Chemical Mixtures: Parabens and Triclosan

Shakila Balkhi, Simrum Bhullar & Kierah Leverton

Department of Environmental and Occupational Health California State University, Northridge

Low Exposure Health High Exposure ABSTRACT Part of Endocrine System Hormones Produced Hormone Regulates Effects Health Effects Triclosan and parabens are anthropogenic chemicals that are used in personal care products to reduce or prevent bacterial contamination as well as preserve the product. These chemicals have been introduced into the cosmetic industry to lengthen the Pineal gland (brain) Melatonin Circadian rhythm and shelf life of most products. reproductive hormones. Pituitary gland (brain) – Anterior Lobe Hormones: Adrenal gland stimulation Dwarfism (in children); Gigantism (in Adrenocorticotropic These chemicals have not been in use long enough to determine long term health effects and have created an experimental works closely with the for hormone production; Imbalance of internal children); Imbalance hormone (ACTH), generation within our society. However, animal studies have predicted the chemicals to affect the endocrine system via hormone Hypothalamus. Follicle-stimulating maintain healthy body functions of the body. of internal functions disruption. Comparison of Triclosan and parabens will examine related mechanisms of actions and similarities between the hormone (FSH), composition in children of the body. chemicals. Growth hormone (GH), and aids in healthy bone, Luteinizing hormone (LH), muscle mass and fat Scientific literature was reviewed to determine possible health effects, bioaccumulation, mechanisms of action, and regulations of Prolactin, and distribution; breast milk the chemicals. Further review of studies determined Triclosan and parabens may have synergistic effects when interacting. Thyroid-stimulating hormone (TSH). Posterior production; kidney Lobe Hormones: function. Anti-diuretic hormone INTRODUCTION (ADH), and Oxytocin. Triclosan is a synthetic antimicrobial agent that is commonly used in a variety of personal care products including make up, soaps, toothpastes, deodorants, and hand sanitizers. It was first introduced in hospitals in the 1970s for its antimicrobial properties and production has dramatically increased since. Parabens have been in the market since the 1930s and are the most common Testes (male) Testosterone Sperm production; normal Decreased sex drive, preservatives found in cosmetics and personal care products. Many studies have shown concern with these products causing development of male muscle mass, sperm endocrine disruption due to their estrogenic properties. characteristics. count; body hair loss.

ROUTES OF EXPOSURE

Triclosan is a common chemical found in toothpaste, mouthwash, deodorants, soaps, textiles, toys, Thymus (upper chest) Thymosin (only until Production and maturation Development of liquid dishwashing soap and plastic kitchenware. It is known for its antiseptic properties and is puberty – then is inactive.) of T-lymphocytes. immune system in detected in aquatic environments and in food sources (12). The routes of exposure for Triclosan are early stages of life. through ingestion and dermal absorption. Studies have shown about 6.3% of Triclosan is absorbed into Thyroid (neck) T3 (tri-iodothyronine) and Metabolism Hypothyroidism: Hyperthyroidism: the human skin just 24 hours after application, in vitro (12). T4 (thyroxine). Fatigue, weakness, Anxiety, rapid weight gain, etc. heartbeat, weight loss, etc. Parabens are chemicals used as preservatives in pharmaceuticals, cosmetics, lotions, skin cleansers, hair products (9). They are used to prevent bacteria growth and have been commonly used since the 1950s. MECHANISMS OF ACTION About 85% of cosmetic products have them (1). The routes of exposure for parabens are from ingestion, dermal absorption, and inhalation from The mechanisms of EDC’s include chemicals binding to hormone receptors and exerting direct agonist or antagonist actions, contaminated air and dust. Parabens are quickly metabolized in the liver exerting indirect agonist or antagonist actions, or binding to allosteric sites and yielding unexpected effects at low concentrations which results in the distribution of free parabens and adducts of PHBA, (5). glucuronide, sulfate, and glycine adducts (14).

