrine receptors between female and male fetuses. ...
Article
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Objective To explore windows of vulnerability to prenatal urinary phenol concentrations and preterm birth. Design Prospective cohort. Setting A large fertility center in Boston, Massachusetts. Patient(s) A total of 386 mothers who sought fertility treatment and gave birth to a singleton between 2005 and 2018. Intervention(s) None. Main outcome measure(s) Singleton live birth with gestational age <37 completed weeks. Result(s) Compared with women with non-preterm births, urinary bisphenol A (BPA) concentrations were higher across gestation among women with preterm births, particularly during mid-to-late pregnancy and among those with female infants. Second trimester BPA concentrations were associated with preterm birth (Risk Ratio [RR] 1.24; 95%CI: 0.92, 1.69), which was primarily driven by female (RR 1.40; 95%CI: 1.04, 1.89) and not male (RR 0.85; 95%CI 0.50, 1.46) infants. First trimester paraben concentrations were also associated with preterm birth (RR 1.17; 95%CI: 0.94, 1.46) and similarly the association was only observed for female (RR 1.46; 95% CI: 1.10, 1.94) and not male infants (RR 0.94; 95%CIC: 0.72, 1.23). First trimester urinary bisphenol S concentrations showed a suggested risk of preterm birth (RR 1.25; 95%CI: 0.82, 1.89), although the small case numbers precluded sex-specific examination. Conclusion(s) We found preliminary evidence of associations between mid-to-late pregnancy BPA and early pregnancy paraben concentrations with preterm birth among those with female infants only. Preterm birth risk may be compound, sex, and window specific. Given the limited sample size of this cohort, results should be confirmed in larger studies, including fertile populations.
... Although a recent meta-analysis found that oxybenzone is associated with reproductive adverse effects in fish, the summarized literature was nonuniform and the results therefore uninformative. 50 Among human research participants, a prospective study noted reduced fecundity when men were exposed to benzophenone-2 and 4-hydroxybenzophenone, but the findings could be explained by study confounding. 51 One systemic review, which evaluated both animal and human studies, found that high levels of oxybenzone exposure during pregnancy were associated with decreased gestational age in male neonates and decreased birthweight in female neonates. ...
... 51 One systemic review, which evaluated both animal and human studies, found that high levels of oxybenzone exposure during pregnancy were associated with decreased gestational age in male neonates and decreased birthweight in female neonates. 50 However, high heterogeneity limited the usefulness of the study findings. 50 ...
... Abschließend deuten auch Ergebnisse unserer Arbeitsgruppen aus den vergangen Jahren stark darauf hin, dass der häufig in Sonnencremes eingesetzte UV-Filter Benzophenon-3 zu einer Veränderung des fetalen Wachstums und des Geschlechterverhältnisses der Nachkommen bei Mäusen führen kann [36]. Benzophenon-3 lässt sich ebenfalls den Umweltgiften zuordnen, da sich dieser Stoff unter anderem in Abwässern wiederfinden lässt [13] und seit kurzer Zeit zunehmend im Kontext der Reproduktionsbiologie auf seine reproduktiven Effekte im weiblichen Organismus hin untersucht wird [12,36,37]. Studien zu dessen Effekten nach isolierter Exposition sowie in Kombination mit anderen Umweltgiften, wie BPA, befinden sich derzeit auch in unserer Arbeitsgruppe in Durchführung und werden wichtige Ergebnisse zu gesundheitsrelevanten Konsequenzen einer perinatalen Exposition zutage fördern. ...
Article
Background Exposure to environmental chemicals is ubiquitous in industrialized countries.Objectives Defining paths of exposure and health-related effects with regard to female reproductive parameters, perinatal programming and intrauterine fetal development.Methods Evaluation of and reflection on the recent body of literature on this topic and a presentation of novel findings and relevant future perspectives.ResultsEpidemiologic studies have proven that, in today’s environment, humans and animals alike are exposed to environmental toxicants and that, despite strict regulations, health effects cannot be ruled out, but appear instead highly likely. Mechanistic research can contribute to a better understanding of these threats and highlight their urgency.Conclusions Following novel epidemiologic and experimental studies, the significance of and risks to reproduction and infant development from environmental toxicants can be better understood and political decision-making and medical prevention of health effects further advanced.
... Oxybenzone is one of the most studied UV filters. Its occurrence and toxicity have been emphasized on a wide range of organisms, including species from multiple trophic levels (Ghazipura et al. 2017;Kim and Choi 2014). However, only a few studies have investigated its impact at the molecular scale to determine the cause and the underlying mechanisms of the toxicity. ...
Thesis
UV filters are the active components of sun protection products and are used as stabilizing agents in cosmetics and industrial products. Several studies reported the worldwide occurrence of UV filters in coastal waters and demonstrated their bioaccumulation and toxic effects on aquatic organisms. Marine bacteria dominate the marine biomass and are crucial for biogeochemical cycles. Notwithstanding their essential roles, the toxicity of UV filters has never been assessed on microorganisms. This thesis aims to explore the effects of the most occurrent organic UV filters, taking into account the physiological, morphological, and molecular response, on environmentally relevant heterotrophic bacteria, isolated from the bay of Banyuls (NW Mediterranean Sea, France). This project demonstrated the species and compound-dependent bactericidal effects of common organic UV filters on marine bacteria and contributed to a better understanding of the cellular response induced by UV filter exposure. We showed, via morphological investigation and quantitative proteomics, that bacteria exhibited a variety of stress-related molecular responses, emphasizing that bacteria are suitable for ecotoxicological studies. Future meta-omic research on natural and artificial communities will enable us to assess the impact of anthropogenic inputs on the functions of microbial communities.
... Deste modo, além da exposição direta durante a aplicação (através da pele ou inalação) de compostos como PCPs ou consumo de produtos farmacêuticos ou drogas ilícitas, o consumo de água e alimentos é uma importante via de exposição aos contaminantes emergentes para os seres humanos. Embora até o momento poucos estudos tenham investigado os potenciais efeitos adversos relacionados aos contaminantes emergentes em seres humanos, suspeita-se que a exposição a compostos como a benzofenona possa estar relacionada a efeitos reprodutivos (GHAZIPURA et al., 2017). Além disso, as fragrâncias galaxolida e tonalida parecem se acumular em tecidos adiposos de seres humanos (SCHIAVONE et al., 2010). ...
... This is of concern because oxybenzone has been reported to disrupt the endocrine system in humans and has been linked to female infertility and low birth weight; further study is needed to evaluate the causality of this association. [38][39][40] Significant transdermal penetration and detectable plasma levels after maximal usage sunscreen application (ie, to 75% of body surface area, at 2 mg/cm 2 ) have also been demonstrated for avobenzone, octocrylene, ecamsule, homosalate, octisalate, and octinoxate, even after a single application. 36,37 All 6 active ingredients were detectable in plasma for up to 21 days. ...
Article
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The effects of solar radiation on human skin differ based on skin phototype, the presence or absence of photodermatoses, biological capacity to repair DNA damage, wavelength, intensity of sun exposure, geographic latitude, and other factors, underscoring the need for a more tailored approach to photoprotection. To date, the focus of photoprotection guidelines has been to prevent sunburn and DNA damage induced by ultraviolet (UV) radiation, both UVB and UVA; however, several recent studies have shown that visible light (VL) also generates reactive oxygen and nitrogen species that can contribute to skin damage and pigmentation on the skin, particularly in people of color. Therefore, dark-skinned individuals, while naturally better protected against UVB radiation by virtue of high eumelanin content in melanocytes, may need additional protection from VL-induced skin damage. The current options for photoprotection products need to expand, and potential strategies against VL include the addition of iron oxide, titanium dioxide, and biologically relevant antioxidants to sunscreen formulations, as well as supplementation with orally active antioxidants.
