Pharmaceuticals and Personal Care Products (PPCPs): Triclosan Chris Aguillon, Jennifer Newman and Antonio Machado Department of Environmental and Occupational Health California State University, Northridge ______Green Chemistry in Higher Education Symposium U.C. Berkeley October 26, 2010

Abstract Fate and Transport

This project focuses on the effects of triclosan in the environment. Triclosan is a widely used antibacterial agent that is Triclosan is lipophilic and resists environmental degradation. Its tendency to adsorb to soil and other environmental frequently found in different environmental strata. The goal of this project is to review existing literature regarding the sediments increases its potential to bioaccumulate in plants and aquatic organisms. Triclosan is among the most environmental fate and transport of triclosan and the potential for environmental health effects at low concentrations. Our commonly identified PPCPs in water systems. Figure 3 illustrates the fate and transport of triclosan in the environment. purpose is to assess the potential for triclosan to interact with other chemicals in the environment that exert health effects Figure 3: Triclosan Environmental Fate and Transport through common mechanisms of action. Introduction

Pharmaceuticals and Personal Care Products (PPCPs) include numerous chemical substances, such as prescription and over-the-counter therapeutic drugs, veterinary drugs, cosmetics, and fragrances. Numerous studies have demonstrated the occurrence of PPCPs in water systems. Further evidence suggests that many of these products are capable of causing ecological harm and have the potential to negatively impact human health (1). Antibiotics are generally designed to inhibit bacterial growth and proliferation. These drugs constitute a significant portion of PPCPs in water supplies. Along with human use, antibiotic treatment is common in veterinary medicine, especially in metaphylaxis. Antibacterial and antimicrobial agents are also considered antibiotics as they are designed to inhibit bacterial growth. Triclosan is a synthetic antimicrobial agent that is commonly used in consumer products, including soaps, hand sanitizers, toothpastes, deodorants, textiles, shoes, and toys.

• In 1972, triclosan was first used in the health care industry (2). • Between 1976 and 2010,the United States Patent and Trademark Office issued over 2,900 patents containing the word “triclosan” (3). • A recent FDA Consumer Update reveals that the agency has not received any evidence that triclosan provides an extra benefit to health when added to certain consumer products such as hand soap (4). • The dramatic increase in the number of household products containing triclosan has raised concerns of the agent’s impact on human health and the environment (Figure 1). 1. Total triclosan (free plus conjugated) was detected in nearly 75% of urine samples (10). 2. Wastewater treatment processes effectively remove up to 95% of triclosan from treated water (11). Figure 1: Triclosan Production History 3. Triclosan was the second most abundant (mean concentration = 12.6 mg/kg) when PPCPs were measured in archived U.S. biosolids (12). 4. Triclosan undergoes phototransformation in aqueous solution to form 2,8-dichlorodibenzo-p-dioxin. Three congeners, 2,3,7-TCDD, 1,2,8-TricDD, and 1,2,3,8-TCDD, also form during chlorine disinfection (13). Triclosan Production History 5. Triclosan was one of the most frequently identified compounds and was detected at some of the highest concentrations among 95 organic wastewater 12 contaminants from 139 streams across the U.S. (14). 6. Triclosan concentration was the highest among PPCPs measured in dewatered municipal biosolids applied to an agricultural field (15). 10 7. Triclosan accumulated in soybean roots and translocated to above ground parts in soil treated with biosolids and contaminated irrigation water (16). 8 8. Sewage treatment processes transform triclosan into methyl triclosan, which is more lipophilic (17). The lipid concentration of methyl triclosan was as high as 365 ng/g (lipid basis) in fish from various lakes in Switzerland (18). 6 9. Triclosan degrades to 2,4-Dichlorophenol when low concentrations of triclosan (<0.1µg/L) are added to tap water with free chlorine concentrations 4 (<1mg/L) (19). 2 Potential Environmental Health Effects