Parabens are known xenoestrogens and create excess estrogen in the body by binding to estrogen receptor sites (6). According to the Journal of Applied Toxicology, Triclosan also exerts estrogenic activities by inducing luciferase activities in an ER reporter gene assay (7). BIOACCUMULATION AND PERSISTENCE This schematic represents the different mechanisms of estrogen signaling: (8) A high enough concentration of both these chemicals can

cause endocrine system disruption in fish, which can lead to I. Direct genomic signaling pathway- binds the E2 (17-Beta-estrodial) and reproductive and behavioral problems. When animals ER (estrogen receptor) complex directly to the ERE (estrogen response consume these poisoned fish, the chemicals bio accumulate element) up the food chain and increase in toxicity (1). II. Indirect genomic signaling pathway- E2-activated ER’s bind DNA through

through protein-protein interactions with transcription factors as their The International Journal of Environmental Research and respective response elements Public Health found that high levels of Triclosan were found III. Non-genomic signaling pathway- binds E2 with ER at the plasma in 60% of human milk samples, and in 75% of human urine membrane, which activates various protein-kinase cascades and can samples (2). lead to changes in gene expression due to phosphorylation of

transcription factors Triclosan is also found in aquatic and terrestrial environments IV. Ligand-independent signaling pathway- ER activation and target gene through the dumping of consumer products that ultimately According to a study done on parabens in surface water and transcription through phosphorylation of ER’s fish from the greater Pittsburgh area, methyl paraben and butyl find their to wastewater treatment plants. In addition, paraben were found in surface waters at concentrations Triclosan persists in anaerobic conditions and is therefore ranging from 2.2 to 17.3 and 9.2 and 12.0 ppt, respectively (3). present in sediment (2). EFFECTS ON ENDOCRINE SYSTEM

Chemical Endocrine Disruption Amount Methyl- and butyl-paraben Increase in Thyroid Hormone 1000 mg/kg/day (11) ENDOCRINE SYSTEM production Triclosan Positive association with T3 levels Urinary concentrations (9) The endocrine system is a collection of glands that secrete and produce hormones in the n n body that regulate the activity of cells and organs. The hormones are released into the Methyl-, ethyl-, -propyl-, and - Inhibited estrogen receptor binding 1,000,000-fold molar excess (15) bloodstream and are essentially chemical messengers of the body. butyl-paraben Parabens Bind to estrogen receptors 500,000-fold molar excess (16) The main parts of the endocrine system are the thyroid gland, pituitary gland, parathyroid glands, adrenal glands, pancreas, testicles (in males), and ovaries (in Parabens Estrogenic Activity (15) females). Triclosan Displaced estradiol from estrogen 10¯⁵M (19) receptors Studies on animals have shown that Triclosan exposure can modulate estrogen dependent responses (2). Triclosan Mouse mammary tumor cells & 10¯⁷M & 10¯⁶ respectively (19) Human breast cancer cells. This system helps regulate the body’s physical, neurological, homeostasis, and sexual development(4). REGULATIONS