... Benzophenones (BPs) are one of the emerging environmental pollutants and are listed in the group of endocrinedisrupting chemicals (EDCs) which can interfere with the function of human and animal hormones (Yang et al. 2013;Darbre 2019). These compounds are used in personal care products, cosmetics, sunglasses, plastic packaging, and sunscreens as UV protectors (Ghazipura et al. 2017). BPs may naturally be present in some foods such as grapes, mountain papaya, and black tea (Heurung et al. 2014). ...
Article
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In recent decades, emerging environmental pollutants such as endocrine-disrupting chemicals (EDCs) have become a particular concern. This study examined the association of maternal exposure to benzophenones as one of the EDCs with gestational age and evaluated their effects on birth outcomes including birth weight, birth length, head circumference, and Ponderal Index. We assessed 166 pregnant mothers of the PERSIAN cohort population of Isfahan, Iran, in the 1st and 3rd trimesters of pregnancy and their infants at birth. Four common benzophenones (BPs) 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 urinary concentrations of 4-OH-BP, BP-3, BP-1, and BP-8 in the 1st trimester were 6.62, 7.5, 4.39, and 1.32 µg/g creatinine and those in the 3rd trimester were 3.15, 16.98, 9.95, and 1.04 µg/g creatinine, respectively. BP-3 was the predominant metabolite in both trimesters. There was a significant correlation between BP-3, BP-1, and 4-OH-BP levels (p < 0.05) but not BP-8. BP-1 showed a significant positive association with gestational age (GA) in all infants in the 1st trimester, but a negative association was observed between BP-3 and BP-1 levels and GA in girls. Classification of infants’ birth weight for different GAs represented that the majority of them were appropriate for GA. However, boys’ weights were heavier than girls. Also, birth outcomes of preterm (< 37 weeks) infants were noticeably lower than term infants (37–42 weeks). This study demonstrated that benzophenone derivatives especially BP-3 can affect the duration of pregnancy and consequently fetal growth in the early and late stages of pregnancy. This is more pronounced in girls; however, more investigations in a different population are needed to prove the results. Therefore, the application of these compounds as a UV protector requires precise regulation to reduce exposure, especially in pregnant women.
... UV filters may cause toxic effects on several organisms such as humans, rats and aquatic organisms [16,18,29,30]. However, the existing data are not consistent, particularly regarding BP-3 and TiO 2 NPs toxicity. ...
Article
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UV filters are potentially harmful to marine organisms. Given their worldwide dissemination and the scarcity of studies on marine fish, we evaluated the toxicity of an organic (oxybenzone) and an inorganic (titanium dioxide nanoparticles) UV filter, individually and in a binary mixture, in the turbot (Scophthalmus maximus). Fish were intraperitoneally injected and a multi-level assessment was carried out 3 and 7 days later. Oxybenzone and titanium dioxide nanoparticles induced mild effects on turbot, both isolated and in mixture. Neither oxidative stress (intestine, liver and kidney) nor neurotoxicity (brain) was found. However, liver metabolic function was altered after 7 days, suggesting the impairment of the aerobic metabolism. An increased motility rate in oxybenzone treatment was the only behavioural alteration (day 7). The intestine and liver were preferentially targeted, while kidney and brain were unaffected. Both infra- and supra-additive interactions were perceived, with a toxicodynamic nature, resulting either in favourable or unfavourable toxicological outcomes, which were markedly dependent on the organ, parameter and post-injection time. The combined exposure to the UV filters did not show a consistent increment in toxicity in comparison with the isolated exposures, which is an ecologically relevant finding providing key information towards the formulation of environmentally safe sunscreen products.
... In addition, decrease in egg production, hatching, testosterone, and steroidogenic genes were reported for other vertebrate animals exposed to BP-3. 52 However, based on continuous release of BP-3 to water bodies as well as its physicochemical properties further studies should be performed to investigate levels and effects induced by BP-3 worldwide. ...
Article
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The occurrence of emerging contaminants (ECs) in the aquatic systems under influence of urban areas have been considered as an environmental marker of anthropogenic contamination. In this study 10 ECs were investigated in sediment samples from Santos Bay using a quick, easy, cheap, effective, rugged, and safe method with determination by liquid chromatography tandem mass spectrometry. The method showed acceptable accuracy (51-116%) and precision (relative standard deviation (RSD) ≤ 9), limits of quantification in ng g-1 levels and matrix effect lower than 29%. Environmental occurrence of benzophenone-3, caffeine, ketoconazole and triclocarban was detected in two campaigns (2015 and 2019), with concentrations ranging from < 1 to 470 ng g-1. Caffeine and triclocarban were the most abundant target chemicals occurring in up to 71 and 100% of the sample point, respectively. The results indicated that ECs in sediment samples came from diffused sources as the discharge of treated and untreated sewage in the estuary.
... Furthermore, oxybenzone was identified as an allergen in 1-3% of the population [77] and while allergic reactions to sunscreens affect only a small proportion of the population, oxybenzone is a common photoallergic agent [78]. In addition to the weight of epidemiological cues, as described in more detail above, mammalian toxicological studies similarly point to oxybenzone's effects on the structure and function of tissues including endocrine organs [79]. Regardless, some dermatologists continue to promote chemical sunscreens as the ultimate means of sun safety and call for epidemiological studies to detect a "population-wide signal" for an effect of sunscreen use on human health before even entertaining the possibility that oxybenzone might cause harm. ...
Article
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Background Technological advancements make lives safer and more convenient. Unfortunately, many of these advances come with costs to susceptible individuals and public health, the environment, and other species and ecosystems. Synthetic chemicals in consumer products represent a quintessential example of the complexity of both the benefits and burdens of modern living. How we navigate this complexity is a matter of a society’s values and corresponding principles. Objectives We aimed to develop a series of ethical principles to guide decision-making within the landscape of environmental health, and then apply these principles to a specific environmental chemical, oxybenzone. Oxybenzone is a widely used ultraviolet (UV) filter added to personal care products and other consumer goods to prevent UV damage, but potentially poses harm to humans, wildlife, and ecosystems. It provides an excellent example of a chemical that is widely used for the alleged purpose of protecting human health and product safety, but with costs to human health and the environment that are often ignored by stakeholders. Discussion We propose six ethical principles to guide environmental health decision-making: principles of sustainability, beneficence, non-maleficence, justice, community, and precautionary substitution. We apply these principles to the case of oxybenzone to demonstrate the complex but imperative decision-making required if we are to address the limits of the biosphere’s regenerative rates. We conclude that both ethical and practical considerations should be included in decisions about the commercial, pervasive application of synthetic compounds and that the current flawed practice of cost-benefit analysis be recognized for what it is: a technocratic approach to support corporate interests.
... Detections of BP-3 in fresh water, sea water, swimming pools, ground water, sediments and even tap water have been reported (Langford et al., 2015;Sánchez-Quiles and Tovar-Sánchez, 2015). Through dermal application and water intake, BP-3 can enter human body and has already been detected in human urine, blood, placental tissues and breast milk (Ghazipura et al., 2017;Wang et al., 2021), which could induce neurotoxicity, cytotoxicity, estrogenic effect, reproductive toxicity and gastrointestinal abnormality in in-vivo and in-vitro studies (Suzuki et al., 2005;Kunz and Fent, 2006;Wang et al., 2021). The ubiquitous occurrence and physiological toxicity characterize the potential risk of BP-3 to both ecosystem and especially human health, which is worthy of public concern (Kim and Choi, 2014;Mao et al., 2018). ...
