ENDOCRINE SYSTEM

REGULATIONS

Country Methyl- and Ethyl-Paraben Propyl- and Butyl Paraben Triclosan

European Union 8g/kg of product (21) Max total [] 1.9g/kg (21) 0.3% (20)

Canada 0.3% (22) 0.3% (22) 0.3% (22)USA Up to 25% (23) Up to 25% (23) Not regulated

Regulations for Triclosan and parabens are minimal and are currently under review within several governments. The European 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.

ABSTRACT

INTRODUCTION

ROUTES OF EXPOSURE

MECHANISMS OF ACTION

BIOACCUMULATION AND PERSISTENCE

CONCLUSION

REFERENCES

Chemical Mixtures: Parabens and Triclosan

Shakila Balkhi, Simrum Bhullar & Kierah Leverton

Department of Environmental and Occupational Health California State University, Northridge

A high enough concentration of both these chemicals can cause endocrine system disruption in fish, which can lead to reproductive and behavioral problems. When animals consume these poisoned fish, the chemicals bio accumulate up the food chain and increase in toxicity (1).

The International Journal of Environmental Research and Public Health found that high levels of Triclosan were found in 60% of human milk samples, and in 75% of human urine samples (2).

Triclosan is also found in aquatic and terrestrial environments through the dumping of consumer products that ultimately find their to wastewater treatment plants. In addition, Triclosan persists in anaerobic conditions and is therefore present in sediment (2).

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 preservatives found in cosmetics and personal care products. Many studies have shown concern with these products causing endocrine disruption due to their estrogenic properties.

Drawing conclusions for the chemicals is challenging because they have not been in existence long enough to conclude they are harmful. However, through literature review these chemicals act using similar mechanisms of action that lead to conclusions of the two acting synergistically. Both Triclosan and parabens mimic pro-estrogenic activities ultimately having an effect on the endocrine system. Further studies need to be conducted in order to determine chemical exposure safety.However, the novelty of the chemicals and their constant use has created an experimental generation for our current society. Taking a preventative approach to these chemicals is recommended as studies have shown them to have harmful effects to animals.

This schematic represents the different mechanisms of estrogen signaling: (8)

I. Direct genomic signaling pathway- binds the E2 (17-Beta-estrodial) and ER (estrogen receptor) complex directly to the ERE (estrogen response element)

II. Indirect genomic signaling pathway- E2-activated ER’s bind DNA through through protein-protein interactions with transcription factors as their respective response elements

III. Non-genomic signaling pathway- binds E2 with ER at the plasma membrane, which activates various protein-kinase cascades and can lead to changes in gene expression due to phosphorylation of transcription factors

IV. Ligand-independent signaling pathway- ER activation and target gene transcription through phosphorylation of ER’s

The mechanisms of EDC’s include chemicals binding to hormone receptors and exerting direct agonist or antagonist actions, exerting indirect agonist or antagonist actions, or binding to allosteric sites and yielding unexpected effects at low concentrations (5).

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).

(1) Good, Kate. "The Disturbing Environmental and Health Impact of Pouring Personal Care Products Down the Drain." One Green Planet. N.p., 30 Jan. 2015. Web. 03 Dec. 2015.(2) International Journal of Environmental Research and Public Health (ISSN 1660-4601; CODEN: IJERGQ; ISSN 1661-7827 for printed edition) is an interdisciplinary, open access journal published monthly online by MDPI.(3) Rez, Lara, Conrad Volz, Drew Michanowicz, Kyle Ferrar, Charles Christian, Diana Lenzner, and Talal El-Hefnawy. "A Study of Parabens and Bisphenol A in Surface Water and Fish Brain Ti." Ecotoxicology 22.4 (2013): 632-41. Ssue from the Greater Pittsburgh Area. 13 May 2013. Web. 03 Dec. 2015.(4) Paulsen, Lisa. "The Health Risks of Chemicals in Personal Care Products and Their Fate in the Environment." 2015. MS. Connecticut College. Digital Commons @ Connecticut College. 2015. Web. 3 Dec. 2015.(5) Endocrine-Disrupting Chemicals and Public Health Protection: A Statement of Principles from The Endocrine Society R. 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 Endocrinology 2012 153:9, 4097-4110(6) Barton-Schuster, Dalene. "Elevated Estrogen Levels Linked to Toxins in Body Care Products." Natural Fertility Infocom. N.p., n.d. Web. 03 Dec. 2015.(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 Triclosan and triclocarban, J. Appl. Toxicol., 34, pages 1060–1067. DOI: 10.1002/jat.3012(8) Peter Vrtačnik, Barbara Ostanek, Simona Mencej-Bedrač, Janja Marc*. The many faces of estrogen signaling. Biochemia Medica 2014;24(3):329-42. http://dx.doi.org/10.11613/BM.2014.035(9)Koeppe, ES, KK Ferguson, JA Colacino, and JD Meeker. "Relationship Between Urinary Triclosan and Paraben Concentrations and Serum Thyroid Measures in NHANES 2007-2008." Science of the Total Environment, 445 (2013): 299-305. (10) Taxvig, C, Vinggaard, AM, Hass, U, Axelstad, M, Boberg, J, Hansen, PR, et al. “Do parabens have the ability to interfere with steroidogenesis?” Toxicol Sci, 106 (2008): 206-1(11) Vo, Thuy T.B, Yeong-Min Yoo, Kyung-Chul Choi, and Eui-Bae Jeung. "Potential Estrogenic Effect(s) of Parabens at the Prepubertal Stage of a Postnatal Female Rat Model." Reproductive Toxicology, 29.3 (2010): 306-316.