The table below details the parts of the endocrine system, hormones produced, hormone regulations, the low exposure health effects, and the high exposure health Regulations for Triclosan and parabens are minimal and are currently under review within several governments. The European effects. Union and Canada currently have regulations for parabens. However, within the United States the Cosmetic Ingredient Review concluded that they were safe in cosmetic products up to 25%. Triclosan is currently not regulated within the US and is under further review. Low Exposure Health High Exposure Part of Endocrine System Hormones Produced Hormone Regulates Effects Health Effects Country Methyl- and Ethyl-Paraben Propyl- and Butyl Paraben Triclosan Adrenal Glands (kidneys) Cortisol and sometimes Cortisol: response to Cortisol: Fatigue, Cortisol: Cushing’s aldosterone stress; use of protein, stomach upset, disease (fatigue, European Union 8g/kg of product (21) Max total [] 1.9g/kg (21) 0.3% (20) carbohydrates and fat; dehydration and skin weight gain, weak blood pressure and changes. muscles, etc) Canada 0.3% (22) 0.3% (22) 0.3% (22) cardiovascular function; Aldosterone: Drop in USA Up to 25% (23) Up to 25% (23) Not regulated inflammation. blood pressure. Hypothalamus (brain) Anti-diuretic hormone Heart rate and blood Imbalance of internal Imbalance of internal CONCLUSION (ADH), pressure, body body functions. body functions. Corticotropin-releasing temperature, fluid and Drawing conclusions for the chemicals is challenging because they have not been in existence long enough to conclude they are hormone (CRH), electrolyte balance, harmful. However, through literature review these chemicals act using similar mechanisms of action that lead to conclusions of Gonadotropin-releasing appetite and body weight, the two acting synergistically. Both Triclosan and parabens mimic pro-estrogenic activities ultimately having an effect on the hormone (GnRH), Follicle glandular secretions of the endocrine system. Further studies need to be conducted in order to determine chemical exposure safety. stimulating hormone stomach and intestines, However, the novelty of the chemicals and their constant use has created an experimental generation for our current society. (FSH), luteinizing hormone production of substances Taking a preventative approach to these chemicals is recommended as studies have shown them to have harmful effects to animals. (LH), Growth hormone- that influence the releasing hormone pituitary gland to release REFERENCES (GHRH) and inhibiting hormones and sleep (1) Good, Kate. "The Disturbing Environmental and Health Impact of Pouring Personal Care Products Down the Drain." (12) Calafat, Antonia M, Xiaoyun Ye, Lee-Yang Wong, John A Reidy, and Larry L Needham. "Urinary Concentrations of One Green Planet. N.p., 30 Jan. 2015. Web. 03 Dec. 2015. Triclosan in the U.S. Population: 2003-2004." Environmental Health Perspectives, 116.3 (2008): 303-307. hormone (GHIH), cycles (2) International Journal of Environmental Research and Public Health (ISSN 1660-4601; CODEN: IJERGQ; ISSN 1661-7827 (13) Durán-Álvarez, J C, B Prado, D González, Y Sánchez, and B Jiménez-Cisneros. "Environmental Fate of Naproxen, for printed edition) is an interdisciplinary, open access journal published monthly online by MDPI. Carbamazepine and Triclosan in Wastewater, Surface Water and Wastewater Irrigated Soil - Results of Laboratory Scale Oxytocin, Prolactin- (3) Rez, Lara, Conrad Volz, Drew Michanowicz, Kyle Ferrar, Charles Christian, Diana Lenzner, and Talal El-Hefnawy. "A Experiments." The Science of the Total Environment, 538 (2015): 350-362. Study of Parabens and Bisphenol A in Surface Water and Fish Brain Ti." Ecotoxicology 22.4 (2013): 632-41. Ssue from the (14) Pycke, BFG, LA Geer, M Dalloul, O Abulafia, and RU Halden. "Maternal and Fetal Exposure to Parabens in a releasing hormone (PRH) Greater Pittsburgh Area. 13 May 2013. Web. 03 Dec. 2015. Multiethnic Urban US Population." Environment International, 84 (2015): 193-200. (4) Paulsen, Lisa. "The Health Risks of Chemicals in Personal Care Products and Their Fate in the Environment." 