Article
Microplastics (MPs) are global pollutants with heightened environmental and health concerns in recent years because of their worldwide distribution across aquatic environments, ability to load chemical contaminants and the potential for ingestion by animals, including human. In this study, three commonly used and environmentally detected plastics, i.e. polystyrene, polyethylene, polypropylene with sizes of 550, 250 and 75 μm, plus two submicron-sized polystyrene microplastics (5 and 0.5 μm) were assessed as solid adsorbents for a prevalent UV filter, benzophenone-3 (BP-3). The affinity and process of adsorption exhibited differentials among different sizes and types of MPs. Apparent desorption of BP-3 from MPs under simulated gastrointestinal conditions was not significantly enhanced, which might be due to the presence of the enzyme proteins, indicating potential risk of the contaminants carried by MPs. The desorption of BP-3 from MPs was affected by the size, type of MPs and the components of the gastrointestinal fluid.
... • Mineral sunscreens containing zinc oxide or titanium dioxide as active ingredients are much safer alternatives to those containing oxybenzone (Benzophenone-3). Oxybenzone is an established EDC with estrogenic and androgenic activities, and the agent is prevalent in the body fluids of humans [93]. • Minimize exposure to air-born EDCs (Dioxins) with smoking cessation and by wearing facial masks with air filters when outside on poor air quality days or in cities with high levels of air pollution: https://www.iqair.com/us/world-air-quality-ranking; ...
Article
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The relationship between endocrine disrupting chemicals (EDCs) and the pathogenesis of acne vulgaris has yet to be explored in the literature. Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit. The pathogenesis of acne involves several hormonal pathways, including androgens, insulin-like growth factor 1(IGF-1), estrogens, and corticosteroids. EDCs influence these pathways primarily through two mechanisms: altering endogenous hormone levels and interfering with hormone receptor function. This review article describes the mechanistic links between EDCs and the development of acne lesions. Highlighted is the contributory role of androgen receptor ligands, such as bisphenol A (BPA) and mono-2-ethylhexyl Phthalate (MEHP), via upregulation of lipogenic genes and resultant exacerbation of cholesterol synthesis. Additionally discussed is the protective role of phytoestrogen EDCs in counteracting androgen-induced sebocyte maturation through attenuation of PPARy transcriptional activity (i.e., resveratrol) and restoration of estrogen-regulated TGF-B expression in skin cells (i.e., genistein). Examination of the relationship between EDCs and acne vulgaris may inform adjunctive avenues of treatment such as limiting environmental exposures, and increasing low-glycemic, plant-rich foods in the diet. With a better understanding of the cumulative role that EDCs play in acne, clinicians can be better equipped to treat and ultimately improve the lives of their patients.
... The persistence of traces (1-100 ng L − 1 ) of these pollutants is harmful to living organisms (Bueno et al., 2012). For example, 3-benzophenone shows endocrine disruption in water and toxicity to humans (Ghazipura et al., 2017). Metformin, an anti-diabetic molecule could adversely affect human health (Velázquez and Oliván, 2020). ...
Article
Enormous research studies on the abatement of anthropogenic aquatic pollutants including organic dyes, pesticides, cosmetics, antibiotics and inorganic species by using varieties of semiconductor photocatalysts have been reported in recent decades. Besides, many of these photocatalysts suffer in real applications owing to their high production cost and low stability. In many cases, the photocatalysts themselves are being considered as secondary pollutants. To eliminate these drawbacks, the green synthesized photocatalysts and the use of biopolymers as photocatalyst supports are considered in recent years. In this context, recent developments in green synthesized metals, metal oxides, other metal compounds, and carbon based photocatalysts in water purification are critically reviewed. Furthermore, the pivotal role of biopolymers including chitin, chitosan, cellulose, natural gum, hydroxyapatite, alginate in photocatalytic removal of aquatic pollutants is comprehensively reviewed. The presence of functional groups, electron trapping ability, biocompatibility, natural occurrence, and low production cost are the major reasons for using biopolymers in photocatalysis. Finally, the summary and conclusion are presented along with existing challenges in this research area.
... Human data According to the review by Siller et al. (2018), statistically significant associations between BP-3 exposure during pregnancy and varying birth outcomes have been reported in various studies. One study reported shorter pregnancy length in women gestating male fetuses, two studies reported higher birth weights in male neonates, and one found lower birth weights in female neonates (Ghazipura et al., 2017). ...
Book
The SCCS adopted this document at its plenary meeting on 30-31 March 2021 (77 pages) Mise en ligne le 15 Avril 2021 https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs_o_247.pdf
... [5] BP-3 is widely used in medicine, industry, and as a food additive. [6,7] As a component of organic sunscreen, BP-3 protects human skin and hair from damage caused by excessive UV radiation and can bioaccumulate in biota, causing adverse effects on aquatic organisms [8][9][10] as BP-3 can reach the aquatic environment as a result of recreational activities or as inputs that are released into rivers because effluent treatment plants are unable to remove it. [11] Environmental toxicity studies revealed that BP-3 was capable of inducing high acute toxicity (inhibition of growth or mortality) in Chlorella vulgaris, Daphnia magna e Danio rerio after 48 or 96 h of exposure. ...
Article
Benzophenone-3 (BP-3) is a common component of organic sunscreen widely used that can affect especially aquatic ecosystems health, including fish. To verify the biological effects of low concentrations of BP-3 on blood cells, one hundred and forty zebrafish (D. rerio) were used and then randomly divided into five groups: control group (water), solvent group (alcoholic water), and BP-3 group (BP-3 at 7 mg L À1 , BP-3 at 70 mg L À1 , and BP-3 at 700 mg L À1). The blood slices were stained with Panoptic stain and with Giemsa solution for the hematological analysis. During the exposure to BP-3, no behavioral changes were observed. Although no significant difference in total leuko-cytes occurred, an increase in neutrophils and a reduction of lymphocytes at the highest concentration on both 7th and 14th days were detected. The total and cytoplasmic area of erythrocytes on the 7th day at the highest concentration were reduced. In addition, alterations on the erythro-cyte nuclear morphology in fish exposed to BP-3 were usually visualized, mainly when considered the occurrence of blebbed nucleus and micronucleus, indicating that BP-3 exhibits cytotoxic and mutagenic effects. The results indicate that BP-3 can interfere with the morphophysiology of aquatic organisms. ARTICLE HISTORY
... Deste modo, além da exposição direta durante a aplicação (através da pele ou inalação) de compostos como PCPs ou consumo de produtos farmacêuticos ou drogas ilícitas, o consumo de água e alimentos é uma importante via de exposição aos contaminantes emergentes para os seres humanos. Embora até o momento poucos estudos tenham investigado os potenciais efeitos adversos relacionados aos contaminantes emergentes em seres humanos, suspeita-se que a exposição a compostos como a benzofenona possa estar relacionada a efeitos reprodutivos (GHAZIPURA et al., 2017). Além disso, as fragrâncias galaxolida e tonalida parecem se acumular em tecidos adiposos de seres humanos (SCHIAVONE et al., 2010). ...
... Endocrine disrupting chemicals (EDCs) are exogenous chemicals that can interfere with any aspect of hormone action (Zoeller et al., 2012). Phthalates and phenols are among the most studied EDCs due to concerns of their reproductive and developmental toxicity (Mustieles et al., 2015;Giulivo et al., 2016;Aker et al., 2019;Ghazipura et al., 2017;Peretz et al., 2014;De Felice et al., 2015;Carvaillo et al., 2019;Johnson et al., 2016;Jamal et al., 2019;Nowak et al., 2018;European Chemicals Agency, 2016;Benjamin et al., 2017). Humans are widely exposed to phthalates and phenols from use of plastics, food packaging materials, personal care products, and numerous other everyday consumer products (Mustieles et al., 2015;Freire et al., 2019;Liao and Kannan, 2014;Weatherly and Gosse, 2017;Karpuzoglu et al., 2013;Centers for Disease Control and Prevention, 2017;Calafat et al., 2008;Xu et al., 2020). ...