Amount Amount Produced (MillionPounds) 0 1972 1986 1990 1994 1998 2002 Year of Production The widespread use of consumer products containing triclosan has raised concerns regarding the compound’s potential impacts on the environment and human health. Recent studies demonstrate that triclosan’s structural resemblance with Modified figure obtained from Fang, et al.: Occurrence, Efficacy, Metabolism, & Toxicity of Triclosan (5) non-steroidal estrogens makes the compound a probable endocrine disruptor. Furthermore, UV exposure and heat readily converts triclosan into various chlorinated dibenzo-p-dioxins (13). Biotransformation Triclosan Affects Sex and Thyroid Hormones Pathways Most commercial uses of triclosan result in ingestion and dermal absorption. Although the metabolic activity of triclosan is not fully understood in humans, several studies have demonstrated probable biotransformation pathways. Triclosan is likely Table 2: Hormone Pathways Impacted by Triclosan metabolized to glucuronide and sulfate conjugates (Figure 2). Table 1 provides a summary of triclosan’s primary metabollic pathways. Endpoint Concentration/Dose Species/Cell Type Inhibits estrogen-responsive gene activity 10µM MCFT human breast cancer cells(20) Figure 2: Simplified Schematic of Triclosan Metabolism Decreases testosterone induced CAT reporter gene S115 + A mouse mammary tumor activity and inhibits transcription activity induced by 10µM cells(20) testosterone Chemical Identification Molecular weight: 289.54 Impair LH-induced testosterone production 1µM Rat/testicular Leydig cell(21) pKa = 7.9 Increased uterine weight and early vaginal opening 4.69mg/kg Rat (22) log Kow = 4.76 Solubility: 0.01 g/L Inhibition of estrogen sulfonation 0.09nM Sheep placenta (23) Highly soluble (>1,000 g/L) Suppresses serum thyroxine (T4) concentrations 30mg/kg Rat (20) Potential Human Toxicological Effects • Disruption of the sex hormone pathways has the potential to impact human brain development, reproductive development, and onset of puberty. (20) • Alterations to serum thyroxine (T4) concentrations can cause neuropsychological development in children and alterations in sexual maturation. (20) • Dioxins are known to alter sex hormones, decrease fertility, cause birth defects, cause cancer, and weaken the immune system. (24) Ecotoxicological Effects • Changes fin length and sex ratio in Japanese Medaka fish and potentially induces vitellogenin. (25,26) Modified figure obtained from Fang, et al.: Occurrence, Efficacy, Metabolism, & Toxicity of Triclosan (5) • Increases the rate of metamorphosis and tail fin gene expression in the North American Bull Frog. (27) • Potentially leads to an increase in antibiotic resistant bacteria. (28) Table 1: Biotransformation of Triclosan Key Points Route of Exposure Model Biotransformation Pathways Primary Metabolites • Exposure to triclosan is widespread in the U.S. Skin Cells • Glucuronidation • Triclosan glucuronide • There is a potential for triclosan to interact with other endocrine disruptors in the environment to produce Human (in vitro) • Sulfonation • Triclosan sulfate (6) additive or synergistic effects. Liver Microsomes • The FDA is currently reviewing new evidence about the potential harm of triclosan. Human • Glucuronidation • Triclosan glucuronide (7) (in vitro) • The FDA has not received evidence that triclosan provides any extra health benefit when added to certain consumer products such as hand soap. (4) Liver Cytosol Human • Sulfonation • Triclosan sulfate (7) REFERENCES (in vitro) 1. US EPA Pharmaceuticals and Personal Care Products (PPCPs). Frequent Questions. 15. Pharmaceutical and Personal Care Products in Tile Drainage Following Surface Spreading and Oral • Glucuronidation • Triclosan glucuronide [Online] April 20, 2010. [Cited: October 15, 2010.] http://www.epa.gov/ppcp/faq.html. Injection of Dewatered Municipal Biosolids to an Agricultural Field. M. Edwards, et al. 2009, Sci of Human 2. Glaser, Aviva. The Ubiquitous Triclosan: a common antibacterial agent exposed. the Total Env, Vol. 44, pp. 4220-4230. (in vivo) • Sulfonation • Triclosan sulfate (8) Pesticides and You. 3, 2004, Vol. 24, pp. 12-17. 16. Uptake of Pharmaceutical and Personal Care Products by Soybean Plants from Soil Supplied 3. USPTO Patent Full-Text and Image Database. US Patent Collection Triclosan. [Online] with Biosolids and Irrigated with Contaminated Water. Chen Xi Wu, et al. 2010. Env Sci and Tech 10 13, 2010. [Cited: 10 13, 2010.] http://patft.uspto.gov/netacgi/nph Vol. 44, pp. 6157-6161. • Aromatic hydroxylation • Monohydroxylated triclosan* 4. US FDA. 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