Oxybenzone

oxybenzone

 (Chemical Abstract Service Registry Number 131-57-7; IUPAC Name (2-hydroxy-4-methoxyphenyl)-phenylmethanone; Benzophenone-3, Milestab 9, Escalol 567, Eusolex 4360)

Oxybenzone Contamination in the Environment and the Public

Oxybenzone is a ubiquitous environmental contaminant – it is found in streams, rivers, lakes, and in marine environments from the Arctic Circle (Barrow, Alaska) to the beaches and coral reefs along the equator [1],[2],[3],[4].  It is considered an environmental hazard in many locations[5]. It is found in very high concentrations in swimming pools and hot tubs[6], and even in our drinking water (municipal treated and desalinated sources)[7],[8].  Swimmers directly contaminate water sources, but point and non-point sewage and treated waste-water effluent discharges are the largest source of contamination.
Oxybenzone can be absorbed directly through the skin, either from application of sunscreen product onto the skin, or by absorption from swimming in either swimming pools or along beaches[9],[10],[11].  Oxybenzone in a commercial sunscreen formulation can transfer from the lotion or spray into the body, and be detected in urine within 30 minutes to several hours of application[12],[13].  Oxybenzone body-contamination is widely prevalent in the general human population, with some nationalities having higher levels than others[14]. One study found that 96.8% of participants’ urine was contaminated with oxybenzone, indicating the almost-universal prevalence of exposure in the human population[15],[16].  Oxybenzone can contaminate semen[17], placenta and breastmilk of marine mammals and humans[18],[19],[20],[21].  Oxybenzone can both bioaccumulate, and can be biomagnified[22]. Oxybenzone has been found in bird eggs, fish, coral, humans, and other marine mammals[23],[24].

Oxybenzone Ecotoxicology

     Oxybenzone and many of its metabolites are documented mutagens, especially when exposed to sunlight[25],[26],[27],[28],[29].  They can cause genotoxicity either from induction of photo-oxidative stress or adduction to DNA directly through bio-activation by cytochrome P450 enzymes[30],[31],[32].  Oxybenzone and other benzophenones can induce pro-carcinogenic activities by inducing cell proliferation in cancer cells lines that are receptive to estrogenic compounds[33],[34],[35].  Recent studies have also documented that oxybenzone increases metastasis potential (cellular proliferation) via a non-estrogenic mechanism[36].
Oxybenzone is a photo-toxicant, especially in the presence of ultraviolent light4.  This means that the greater the light intensity, especially in the UV and near-UV spectrum, new forms of toxicity manifest, and usually in a dose-dependent manner of both oxybenzone and light.
In mammals, especially humans, oxybenzone has been shown to induce photo-allergic contact dermatitis in 16%-25% of the population[37],[38],[39].  Oxybenzone causes toxicity to sperm development and sperm viability, reduced prostate weight in mature males, and reduced uterine weight in juvenile females[40],[41]. In rodents, it reduced fecundity and induced idiopathic sudden death in lactating mothers[42].  Several recent studies have shown a strong association between urinary and seminal oxybenzone concentrations and increased reproductive diseases and reduced fecundity[43],[44]. There is a building body of evidence of the estrogenic and anti-androgenic endocrine disrupting mechanisms of oxybenzone in mammals[45],[46]. One study indicated an increased occurrence of endometriosis in women exposed to concentrations of oxybenzone, while another study showed a positive association with uterine leiomyoma[47],[48].  Oxybenzone has also been associated with altered timing of breast development in girls[49].
Oxybenzone is a notorious estrogenic endocrine disruptor, causing male fish to become feminized and inducing egg protein production in males and juveniles[50],[51],[52].  Oxybenzone causes a reduction in the number of eggs a female fish will produce[53],[54],[55]. In fish, oxybenzone is metabolized into benzophenone-1, a much more potent estrogenic disruptor[56]. Oxybenzone will also cause radical behavioral changes in fish, causing them to lose “territorial” behavior[57].
Oxybenzone can have devastating effects on invertebrates, especially on juvenile developmental stages4.  In coral, it can cause coral bleaching, DNA damage, planula deformity, mortality, and skeletal endocrine disruption4.  For coral planula, gross toxicological effects were seen as low as 6.5 ppbillion in a 24-hour period, and cellular effects were seen as low as 72 pptrillion in a 4-hour period. In bivalves, growth inhibition occurred around 2-3 ppmillion[58].  In shrimp larvae, growth inhibition was seen around 421 ppbillion49.
Oxybenzone is even toxic to microalgae, such as Isochrysis galbana, at levels comparable to coral, such as 4 ppbillion49.
Oxybenzone is also associated with several human diseases, especially of fetal-development diseases associated with prenatal exposure to oxybenzone[59],[60].  Hisrschsprung’s disease, a development abnormality thought to afflict every 1 in 2,000 births, has been linked to maternal exposure to oxybenzone, by interfering with the migration neural crest cells during embryonic development[61].