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Background Parental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown. Methods We included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples’ joint mixtures in relation to preterm birth. Results PCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples’ total mixture concentrations. Conclusion In this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome.
... [5] BP-3 is widely used in medicine, industry, and as a food additive. [6,7] As a component of organic sunscreen, BP-3 protects human skin and hair from damage caused by excessive UV radiation and can bioaccumulate in biota, causing adverse effects on aquatic organisms [8][9][10] as BP-3 can reach the aquatic environment as a result of recreational activities or as inputs that are released into rivers because effluent treatment plants are unable to remove it. [11] Environmental toxicity studies revealed that BP-3 was capable of inducing high acute toxicity (inhibition of growth or mortality) in Chlorella vulgaris, Daphnia magna e Danio rerio after 48 or 96 h of exposure. ...
... Interestingly, it was also found in amniotic fluids and placenta (Krause et al., 2018;Valle-Sistac et al., 2016) as well as in breast tissue (Barr et al., 2018) and milk (Molins-Delgado et al., 2018;Schlumpf et al., 2010). So far, several studies have reported that the exposure to BP3 and its derivatives alters the female and male reproductive systems of humans and rodents (Ghazipura et al., 2017;Kim and Choi, 2014;Minguez-Alarcon et al., 2019;Nakamura et al., 2018;Santamaria et al., 2019, Santamaria, 2020Schlumpf et al., 2008). Although BP3 has been shown to possess weak estrogenic activity compared to 2,4-dihydroxybenzophenone using in vitro models (Molina-Molina et al., 2008), the concentration of BP3 is ten times higher than its metabolite in human milk which may suggest a possible influence on the development of the mammary gland (Molins-Delgado et al., 2018). ...
Article
The plastic monomer and plasticizer bisphenol A (BPA), and the UV-filter benzophenone-3 (BP3) have been shown to have estrogenic activities that could alter mammary gland development. Our aim was to analyze whether BPA or BP3 direct exposure affects the functional differentiation of the mammary gland using an in vitro model. Mammary organoids were obtained and isolated from 8 week-old virgin female C57BL/6 mice and were differentiated on Matrigel with medium containing lactogenic hormones and exposed to: a) vehicle (0.01% ethanol); b) 1x10-9M or 1x10-6M BPA; or c) 1x10-12M, 1x10-9M or 1x10-6M BP3 for 72 h. The mRNA and protein expression of estrogen receptor alpha (ESR1) and progesterone receptor (PR) were assessed. In addition, mRNA levels of PR-B isoform, glucocorticoid receptor (GR), prolactin receptor (PRLR) and Stat5a, and protein expression of pStat5a/b were evaluated at 72 h. The mRNA and protein expression of milk proteins and their DNA methylation status were also analyzed. Although mRNA level of PRLR and GR was similar between treatments, mRNA expression of ESR1, total PR, PR-B and Stat5a was increased in organoids exposed to 1x10-9M BPA and 1x10-12M BP3. Total PR expression was also increased with 1x10-6M BPA. Nuclear ESR1 and PR expression was observed in all treated organoids; whereas nuclear pStat5a/b alveolar cells was observed only in organoids exposed to 1x10-9M BPA and 1x10-12M BP3. The beta-casein mRNA level was increased in both BPA concentrations and 1x10-12M BP3, which was associated with hypomethylation of its promoter. The beta-casein protein expression was only increased with 1x10-9M BPA or 1x10-12M BP3. In contrast, BPA exposure decreased alpha-lactalbumin mRNA expression and increased DNA methylation level in different methylation-sensitive sites of the gene. Also, 1x10-9M BPA decreased alpha-lactalbumin protein expression. Our results demonstrate that BPA or BP3 exposure alters milk protein synthesis and its transcriptional regulation during mammary gland differentiation in vitro.
... Many marine species, especially corals and fish, will have a very defined duration in which to spawn (full moon) of a single month for the entire year. Several studies have shown that certain petrochemical UV-filter ingredients can be toxic to gametes and may even prevent successful fertilization events (Blüthgen et al., 2012;Coronado et al., 2008;Ghazipura et al., 2017;Rehfeld et al., 2018;Xu et al., 2021). Fertilization/spawning events may not be the only critical facet of an organism's life cycle. ...
Article
In 2019, sands in nearby runoff streams from public beach showers were sampled on three islands in the State of Hawaii and tested for over 18 different petrochemical UV filters. Beach sands that are directly in the plume discharge of beach showers on three of the islands of Hawaii (Maui, Oahu, Hawai’i) were found to be contaminated with a wide array of petrochemical-based UV-filters that are found in sunscreens. Sands from beach showers across all three islands had a mean concentration of 5,619 ng/g of oxybenzone with the highest concentration of 34,518 ng/g of oxybenzone at a beach shower in the Waikiki area of Honolulu. Octocrylene was detected at a majority of the beach shower locations, with a mean concentration of 296.3 ng/g across 13 sampling sites with the highest concentration of 1,075 ng/g at the beach shower in Waikiki. Avobenzone, octinoxate, 4-methylbenzylidene camphor and benzophenone-2 were detected, as well as breakdown products of oxybenzone, including benzophenone-1, 2,2'-dihydroxy-4-methoxybenzophenone, and 4-hydroxybenzophenone. Dioxybenzone (DHMB) presented the highest concentration in water (75.4 ng/mL), whereas octocrylene was detected in all water samples. Some of these same target analytes were detected in water samples on coral reefs that are adjacent to the beach showers. Risk assessments for both sand and water samples at a majority of the sampling sites had a Risk Quotient >1, indicating that these chemicals could pose a serious threat to beach zones and coral reef habitats. There are almost a dozen mitigation options that could be employed to quickly reduce contaminant loads associated with discharges from these beach showers, like those currently being employed (post-study sampling and analysis) in the State of Hawaii, including banning the use of sunscreens using petrochemical-based UV filters or educating tourists before they arrive on the beach.
... Interestingly, 11-KT was higher in the intermediate group (Fig. 5). Contrary to the well-established relationship between cortisol (stress) and learning, androgen levels appear to be mainly associated with reproductive features (for a review, see Ghazipura et al., 2017). Although some studies (Knapp et al., 1999;Hirschenhauser et al., 2004;Rodgers et al., 2006) have shown controversial results regarding androgens' effect on parental care in bony fishes, the association between 11-KT and learning is not conclusive in this study, our results may indicate some role of the hormone, opening pathways for more profound studies in the future. ...
Article
Individuals within a population present behavioral responses that vary according to intrinsic and extrinsic factors such as ontogenetic phase, nutritional status, reproductive stage, and previous experiences. These differences can be explained by endogenous changes, such as hormone release, that can modulate reproductive behaviors, stress response, and cognitive processes. In order to investigate the relationship between behavior and hormonal levels in the fighting fish Betta splendens, the present study characterized nest building, aggressive behavior, learning of a task, and levels of cortisol and 11-ketotestosterone (11-KT) in 86 male Fighting fish. At the beginning of the experiment (days 1-4), fish were characterized as nest builders, intermediate builders, or non-builders. They were then sequentially tested for aggression (days 7-8), learning performance (days 11-21), and circulating hormone levels (day 23). Nest builders showed the lowest hormonal levels at the end of the experiment and low aggressiveness; Intermediate builders presented low cortisol, but high KT levels and best learned the task; Non-builders were the most aggressive animals with higher cortisol levels (at day 23). Our data suggest that in B. splendens, aggressive behavior and learning performance are related to the relative investment in reproduction and variation in circulating levels of corticosteroids and androgens.