2015. MS. (15) Byford, J.R, L.E Shaw, M.G.B Drew, G.S Pope, M.J Sauer, and P.D Darbre. "Oestrogenic Activity of Parabens in MCF7 or inhibiting hormone Connecticut College. Digital Commons @ Connecticut College. 2015. Web. 3 Dec. 2015. Human Breast Cancer Cells." Journal of Steroid Biochemistry and Molecular Biology, 80.1 (2002): 49-60. (5) Endocrine-Disrupting Chemicals and Public Health Protection: A Statement of Principles from The Endocrine Society R. (16) Routledge, Edwin J, Joanne Parker, Jenny Odum, John Ashby, and John P Sumpter. "Some Alkyl Hydroxy Benzoate (PIH), Thyrotropin Thomas Zoeller, T. R. Brown, L. L. Doan, A. C. Gore, N. E. Skakkebaek, A. M. Soto, T. J. Woodruff, and F. S. Vom Saal Preservatives (Parabens) Are Estrogenic." Toxicology and Applied Pharmacology, 153.1 (1998): 12-19. Endocrinology 2012 153:9, 4097-4110 (17) Blair, RM, H Fang, WS Branham, BS Hass, SL Dial, CL Moland, WD Tong, LM Shi, R Perkins, and DM Sheehan. "The releasing hormone (TRH): (6) Barton-Schuster, Dalene. "Elevated Estrogen Levels Linked to Toxins in Body Care Products." Natural Fertility Infocom. Estrogen Receptor Relative Binding Affinities of 188 Natural and Xenochemicals: Structural Diversity of Ligands." N.p., n.d. Web. 03 Dec. 2015. Toxicological Sciences, 54.1 (2000): 138-153. triggers the release of (7) Huang H., Du G., Zhang W., Hu J., Wu D., Song L., Xia Y. and Wang X. (2014), The in Vitro estrogenic activities of (18) K.L, Pedersen, Pedersen S.N, Christiansen L.B, B Korsgaard, and P Bjerregaard. "The Preservatives Ethyl-, Propyl- and Triclosan and triclocarban, J. Appl. Toxicol., 34, pages 1060–1067. DOI: 10.1002/jat.3012 Butylparaben Are Oestrogenic in an in Vivo Fish Assay." Basic & Clinical Pharmacology & Toxicology, 86.3 (2000): 110-113. thyroid stimulating (8) Peter Vrtačnik, Barbara Ostanek, Simona Mencej-Bedrač, Janja Marc*. The many faces of estrogen signaling. (19) Gee, R. H, A Charles, N Taylor, and P. D Darbre. "Oestrogenic and Androgenic Activity of Triclosan in Breast Cancer Biochemia Medica 2014;24(3):329-42. http://dx.doi.org/10.11613/BM.2014.035 Cells." Journal of Applied Toxicology, 28.1 (2008): 78-91. hormone (TSH). (9)Koeppe, ES, KK Ferguson, JA Colacino, and JD Meeker. "Relationship Between Urinary Triclosan and Paraben (20) SCCS (Scientific Committee on Consumer Safety), Opinion on triclosan, ADDENDUM to the SCCP Opinion on Triclosan Concentrations and Serum Thyroid Measures in NHANES 2007-2008." Science of the Total Environment, 445 (2013): 299- (SCCP/1192/08) from January 2009, 22 March 2011 305. (21) SCCS (Scientific Committee on Consumer Safety), Opinion on parabens, 14 December 2010, revision of 22 March 2011 Ovaries (female) Estrogen/Progesterone Female System Low bone density (10) Taxvig, C, Vinggaard, AM, Hass, U, Axelstad, M, Boberg, J, Hansen, PR, et al. “Do parabens have the ability to interfere (22) http://www.hc-sc.gc.ca/cps-spc/cosmet-person/labelling-etiquetage/ingredients-eng.php#a4.7 Health with steroidogenesis?” Toxicol Sci, 106 (2008): 206-1 Canada/Consumer Product Safety/Safety of Cosmetic Ingredients. Web 26 Nov. 2015. Islet Cells (pancreas) Insulin and glucagon Blood glucose levels Hyperglycemia Hypoglycemia (11) Vo, Thuy T.B, Yeong-Min Yoo, Kyung-Chul Choi, and Eui-Bae Jeung. "Potential Estrogenic Effect(s) of Parabens at the (23) http://www.fda.gov/cosmetics/productsingredients/ingredients/ucm128042.htm FDA/Cosmetics/Parabens Web. 27 Prepubertal Stage of a Postnatal Female Rat Model." Reproductive Toxicology, 29.3 (2010): 306-316. Nov. 2015 Parathyroid (neck) Parathyroid hormone Calcium regulation Osteoporosis