(12) Calafat, Antonia M, Xiaoyun Ye, Lee-Yang Wong, John A Reidy, and Larry L Needham. "Urinary Concentrations of Triclosan in the U.S. Population: 2003-2004." Environmental Health Perspectives, 116.3 (2008): 303-307.

(13) Durán-Álvarez, J C, B Prado, D González, Y Sánchez, and B Jiménez-Cisneros. "Environmental Fate of Naproxen, Carbamazepine and Triclosan in Wastewater, Surface Water and Wastewater Irrigated Soil - Results of Laboratory Scale Experiments." The Science of the Total Environment, 538 (2015): 350-362. (14) Pycke, BFG, LA Geer, M Dalloul, O Abulafia, and RU Halden. "Maternal and Fetal Exposure to Parabens in a Multiethnic Urban US Population." Environment International, 84 (2015): 193-200. (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 Human Breast Cancer Cells." Journal of Steroid Biochemistry and Molecular Biology, 80.1 (2002): 49-60. (16) Routledge, Edwin J, Joanne Parker, Jenny Odum, John Ashby, and John P Sumpter. "Some Alkyl Hydroxy Benzoate Preservatives (Parabens) Are Estrogenic." Toxicology and Applied Pharmacology, 153.1 (1998): 12-19. (17) Blair, RM, H Fang, WS Branham, BS Hass, SL Dial, CL Moland, WD Tong, LM Shi, R Perkins, and DM Sheehan. "The Estrogen Receptor Relative Binding Affinities of 188 Natural and Xenochemicals: Structural Diversity of Ligands." Toxicological Sciences, 54.1 (2000): 138-153.(18) K.L, Pedersen, Pedersen S.N, Christiansen L.B, B Korsgaard, and P Bjerregaard. "The Preservatives Ethyl-, Propyl- and Butylparaben Are Oestrogenic in an in Vivo Fish Assay." Basic & Clinical Pharmacology & Toxicology, 86.3 (2000): 110-113.(19) Gee, R. H, A Charles, N Taylor, and P. D Darbre. "Oestrogenic and Androgenic Activity of Triclosan in Breast Cancer Cells." Journal of Applied Toxicology, 28.1 (2008): 78-91. (20) SCCS (Scientific Committee on Consumer Safety), Opinion on triclosan, ADDENDUM to the SCCP Opinion on Triclosan (SCCP/1192/08) from January 2009, 22 March 2011(21) SCCS (Scientific Committee on Consumer Safety), Opinion on parabens, 14 December 2010, revision of 22 March 2011(22) http://www.hc-sc.gc.ca/cps-spc/cosmet-person/labelling-etiquetage/ingredients-eng.php#a4.7 Health Canada/Consumer Product Safety/Safety of Cosmetic Ingredients. Web 26 Nov. 2015.(23) http://www.fda.gov/cosmetics/productsingredients/ingredients/ucm128042.htm FDA/Cosmetics/Parabens Web. 27 Nov. 2015

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 shelf life on all products. The chemicals have not been in use long enough to determine long term health effects and have created an experimental generation within our society. However, animal studies have predicted the chemicals to act and effect the endocrine system via hormone disruption. Comparison of Triclosan and parabens will examine related mechanisms of actions and similarities between the chemicals.

Scientific literature was reviewed to determine possible health effects, bioaccumulation, mechanisms of action, and regulations of the chemicals. Further review of studies determined Triclosan and parabens may have synergistic effects when interacting.

The endocrine system is a collection of glands that secrete and produce hormones in the body that regulate the activity of cells and organs. The hormones are released into the bloodstream and are essentially chemical messengers of the body.

The main parts of the endocrine system are the thyroid gland, pituitary gland, parathyroid glands, adrenal glands, pancreas, testicles (in males), and ovaries (in females).

Studies on animals have shown that Triclosan exposure can modulate estrogen dependent responses (2).

This system helps regulate the body’s physical, neurological, homeostasis, and sexual development(4).