... Studies have shown that oxybenzone and octinoxate are largely responsible for contact allergic reactions and are considered to disrupt the endocrine system in humans because they can penetrate intact skin (their concentration can be measured in urine and serum) (70). These filters have been shown to have an anti-androgenic and estrogenic effect, they may affect pregnancy duration, and they have been linked to coral reef bleaching (70)(71)(72). Although there are conflicting data about the safety of chemical filters (some studies dismiss the theory of endocrine disruption) (73,74), safe and appropriate use of sunscreen products should be encouraged. ...
Article
The main environmental element causing photoaging is ultraviolet (UV) light, and this involves an extrinsic mechanism of skin aging superimposed on an intrinsic process. Clinical (evident) characteristics of photoaging include the presence of deep wrinkles, deterioration of skin laxity, and hyperpigmentation. In the UV light spectrum, UVA and UVB radiation cause the most damage in photoaging. UVB light has shorter wavelengths and is mostly absorbed by the stratum corneum, causing erythema and changes in the epidermis, whereas UV rays with longer wavelengths (i.e., UVA) penetrate to the deepest layer of the skin (i.e., the dermis) and interact with DNA. As a result of UV radiation, chemical reactions in the skin produce reactive oxygen species (ROS), which cause protein denaturation, impairment of RNA and DNA synthesis, and damage to the skin structure. Using local sunscreen agents can not only prevent sunburn, but also help prevent photocarcinogenesis and photoaging. Therefore, many epidemiological studies have been conducted with results showing credible and positive evidence for the safety and efficacy of sunscreen to prevent photoaging and photocarcinogenesis.
... Further, the results of several studies on organic filters to protect the skin against UVR have found that after topical use, they are absorbed by human skin and may cause many adverse effects and, due to their penetration, they cause phototoxic plus photoallergic reactions in the body (Giokas et al. 2007;Haisma and Schuttelaar 2017). Other harmful effects of these filters include allergic reactions, dermatitis, anaphylaxis, and male fertility disorders by affecting sperm function (Lautenschlager et al. 2007;Chen et al. 2013;Ghazipura et al. 2017;Joensen et al. 2017). Thus, efforts are continuously made to find natural compounds with biological potentials to be applied in transdermal formulations, especially in sunscreens (including absorption and dispersion properties), which can be introduced as an alternative to artificial compounds in sunscreens (Saewan and Jimtaisong 2015;Li et al. 2017). ...
Article
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Phlorotannins are polyphenolic compounds in brown algae and can be used as a natural UV filter in sunscreen formulations. The aim of the present study was to characterize the biological activities of phlorotannins-rich fractions from the brown alga Polycladia myrica and to validate the protective effect as well as stability of cream formulation with phlorotannins against UVR. With respect to antioxidant properties, the ethyl acetate fraction (EF) possessed the highest DPPH radical scavenging (65 ± 0.2%), and the highest antioxidant activity (11.2 ± 0.2 μg ASA mg⁻¹). The EF was active against Gram-positive bacteria with EF effectively reducing UVB-induced cytotoxicity in HaCaT keratinocytes. The cream formulation with 5% EF revealed a high sun protective factor (31.79 ± 4.73), UVA/PF (24.67 ± 4.03), critical wavelength (383.2 ± 0.1 nm), and UVA/UVB ratio (0.98 ± 0.01). The cream formulation was completely homogeneous and had a pH close to human skin pH. The cream was stable in the cooling-heating cycle and the DPPH scavenging activity of the cream was not altered for 30 days of storage at temperatures of 4–40 °C. These findings are promising for the use of brown alga P. myrica extract as a valuable source of sunscreen protective substance for pharmaceutical and cosmetic applications.
... Within the CLP regulation (EC No. 1272/2008) (classification, labeling, and packaging) [16], BP-3 is not considered to meet the criteria for reproductive toxicity classification [7]. Systematic reviews have highlighted a varying relationship between BP-3 exposure and estrogenic, androgenic, and antiandrogenic activities frequently reported in vivo and in vitro [17,18]. However, the clinical relevance of the endocrine effects in these studies is not always clear, and uncertainty remains over when the observed endocrine effects can be interpreted as adverse. ...
Article
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Safety assessment of UV filters for human health by the Scientific Committee on Consumer Safety (SCCS) is based on the estimation of internal dose following external (skin) application of cosmetic products, and comparison with a toxicological reference value after conversion to internal dose. Data from human biomonitoring (HBM) could be very useful in this regard, because it is based on the measurement of real-life internal exposure of the human population to a chemical. UV filters were included in the priority list of compounds to be addressed under the European Human Biomonitoring Initiative (HBM4EU), and risk assessment of benzophenone-3 (BP-3) was carried out based on HBM data. Using BP-3 as an example, this study investigated the benefits and limitations of the use of external versus internal exposure data to explore the usefulness of HBM to support the risk assessment of cosmetic ingredients. The results show that both approaches did indicate a risk to human health under certain levels of exposure. They also highlight the need for more robust exposure data on BP-3 and other cosmetic ingredients, and a standardized framework for incorporating HBM data in the risk assessment of cosmetic products.
... Based on acute toxicity tests, performed using single substances, adverse effects on aquatic invertebrates are estimated to occur at a concentration range of µg/L for BP-12 and in the low mg/L range for BP, BP-1, -3, -4, -6, -7 and -8. Since many of the possible toxic effects towards humans and animals have already been reviewed elsewhere (Díaz-Cruz and Barceló, 2009;Ghazipura et al., 2017;Kim and Choi, 2014), Table 1 provides a brief overview of respective ecotoxicological and hormonal data. ...
Article
Benzophenone-type UV filters (BPs) represent a very diverse group of chemicals that are used across a range of industrial sectors around the world. They are found within different environmental compartments (e.g. surface water, groundwater, wastewater, sediments and biota) at concentrations ranging from ng/L to mg/L. Some are known as endocrine disruptors and are currently within the scope of international regulations. A structural alert for high potential of endocrine disrupting activity was assigned to 11 BP derivatives. Due to the widespread use, distribution and disruptive effects of some BPs, knowledge of their elimination pathways is required. This review demonstrates that biodegradation and photolytic decomposition are the major elimination processes for BP-type UV filters in the environment. Under aerobic conditions, transformation pathways have only been reported for BP, BP-3 and BP-4, which are also the most common derivatives. Primary biodegradation mainly results in the formation of hydroxylated BPs, which exhibit a structure-related increase in endocrine activity when compared to their parent substances. By combining 76 literature-based transformation products (TPs) with in silico results relating to their receptor activity, it is demonstrated that 32 TPs may retain activity and that further knowledge of the degradation of BPs in the environment is needed.
... In addition, BPs have been linked to hormone disruption, cell damage, and fecundity reduction in human beings (Han et al., 2016) and reproduction system disruption in rats (Ghazipura et al., 2017). Lozano et al. (2020) reviewed several studies that reported the bioaccumulation and toxic effects of BPs in marine species, e.g., corals, crustaceans, and algae. ...