Emerging Science regarding Oxybenzone: a human-health warning.

Oxybenzone can contaminate hot-tubs and swimming pools with concentrations in the parts per billion5.  If these pools use chlorine or bromine as a disinfectant, the oxybenzone undergoes a chemical reaction and can become “chlorinated” or “brominated – meaning a chlorine or bromine is conjugated to the oxybenzone, changing its chemical structure and chemistry[62],[63].  Very recent studies show that the chlorinated forms of oxybenzone are significantly more toxic than normal oxybenzone, acting as significant DNA damage agents[57],[58],[64].  A by-product of this oxybenzone chlorination is chloroform[65].

[1] Tsui et al (2014) Occurrence, distribution and ecological risk assessment of multiple classes of UV filters in surface waters from different countries.  Water Res 15:55-65.

[2] Balmer et al (2005) Occurrence of some organic UV filters in wastewater, in surface waters, and in fish from Swiss Lakes. Environ Sci Technol 39:953-962.

[3] Tashiro & Shimizu (2013) Concentration of organic sun-blocking agents in seawaters of beaches and coral reefs of Okinawa Island, Japan. Mar Pollut. Bull 77:333-340.

[4] Downs et al (2015) Toxicolopathological effects of the sunscreen UV filter, Oxybenzone (benzophenone-3), on coral planulae and cultured primary cells and its environmental contamination in Hawaii and the U.S. Virgin Islands. Arch Environ Contam Toxicol. DOI 10.1007/s00244-015-0227-7

[5] Sang & Leung (2016) Environmental occurrence and ecological risk assessment of organic UV filters in marine organisms from Hong Kong coastal waters. Sci Total Enviro 556-567:489-498.

[6] Ekowati et al (2016) Occurrence of Pharmaceuticals and IV filters in swimming pools and spas. Environ Sci Poll Res. DOI 10.1007/s11356-016-6560-1

[7] Dia-Cruz et al (2012) Analsis of UV filters in tap water and other clean waters in Spain. Analyltical and Bioanalytical Chemistry 402:2325-2333.

[8] Da Silva et al (2015) The occurrence of UV filters in natural and drinking water in Sao Paulo State (Brazil). Environ Sci Pollut Res 22:19706-19715.

[9] Jiang et al (1999) Absorption of sunscreens across human skin: an evaluation of commercial products for children and adults. Br J Clin Pharmacol 48:635-638.

[10] Janjua et al (2004) Systemic absorption of the sunscreens benzophenone-3, oxtyl-methoxycinnamate, and 3-(4-methyl-benzylidene)camphor after whole-body topical application and reproductive hormone levels in humans. J Incest Dermatol 123:57-61.

[11] Kunisue et al (2010) Analysis of five benzophenone-type UV filters in human urine by liquid chromatography-tandem mass spectrometry. Analytical Methods 2:707-713.

[12] Meeker et al (2013) Distribution, variability, and predictors of urinary concentrations of phenols and parabens among pregnant women in Puerto Rico. Environ Sci Tech 47:3439-3447.

[13] Gonzalez et al (2002) Percutaneous absorption of benzophenone-3, a common component of topical sunscreens. Clin Exper Dematology 27:691-694

[14] Wang & Kannan. Characteristic profiles of benzophenone-3 and its derivatives in urine of children and adults from the United States and China. Environ Sci Technol. 47: 12532-13538.

[15] Calafat et al (2008) Concentrations of the sunscreen agent benzophenone-3 in residents of the United States: National Health and Nutrition Examination Survey 2003-2004. Environ Health Perspect 116:893-897.