The table below details the parts of the endocrine system, hormones produced, hormone regulations, the low exposure health effects, and the high exposure health effects.

Triclosan is a common chemical found in toothpaste, mouthwash, deodorants, soaps, textiles, toys, liquid dishwashing soap and plastic kitchenware. It is known for its antiseptic properties and is detected in aquatic environments and in food sources (12). The routes of exposure for Triclosan are through ingestion and dermal absorption. Studies have shown about 6.3% of Triclosan is absorbed into the human skin just 24 hours after application, in vitro (12).

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. About 85% of cosmetic products have them (1). The routes of exposure for parabens are from ingestion, dermal absorption, and inhalation from contaminated air and dust. Parabens are quickly metabolized in the liver which results in the distribution of free parabens and adducts of PHBA, glucuronide, sulfate, and glycine adducts (14).

According to a study done on parabens in surface water andfish from the greater Pittsburgh area, methyl paraben and butyl paraben were found in surface waters at concentrations ranging from 2.2 to 17.3 and 9.2 and 12.0 ppt, respectively (3). EFFECTS ON ENDOCRINE SYSTEM

Part of Endocrine System Hormones Produced Hormone Regulates Low Exposure Health Effects

High Exposure Health Effects

Adrenal Glands (kidneys) Cortisol and sometimes aldosterone

Cortisol: response to stress; use of protein, carbohydrates and fat; blood pressure and cardiovascular function; inflammation.

Cortisol: Fatigue, stomach upset, dehydration and skin changes.Aldosterone: Drop in blood pressure.

Cortisol: Cushing’s disease (fatigue, weight gain, weak muscles, etc)

Hypothalamus (brain) Anti-diuretic hormone (ADH),Corticotropin-releasing hormone (CRH), Gonadotropin-releasing hormone (GnRH), Follicle stimulating hormone (FSH), luteinizing hormone (LH), Growth hormone-releasing hormone (GHRH) and inhibiting hormone (GHIH),Oxytocin, Prolactin-releasing hormone (PRH) or inhibiting hormone (PIH), Thyrotropin releasing hormone (TRH): triggers the release of thyroid stimulating hormone (TSH).

Heart rate and blood pressure, body temperature, fluid and electrolyte balance, appetite and body weight, glandular secretions of the stomach and intestines, production of substances that influence the pituitary gland to release hormones and sleep cycles

Imbalance of internal body functions.

Imbalance of internal body functions.

Ovaries (female) Estrogen/Progesterone Female System Low bone density Islet Cells (pancreas) Insulin and glucagon Blood glucose levels Hyperglycemia HypoglycemiaParathyroid (neck) Parathyroid hormone Calcium regulation Osteoporosis

Part of Endocrine System Hormones Produced Hormone Regulates Low Exposure Health Effects

High Exposure Health Effects

Pineal gland (brain) Melatonin Circadian rhythm and reproductive hormones.

Pituitary gland (brain) – works closely with the Hypothalamus.

Anterior Lobe Hormones:Adrenocorticotropic hormone (ACTH), Follicle-stimulating hormone (FSH),Growth hormone (GH),Luteinizing hormone (LH), Prolactin, and Thyroid-stimulating hormone (TSH). Posterior Lobe Hormones:Anti-diuretic hormone (ADH), and Oxytocin.

Adrenal gland stimulation for hormone production; maintain healthy body composition in children and aids in healthy bone, muscle mass and fat distribution; breast milk production; kidney function.

Dwarfism (in children); Imbalance of internal functions of the body.

Gigantism (in children); Imbalance of internal functions of the body.

Testes (male) Testosterone Sperm production; normal development of male characteristics.

Decreased sex drive, muscle mass, sperm count; body hair loss.

Thymus (upper chest) Thymosin (only until puberty – then is inactive.)

Production and maturation of T-lymphocytes.

Development of immune system in early stages of life.

Thyroid (neck) T3 (tri-iodothyronine) and T4 (thyroxine).

Metabolism Hypothyroidism: Fatigue, weakness, weight gain, etc.

Hyperthyroidism: Anxiety, rapid heartbeat, weight loss, etc.

Chemical Endocrine Disruption AmountMethyl- and butyl-paraben Increase in Thyroid Hormone

production1000 mg/kg/day (11)

Triclosan Positive association with T3 levels Urinary concentrations (9)Methyl-, ethyl-, n-propyl-, and n- butyl-paraben

Inhibited estrogen receptor binding 1,000,000-fold molar excess (15)

Parabens Bind to estrogen receptors 500,000-fold molar excess (16)

Parabens Estrogenic Activity (15)

Triclosan Displaced estradiol from estrogen receptors

10¯⁵M (19)

Triclosan Mouse mammary tumor cells & Human breast cancer cells.

10¯⁷M & 10¯⁶ respectively (19)