Article
Benzophenone (BP) and its derivatives are extensively used as ultraviolet filters in modern society and increasingly being released into the environment. Co-composting of food waste with sawdust and mature compost was successfully demonstrated to treat high BP concentration (927 ± 229 mg kg⁻¹), with a removal efficiency of 97% after 35 days of incubation. The highest biodegradation rate of 55 mg kg⁻¹day⁻¹ was observed at the thermophilic stage. The biodegradation followed second-order kinetics, and the half-life of BP was 1.3 days during the co-composting process. Additionally, malodorous gas emissions from the co-composting process were also analyzed. The malodorous compounds, including ammonia (NH3), hydrogen sulfide (H2S), and volatile organic sulfide compounds (VOSCs), peaked at the thermophilic phase. NH3 and H2S were the main components contributing to 92% and 7.6% of the total malodorous concentration (617 ppm). dimethyl disulfide (28.9 ppb) and dimethyl sulfide (23.5 ppb) concentrations accounted for ∼58.9% of the total VOSC emitted. The malodorous emissions were positively correlated with temperature, pH, and negative with oxygen content during the co-composting. Sawdust and mature compost enhanced oxygen penetration in the compost mixture and thereby reduced odor emission. These results support that co-composting could be a technically and economically feasible treatment technology for the degradation of BP and can be used to treat other emerging organic pollutants.
... A BP-3, cujo coeficiente situa-se de médio para alto, tem lenta biodegradação e baixa volatilização, o que favorece sua adsorção em sedimentos e sólidos em suspensão (GHAZIPURA et al., 2017;PAESE, 2008;ROGGIA et al., 2014), e faz dela o filtro orgânico com maior índice de detecção em amostras ambientais, principalmente em águas recreacionais durante o verão (PAREDES et al., 2014). ...
... A BP-3, cujo coeficiente situa-se de médio para alto, tem lenta biodegradação e baixa volatilização, o que favorece sua adsorção em sedimentos e sólidos em suspensão (GHAZIPURA et al., 2017;PAESE, 2008;ROGGIA et al., 2014), e faz dela o filtro orgânico com maior índice de detecção em amostras ambientais, principalmente em águas recreacionais durante o verão (PAREDES et al., 2014). ...
Article
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Sunscreens are topical preparations containing any number of ultraviolet filters (UVFs). The first part of the review will focus on the recent Food and Drug Administration (FDA) regulations of 2019 and general use of these agents. While sunscreen products are becoming more regulated in the United States, we still lag behind other countries in our options for UVFs. Sun protection to prevent skin cancer and aging changes should be a combination of sun avoidance, protective structures, and clothing as well as use of sunscreen products. Newer and safer products are needed to help supplement and replace older agents as well as improve their cosmetic acceptability. This will be a review of ingredients, local toxicities (i.e. contact dermatitis, photocontact dermatitis), special considerations for children, and cosmesis of sunscreen preparations. Part 2 will focus on the environmental, ecological and human toxicities that have been increasingly related to UVFs.
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https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs_o_247.pdf - Conclusion of the opinion: (1) In light of the data provided and taking under consideration the concerns related to potential endocrine disrupting properties of Benzophenone-3, does the SCCS consider Benzophenone-3 safe when used as a UV-filter in cosmetic products up to a maximum concentration of 6% and up to 0.5% in cosmetic products to protect product formulation? On the basis of safety assessment, and considering the concerns related to potential endocrine disrupting properties of benzophenone-3 (BP-3), the SCCS has concluded that: a. The use of BP-3 as a UV-filter up to a maximum concentration of 6% in sunscreen products, either in the form of body cream, sunscreen propellant spray or pump spray, is not safe for the consumer. b. The use of BP-3 as a UV-filter up to a maximum concentration of 6% in face cream, hand cream, and lipsticks is safe for the consumer. c. The use of BP-3 up to 0.5% in cosmetic products to protect the cosmetic formulation is safe for the consumer. (2) Alternatively, what is according to the SCCS the maximum concentration considered safe for use of Benzophenone-3 as a UV-filter in cosmetic products? In the SCCS’s opinion, the use of BP-3 as a UV filter in the following sunscreen products is safe for the consumer up to a maximum concentration of: a. 2.2% in body creams, in propellant sprays and in pump sprays, provided that there is no additional use of BP-3 at 0.5% in the same formulation for protecting the cosmetic formulation. b. Where BP-3 is also used at 0.5% in the same formulation, the levels of BP-3 used as UV filter should not exceed 1.7% in body creams, in propellant sprays and in pump sprays. (3) Does the SCCS have any further scientific concerns with regard to the use of Benzophenone-3 in cosmetic products? It needs to be noted that the SCCS has regarded the currently available evidence for endocrine disrupting properties of BP-3 as inconclusive, and at best equivocal. This applies to all of the available data derived from in silico modelling, in vitro tests and in vivo studies, either considered individually or taken together. The SCCS considers that, whilst there are indications from some studies to suggest that BP-3 may have endocrine effects, the evidence is not conclusive enough at present to enable deriving a specific endocrine-related toxicological point of departure for use in safety assessment. ________________________________________ Keywords: SCCS, scientific opinion, Benzophenone-3, UV filter, Regulation 1223/2009, CAS Number 131-57-7, EC No 205-031-5 ________________________________________ Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on Benzophenone-3 (CAS No 131-57-7, EC No 205-031-5), preliminary version of 15 December 2020, SCCS/1625/20.
Article
Background Following a growing mistrust in a certain number of ingredients used by the cosmetic industry, it has become popular in recent years for consumers to make their own products at home. This trend now touches on all areas of the industry, but is especially found in the hygiene sector, with shampoos and toothpaste, and the care sector, with moisturizers and sunscreen, products. Objectives The objective of this study is to analyze sunscreen recipes found on the Internet and to assess their level of photoprotective efficacy. Materials and Methods Fifteen Internet recipes were chosen, and then, the products were made in the laboratory following the protocols described. Using an in vitro method, the following efficacy indicators were determined for the preparations made: the Sun Protection Factor (SPF), the Production Factor in the UVA domain (PF‐UVA), and the critical wavelength (λc). Results Three of the 15 recipes studied do not contain any sunscreen and therefore constitute a major risk for users in case of exposure to the sun. The other 12 cannot be considered as sun protection products since all of them have an SPF under 6, the threshold value required in Europe. Conclusion The recipes that we collected on the Internet are very dangerous since some of them have no photoprotective effect whatsoever and most of them do not ensure a sufficient level of photoprotection for the persons using them.
Article
Bisphenols and benzophenone UV-filters are hazardous, high production volume chemicals. There is concern that these contaminants could leach into the environment or be recycled into new products during waste management. To investigate this, nine bisphenols and five benzophenones were quantified in Norwegian e-waste and vehicle fluff. To understand their leachability, equilibrium passive sampling methodology, using polyoxymethylene (POM), was calibrated for these substances, many of which for the first time. This method can differentiate freely dissolved substances in the aqueous phase from those sorbed to suspended colloids and microplastics in the leachate water. Equilibrium POM partitioning was reached within 14 days of shaking; all bisphenols and benzophenone UV-filters exhibited linear isotherms (R² ranged from 0.83 to 1.0), when deriving POM-water partition coefficients (KPOM). Bisphenol A and bisphenol F displayed the highest concentrations, with maximum levels of 246,000 and 42,400 ng g⁻¹, respectively. Logarithms of waste-water partition coefficients (log Kwaste) ranged from 1.7 (benzophenone 2) to 4.5 (bisphenol P). The established KPOM values agreed with measured Kwaste values (within a factor of ~3), unlike octanol-water partition coefficients. This indicated that POM is a better surrogate for waste plastic partitioning than octanol. Results are discussed in the context of assessing risks from waste management in a circular economy.