[16] Calafat et al (2008) Concentrations of the sunscreen agent benzophenone-3 and its derivatives in urine of children and adults from the United Sates and Chine. Environ Sci Technol 47:12532-12538.

[17] Zhang et al (2013) Benzophenone-type filters in urine and blood from children, adults, and pregnant women in China: partitioning between blood and urine as well as maternal and fetal cord blood.  Sci Total Environ 461-462:59-55.

[18] Hany & Nagel (1995) Detection of sunscreen agents in human breast milk. Dtsch Lebensm Rundsch 91:341-345.

[19] Rodriguez-Gomez et al (2014) Determinaion of benzophenone-UV filters in human milk samples using ultrasound-assisted extraction and clean-up with dispersive sorbents followed by UHPLC-MS/MS analysis. Talanta 134:657-664.

[20] Hany & Nagel (1995) Detection of sunscreen agents in human breast milk. Dtsch Lebensm Rundsch 91:341-345.

[21] Hines et al (2015) Concentrations of environmental phenols and parabens in milk, urine, and serum of lactating North Carolina women. Reprod Toxicol 54:120-128.

[22] Gago-Ferrero et al (2012) An overview of UV-absorbing compounds (organic UV filters) in aquatic biota. Anal Bioanal Chem 404:2597-2610.

[23] Silvia fill in reference

[24] Alonso et al (2015) Toxic heritage: maternal transfer of pyrethroid insecticides and sunscreen agents in dolphins from Brazil. Environ Pollut 207:391-402.

[25] Popkin & Prival (1985) Effects of pH on weak and positive control mutagens in the AMES Salmonella plate assay. Mutat Res 142:109–113

[26] Zeiger et al (1987) Salmonella mutagenicity Tests: 3. Results from the testing of 255 chemicals. Environ Mutagen 9:1–110.

[27] Knowland et al (1993) Sunlight-induced mutagenicity of a common sunscreen ingredient. FEBS Lett 324:309–313

[28] NTP (National Toxicology Program) (2006) NTP technical report on the toxicology and carcinogenesis of benzophenone in F344/N rats and B6C3F1 mice. NIH Publication # 06-4469

[29] Nakajima et al (2006) Activity related to the carcinogenicity of plastic additives in the benzophenone group. J UOEH 28:143–156.

[30] Cuquerella et al (2012) Benzophenone photosensitized DNA damage. Acc Chem Res 45:1558–1570

[31] Zhao et al (2013) Substituent contribution to the genotoxicity of benzophenone-type UV filters. Ecotoxicol Environ Saf 95:241–246

[32] Hanson et al (2006) Sunscreen enhancement of UV-induced reactive oxygen species in the skin. Free Radic Biol Med 41:1205–1212.

[33] Kerdivel et al (2013) Estrogenic potency of benzophenone UV filters in breast cancer cells: proliferative and transcriptional activity substantiated by docking analysis. PLoS One 8:e60567. doi:10.1371/journal.pone.0060567.

[34] In et al (2015) Benzophenone-1 and nonylphenol stimulated MCF-7 breast cancer growth by regulating cell cycle and metastasis-related genes via an estrogen receptor a-dependent pathway. J Toxicol Environ Health A 78:492-505.

[35] Kim et al (2015) Growth and migration of LNCaP prostate cancer cells are promoted by triclosan and benzophenone-1 via an androgen receptor signaling pathway. Environ Toxicol Pharmacol 39:568-576.

[36] Phiboonchaiyanan et al (2016) Benzophenone-3 increases metastasis potential in luncg cancer cells via epithelial to mesenchymal transition. Cell Biol Toxicol DOI: 10.1007/s10565-016-9368-3.

[37] Szczurko et al (1994) Photocontact allergy to oxybenzone: ten years of experience.  Photodermatol Photoimmunol Photomed 10:144-147.

[38] Langan and Collins (2006) Photocontact allergy to oxybenzone and contact allergy to lignocaine and prilocaine. Contact Dermatitis 54:174-174.

[39] Chuah et al (2013) Photopatch testing in Asians: a 5-year experience in Singapore. Photodermatol Photoimmunol Photomed 29:116-120.