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Sulisobenzone (BP-4) is one of the benzophenone type UV filters most frequently detected in aquatic ecosystems. As a suspected endocrine disrupting compound, scarce information is available yet about other molecular effects and its mechanism of action. Here, we used an integrated transcriptomic and metabolomic approach to improve the current understanding on the toxicity of BP-4 towards aquatic species. Gilt-head sea bream individuals were exposed at environmentally relevant concentrations (10 μg L⁻¹) for 22 days. Transcriptomic analysis revealed 371 differentially expressed genes in liver while metabolomic analysis identified 123 differentially modulated features in plasma and 118 in liver. Integration of transcriptomic and metabolomic data showed disruption of the energy metabolism (>10 pathways related to the metabolism of amino acids and carbohydrates were impacted) and lipid metabolism (5 glycerophospholipids and the expression of 3 enzymes were affected), suggesting oxidative stress. We also observed, for the first time in vivo and at environmental relevant concentrations, the disruption of several enzymes involved in the steroid and thyroid hormones biosynthesis. DNA and RNA synthesis was also impacted by changes in the purine and pyrimidine metabolisms. Overall, the multiomic workflow presented here increases the evidence on suspected effects of BP-4 exposure and identifies additional modes of action of the compounds that could have been overlooked by using single omic approaches.
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The growing production of cosmetic products such as organic UV filters (OUVFs) in recent years has raised concern regarding their safety to human and environmental health. The inability of wastewater treatment plants in removing these chemical entities and their high octanol-water partition coefficient values tend to result in the persistence of OUVFs in several environmental matrices, leading these to be categorized as "emerging environmental contaminants" because of their unknown risk. Besides aquatic ecosystem contamination, the application of sludge disposal equally threatens terrestrial biota. Besides, the available reviews focusing on levels of OUVFs in aqueous systems (freshwater and marine), instrumental analysis from various samples, and specific toxicity effects, compiled information on the ecotoxicity of OUVFs is currently lacking. Hence, the present manuscript systematically reviews the ecotoxicity of OUVFs in freshwater and marine organisms occupying lower to higher trophic levels, including the underlying mechanisms of action and current knowledge gaps. The available scientific evidence suggests that OUVFs are a prime candidate for environmental concern due to their potential toxic effects. To the best of our knowledge, this is the first document detailing the toxicological effects of OUVFs in aquatic organisms.
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In this study, the synthetical index method was used to calculate the comprehensive effect value (CV) of ultraviolet (UV) absorption capacity, skin permeability, and planarian toxicity of benzophenone-type (BP) compounds. The comparative molecular similarity index analysis (CoMSIA) method with the CV and the molecular structure of BPs as the dependent and independent variables, respectively, was used to construct the BPs comprehensive effect three-dimensional quantitative structure activity relationship model. 2,4-dihydroxybenzophenone (BP-1) and 2-hydroxy-4-methoxybenzophenone (BP-3), which are widely used in sunscreens, were used as the target molecules to design novel BPs with high-efficiency light absorption capacity, low permeability, and low toxicity. A total of 30 novel derivative molecules with CV increased by more than 20% were designed. The practicality and functionality of the novel molecules were evaluated, six novel BPs with stronger UV absorption capacity (increase of 46.01%–277.57%), lower skin permeability (decreased by 50.46%–96.47%), and lower planarian toxicity (decreased by 82.20%–431.79%) were identified. Time-dependent density functional theory was used to analyse the electron excitation of BP molecules. The results revealed that the increased contribution rate of orbital transitions, changes in the main transition orbital pairs (MO pairs), changes in excited state transition dipole moments, and the difference in electron transfer characteristics between the ground state and the excited state enhanced the UV absorption capacity of BP molecules. The docking analysis results of BP molecules with human skin keratin and RNA helicase of Dugesia japonica revealed that the reduction of amino acids involved in van der Waals interaction was the primary cause of the decrease in skin permeability of BP molecules. The weakening of the hydrophobic interaction strength and the decrease of the number are the main reasons for the reduction of the planarian toxicity of BP molecules. Molecular dynamics simulation and binding energy calculation were used to verify the reliability of molecular docking analysis. This article proposed a method for design, evaluation, and screening of UV absorbers to provide theoretical support for the development of novel BP UV absorbers with high-efficiency light absorption capacity, low permeability, and low toxicity.
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The development of a rapid analytical approach for determining levels of antibacterial agents, plasticizers, and ultraviolet filters in biosamples is crucial for individual exposure assessment. We developed an analytical method to determine the levels of four parabens—bisphenols A (BPA) and its analogs, triclosan (TCS), triclocarban, and benzophenone-3 (BP-3)—in human urine. We further measured the levels of these chemicals in children and adolescents. We used a supported liquid extraction (SLE) technique coupled with an isotope-dilution ultraperformance liquid chromatography-tandem mass spectrometry (ID-UPLC-MS/MS) method to assess the detection performance for these chemicals. Forty-one urine samples from 13 children and 28 adolescents were assessed to demonstrate the capability and feasibility of our method. An acceptable recovery (75.6–102.4%) and matrix effect (precision < 14.2%) in the three-level spiked artificial urine samples were achieved, and good performance of the validated ID-UPLC-MS/MS method regarding linearity, limits of detection, and quantitation was achieved. The within-run and between-run accuracy and precision also demonstrated the sensitivity and stability of this analytical method, applied after SLE. We concluded that the ID-UPLC-MS/MS method with SLE pretreatment is a valuable analytical method for the investigation of urinary antibacterial agents, plasticizers, and ultraviolet filters in humans, useful for human biomonitoring.
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Benzophenone-3 (BP3) is an organic UV filter whose presence in the aquatic environment has been linked to detrimental developmental impacts in aquatic organisms such as coral and fish. The genus Rhodococcus has been extensively studied and is known for possessing large genomes housing genes for biodegradation of a wide range of compounds, including aromatic carbons. Here, we present the genome sequence of Rhodococcus sp. USK10, which was isolated from Chinese riverbank sediment and is capable of utilising BP3 as the sole carbon source, resulting in full BP3 mineralisation. The genome consisted of 9,870,030 bp in 3 replicons, a G+C content of 67.2%, and 9722 coding DNA sequences (CDSs). Annotation of the genome revealed that 179 of these CDSs are involved in the metabolism of aromatic carbons. The complete genome of Rhodococcus sp. USK10 is the first complete, annotated genome sequence of a Benzophenone-3-degrading bacterium. Through radiolabelling, it is also the first bacterium proven to mineralise Benzophenone-3. Due to the widespread environmental prevalence of Benzophenone-3, coupled with its adverse impact on aquatic organisms, this characterisation provides an integral first step in better understanding the environmentally relevant degradation pathway of the commonly used UV filter. Given USK10′s ability to completely mineralise Benzophenone-3, it could prove to be a suitable candidate for bioremediation application.
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Although there are several methods for assessing the sun protection factor (SPF) of sunscreen products, there is no standard and reliable in vitro method. Each test entails limitations and drawbacks. Therefore, this study aimed to assess the employability of FTIR as an alternative and quick method to evaluate the efficacy of various sunscreen formulations, their concentrations, and the timing of their application. Infrared radiation has longer wavelengths than ultraviolet, penetrates deeply into the skin, and hence enables the understanding of sunscreens' ability to block the transmission of radiation. The FTIR transmission using synthetic skin to study the effect of sunscreen agents (oxybenzone, octyl methoxycinnamate, titanium dioxide (TiO2), and zinc oxide (ZnO)) was conducted in the range 450-4000cm-1. Comparison studies were made at the peak of 805cm-1. After 2 h of sunscreen application, using the maximum concentrations, the FTIR peak at wavenumber 805cm-1 demonstrated a significant reduction of transmission from 96.55 to 60.09%, 57.59%, 32.02%, and 37.1% for oxybenzone, octyl methoxycinnamate, TiO2, and ZnO respectively (P<0.05). A significant reduction in transmission was observed (P<0.05) with increasing sunscreen concentrations after 2 h of application. Nevertheless, the upper limit of concentration showed no appreciable change from the middle level of concentration, and hence it is cost-effective to employ the middle concentration. Inorganic sunscreens showed a higher protection level than organic. Fixed-dose combinations of sunscreens showed an enhanced effect yet were not synergistic. In conclusion, the use of FTIR spectroscopy with synthetic skin is a quick and user-friendly technique that enables the assessment of the efficacy of sunscreen formulations.