[40] French (1992) NTP technical report on the toxicity studies of 2-hydroxy-4-methoxybenzophenone (CAS No. 131-57-7) administered topically and in dosed feed to F344/N Rats and B6C3F1 mice. Toxic Rep Ser 21:1–14

[41] Schlumpf et al (2008) Developmental toxicity of UV filters and environmental exposure: a review. Int J Androl 31:144–151.

[42] Gulati & Mounce (1997) NTP reproductive assessment by continuous breeding study for 2-hydroxy-4-methoxybenzophenone in Swiss CD-1 mice. NTIS# PB91158477. Environ Health Perspect 105(Suppl 1):313–314

[43] Buck Louis et al (2014) Urinary concentrations of benzophenone-type ultraviolet radiation filters and couple’s fecundity. Amer J Epid. DOI: 10.1093/aje/kwu285.

[44] Buck Louis et al (2015) Urinary concentrations of benzophenone-type ultraviolet light filters and semen quality. Fertility and Sterility. 104:989-996.

[45] Watanabe et al (2015) Metabolism of UV filter benzophenone-3 by rate and human liver microsomes and its effect on endocrine disrupting activity.

[46] Krause et al (2012) Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV filters. Int K Androl 35:424-436.

[47] Kunisue et al (2014) Urinary concentrations of benzophenone-type UV filters in U.S. women and their association with endometriosis.  Environ Sci Technol 46:4624-4632.

[48] Pollack et al (2015) Bisphenol A, benzophenone-type ultraviolet filters, and phthalates in relation to uterine leiomyoma. Environ Res. DOI: 10.1016/j.envres.2014.06.028.

[49] Wolff et al (2015) Environmental phenols and pbertal development in girls. Environ Intl 84:174-180.

[50] Kunz et al (2006) Comparison of in vitro and in vivo estrogenic activity of UV filters in fish. Toxicol Sci 90:349–361.

[51] Kinnberg et al (2015) Endocrine-disrupting effect of the ultraviolet filter benzophenone-3 in zebrafish, Danio rerio. Environ Toxicol Chem 34:2833-2840.

[52] Rodriguez-Fuentes et al (2015) Evaluation of the estrogenic and oxidative stress effects of the UV filter 3-benzophenone in zebrafish (Danio rerio) eleuthero-embryos. Ecotoxicol Environ Safety 115:14-18

[53] Nimrod & Benson (1998) Reproduction and development of Japanese medaka following an early life stage exposure to xenoestrogens. Aquat Toxicol 44:141–156.

[54] Coronado et al (2008) Estrogenic activity and reproductive effects of the UV-filter oxybenzone (2-hydroxy-4- methoxyphenyl-methanone) in fish. Aquat Toxicol 90:182–187.

[55] Bluthgen et al (2012) Effects of the UV filter benzophenone-3 (oxybenzone) at low concentrations in zebrafish (Danio rerio). Toxicol Appl Pharmacol 263:184–194.

[56] Silvia add this reference

[57] Chen et al (2016) UV-filter benzophenone-3 inhibits agonistic behavior in male Siamese fighting fish (Betta splendens). Ecotoxicology 25:302-309.

[58] Paredes et al (2014) Ecotoxicological evaluation of four UV filters using marine organisms from different trophic levels: Isochrysis galbana, Mytilus galloprovincialis, Paracentrotus lividus, and Siriella armata.  Chemosphere 104:44-50.

[59] Wolff et al (2008) Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspec 116:1092-1097.

[60] Tang et al (2013) Associations of prenatal exposure to phenols with borth outcomes. Environ Pollut 178:115-120.

[61] Huo et al (2016) The relationship between prenatal exposure to BP-3 and Hirschspring’s disease. Chemosphere 144:1091-1097.

[62] Zhang et al (2016) Chlorination of oxybenzone: Kinetics, transformation, disinfection byproducts formation, and genotoxicity changes. Chemosphere 154:521-527.

[63] Li et al(2016) Transformation of benzophenone-type UV filters by chlorine: Kinetics, products identification and toxicity assessments. J Hazard Mater 311:263-272.

[64] Sherwood et al (2012) Altered UV absorbance and cytotoxicity of chlorinated sunscreen agencies.  Cutan Ocul Toxicol 31:273-279.

[65] Duirk et al (2013) Reaction of benzophenone UV filters in the presence of aqueous chlorine: kinetics and chloroform formation. Water Res 47:579-576.