Chapter
UV absorbing chemicals are used in numerous consumer products including over-the-counter sunscreens and other personal care products. Furthermore, UV stabilizing chemicals are now widely used in consumer goods including plastics, fabrics, paints, and building materials to protect the products from UV damage. The widespread use of UV absorbing and UV stabilizing chemicals in consumer goods has led to contamination of environmental matrices (including water, sewage, sediment, and dust), wildlife populations, and human bodies. In this chapter, we review the evidence for this widespread contamination, as well as what is known about the effects of some of these chemicals including the UV absorbing chemical oxybenzone (and its metabolites), and benzotriazole derivatives, a class of UV stabilizing chemicals.
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A visible-light-promoted metal-free decarboxylative coupling protocol for the acylation of electron-deficient quinolines using ambient air as an oxidant has been disclosed. This environmental-friendly protocol takes place under mild conditions and is highlighted by using inexpensive photocatalyst and starting materials, thereby integrating C–H functionalization and recent photoredox scenario based on diaryl ketones. This work contributes to a more systematic utilization of α-ketoacids as an efficient source of acyl radicals in acylation of electron-deficient heteroaromatic compounds.
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The distribution of 16 photoinitiators (PIs)—benzophenone (BP) and its five derivatives, 4-methylbenzophenone (4-MBP), methyl-2-benzoylbenzoate (M2BB), 2-ethylhexyl-4-dimethylaminobenzoate (EHDAB), and the other 7 PIs—in packaged juice and milk was assessed using an UPLC-MS/MS with micro-QuEChERS. The validated method demonstrated robust linearity (≥ 0.9908), LOQs (juice: 0.006–7.26 ng/mL; milk: 0.004–6.09 ng/mL), intra- and inter-day accuracy (93.9%–110.1% for juice and 69.7%–114.6% for milk with relative standard deviations (RSDs) of ≤16.8%), and matrix effect with RSDs of ≤14.8%. BP exceeded the LOQ in 100% of 136 packaged juice (14.22 ± 7.60 ng/mL) and 51 milk (8.45 ± 3.25 ng/mL) samples, and the quantitation rates for M2BB and EHDAB in packaged juice were 100%. Notably, the 4-MBP in both juice and milk was significantly related to the packaging material. The method has been successfully applied to evaluate the occurrence and distribution of PIs in packaged juice and milk.
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Benzophenone-type ultraviolet (UV) filters (BPs) are commonly used as sunscreen agents, fragrance enhancers and plastic additives, and are great threats to aquatic organisms due to their high detected concentrations in the aquatic environment. However, few studies on their toxicity and mechanism in fish have been clearly reported. In this study, Chinese rare minnows (Gobiocypris rarus) were exposed to benzophenone (BP), 2,4-dihydroxybenzophenone (BP-1), and 5-benzoyl-4-hydroxy-2-methoxybenzenesulfonic acid (BP-4) at 5, 50, 500 µg/L for 28 d to assess their toxicity. Transcriptomics screening showed that cell cycle, DNA replication and repair were significantly altered pathways (p < 0.05). The altered transcripts were similar to those identified by RNA-seq. DNA damage and 8-OHdG levels were significantly increased at 50 and 500 μg/L groups (p < 0.05). The DNA methylcytosine level was not significantly changed exposure to BP, BP-1 and BP-4. TUNEL assays indicated that hepatic apoptosis was significantly improved at 500 μg/L BP and BP-4 and 50 and 500 μg/L BP-1 (p < 0.05), with the significantly increasing the activity of caspase-3, -8 and -9 (p < 0.05). Molecular docking analysis revealed that BP, BP-1 and BP-4 could bind differently to caspase-3 through different binding interactions. Therefore, BP-1 induced more serious oxidative DNA damage and apoptosis by activating caspase-3 due to two hydroxyl groups than BP and BP-4, which will provide theoretical basis and data support for ecological evaluation of aquatic organisms induced by BPs.
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The increasingly broad and massive use of pharmaceuticals (human, veterinary) and personal care products in industrially developing nations makes their uncontrolled environmental and ecological impact a true concern. Focusing on Nigeria, this systematic literature search (databases: PubMed, ScienceDirect, Google Scholar, EMBASE, Scopus, Cochrane library and African Journals Online) aims to increase visibility to the issue. Among 275 articles identified, 7 were included in this systematic review. Studies indicated the presence of 11 personal care products (15.94%) and 58 pharmaceutical products (84.06%) in surface and ground water, leachates, runoffs, sludge, and sediments. The 42.86% (3/7) of reviewed studies reported 17 analgesics; 71.42% (5/7) reported 16 antibiotics; 28.57% (2/7) reported 5 lipid lowering drugs; 28.57% reported anti-malaria and fungal drugs; 14.29% (1/7) reported estrogen drugs. Different studies report on sunscreen products, hormone, phytosterol, insect repellent, and β1 receptor. Gemfibrozil (<4-730 ng/L), Triclosan (55.1–297.7 ng/L), Triclocarban (35.6–232.4 ng/L), Trimethoprim (<1–388 ng/L) and Tramadol (<2–883 ng/L) had the highest range of concentrations. Findings confirm the need of i) legislation for environmental monitoring, including biota, ii) toxicological profiling of new market products, and iii) sensitization on appropriate use and disposal of pharmaceuticals and personal care products.
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To avoid the harmful effects of UV radiation, benzophenone-type UV filters (BPs) are widely used in personal care products and other synthetic products. Biomonitoring studies have shown the presence of BPs in various human biological samples, raising health concerns. However, there is a paucity of data on the global human exposure to this group of contaminants. In this study, we compiled data on the body burden of BPs along with the possible exposure routes and biotransformation pathways. BPs can easily penetrate the skin barrier and thus, they can be absorbed through the skin. In the human body, BPs can undergo Phase I (mainly demethylation and hydroxylation) and Phase II (mainly glucuronidation and sulfation) biotransformations. From a total of 158 studies, most of the studies are related to urine (concentration up to 92.7 mg L–1), followed by those reported in blood (up to 0.9 mg L–1) and milk (up to 0.8 mg L–1). Among BPs, benzophenone-1 and benzophenone-3 are the most commonly detected congeners. The body burden of BPs is associated with various factors, including the country of residence, lifestyle, income, education level, and ethnicity. The presence of BPs in maternal urine (up to 1.1 mg L–1), placenta (up to 9.8 ng g–1), and amniotic fluid (up to 15.7 μg L–1) suggests potential risks of prenatal exposure. In addition, transplacental transfer of BPs is possible, as demonstrated by their presence in maternal serum and cord serum. The possible association of BPs exposure and health effects was discussed. Future human biomonitoring studies and studies on the potential health effects are warranted. Overall, this review provides a summary of the global human exposure to BPs and can serve as supporting evidence to guide usage in order to protect humans from being exposed to BPs.
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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
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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
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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.
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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.
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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.
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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.
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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.
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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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.