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      Triclosan Exposure Modulates Estrogen-Dependent Responses in the Female Wistar Rat

      , ,
      Toxicological Sciences
      Oxford University Press (OUP)

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          Abstract

          Triclosan is an antimicrobial found in personal care and sanitizing products, such as soaps, toothpaste, and hair products. There have been recent concerns for the possible effects on human health, as triclosan has been detected in human breast milk, blood, and urine samples. In a previous study, we found that triclosan alters serum thyroid hormone and testosterone concentrations in male rats. In the current study, we evaluated the effects of triclosan in the female Wistar rat following exposure for 21 days in the Endocrine Disruptor Screening Program pubertal protocol and the weanling uterotrophic assay (3-day exposure). In the pubertal study, triclosan advanced the age of onset of vaginal opening and increased uterine weight at 150 mg/kg, indicative of an estrogenic effect. In the uterotrophic assay, rats received oral doses of triclosan (1.18, 2.35, 4.69, 9.37, 18.75, 37.5, 75, 150, and 300 mg/kg) alone, 3 microg/kg ethinyl estradiol (EE), or triclosan (same doses as above) plus 3 microg/kg EE. Uterine weight was increased in the EE group (positive control) as compared with the control but was not affected by triclosan alone. However, there was a significant dose-dependent increase in the group cotreated with EE and triclosan (>or= 4.69 mg/kg) as compared with EE alone, indicating a potentiation of the estrogen response on uterine weight. This result was well correlated with potentiated estrogen-induced changes in uterine histology. Serum thyroid hormone concentrations were also suppressed by triclosan in this study, similar to other studies in the male and female rat. In conclusion, triclosan affected estrogen-mediated responses in the pubertal and weanling female rat and also suppressed thyroid hormone in both studies. The lowest effective concentrations in the rodent model are approximately 10 (for estrogen) and 40 (for thyroid hormone) times higher than the highest concentrations reported in human plasma.

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          Most cited references23

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          Co-occurrence of triclocarban and triclosan in U.S. water resources.

          Triclocarban (TCC) and triclosan (TCS) are antimicrobial additives in personal care products. Whereas TCS has been studied extensively, the environmental fate of TCC remains largely unknown. To address this data gap, we performed quantitative structure-activity relationship (QSAR) analyses that suggested a propensity of TCC to persist in various environmental compartments with predicted half-lives ranging from 0.75 days in air to 540 days in sediment. Moreover, concentrations of both antimicrobials were measured in 42 environmental samples from the Greater Baltimore region using a combination of solid-phase extraction, liquid chromatography/mass spectrometry, and isotope dilution. The co-occurrence of TCC and TCS was observed, owing to similar properties, usage, disposal, and environmental half-lives. A linear empirical correlation (R2 = 0.9882) fit the log-log-transformed data from diverse aquatic media and spanned 5 orders of magnitude in concentration. Occurrences of TCC predicted for 85 U.S. streams were statistically indistinguishable from experimental regional data (alpha < or = 0.05). Annual loading of antimicrobials to water resources probably is dominated by activated sludge treatment plants (39-67%), followed by trickling filters (31-54%) and combined and sanitary sewer overflows (2-7% and <0.2%, respectively). Study results suggest that TCC is a previously unrecognized contaminant of U.S. water resources nationwide, likely ranking in the top 10 in occurrence rate and in the top 20 in maximum concentration among 96 organic pollutants considered. The magnitude and frequency of TCC contamination (regional, 6750 ng/L, 68%; predicted nationwide for 1999--2000, 1150 ng/L, 60%) were markedly higher than non-peer-reviewed numbers (240 ng/L, 30%, U.S.) currently used by the U.S. Environmental Protection Agency for evaluating TCC's ecological and human health risks.
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            Pharmacokinetics of triclosan following oral ingestion in humans.

            The number of personal hygiene products containing triclosan has increased rapidly during the last decade, and triclosan is one of the most common antibacterial compounds used in dentifrices today. However, the extent of triclosan exposure has not yet been well described. The potential risks of generating triclosan-resistant pathogenic microorganisms or of the selection of resistant strains are some areas of concern. The aim of the present study was to (1) obtain information on baseline levels of triclosan in plasma and urine, and (2) study the pharmacokinetic pattern of triclosan after a single-dose intake. Ten healthy volunteers were exposed to a single oral dose of 4 mg triclosan by swallowing an oral mouthwash solution. Triclosan in plasma and urine was followed before and up to 8 d after exposure. Triclosan levels in plasma increased rapidly, with a maximum concentration within 1 to 3 h, and the terminal plasma half-life was 21 h. The major fraction was excreted within the first 24 h. The accumulated urinary excretion varied between the subjects, with 24 to 83% of the oral dose being excreted during the first 4 d after exposure. In conclusion, triclosan appears to be readily absorbed from the gastrointestinal tract and has a rapid turnover in humans. The high lipid solubility of the substance gives rise to questions regarding distribution properties and accumulation. The findings of the present study form a basis for greater understanding of the toxicokinetic properties of triclosan in humans.
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              Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats.

              Considerable attention has recently been focused on environmental chemicals that disrupt the reproductive system by altering steroid receptor function. Although numerous in vitro and in vivo methods have been shown to be useful approaches for identifying chemicals that can disrupt reproduction through a direct interaction with the estrogen receptor, it is imperative that the protocols selected be capable of detecting chemicals with a broad range of estrogenic activity. Here we evaluate the reliability of the 3-day uterotrophic assay for detecting chemicals with strong or weak estrogenic activity in both prepubertal and ovariectomized adult Long Evans rats. These data were compared to additional measures of estrogenic activity, which included the age of vaginal opening, the induction of cornified vaginal epithelial cells in ovariectomized adult rats, and estrous cyclicity in intact adult rats. Test chemicals selected for these studies included 17-beta-estradiol, ethynyl estradiol, methoxychlor, 4-tert-octylphenol, 4-nonylphenol and bisphenol A. Data from in vitro receptor binding assays compared the ability of the test chemicals to compete with [3H]-estradiol or [3H]-promegestone for binding to estrogen or progesterone receptors. As expected, the binding affinities for the estrogen receptor ranged from high to low, as reflected by Ki concentrations of 0.4 nM for 17-beta-estradiol and ethynyl estradiol, and 0.05-65 microM for 4-tert-octyphenol, 4-nonylphenol, and methoxychlor. Although none of the test chemicals demonstrated a high affinity for binding to the progesterone receptor, 4-tert-octylphenol and 4-nonylphenol exhibited a weak affinity, with Ki concentrations ranging from 1.2 to 3.8 microM. In vivo studies indicated that the 3-day uterotrophic assay in prepubertal rats was the best method for detecting estrogenic activity when compared with all other end points, based upon the dose-response data for ethynyl estradiol (0.01-0.1 mg/kg), 4-tert-octylphenol (50-200 mg/kg, oral), and 4-nonylphenol (25-100 mg/kg, oral). Although oral doses of ethynyl estradiol (0.01 mg/kg) and 4-nonylphenol (50 mg/kg) induced a significant increase in uterine weight in the prepubertal rats, these doses were ineffective for stimulating a similar response in ovariectomized adult rats. The age of vaginal opening was advanced following oral exposure from postnatal days 21-35 to ethynyl estradiol (0.01 mg/kg), methoxychlor (50 mg/kg), 4-tert-octylphenol (200 mg/kg), and 4-nonylphenol (50 mg/kg). Although bisphenol A (200 mg/kg, oral) induced a significant uterotrophic response within 3 days in prepubertal rats, doses up to 400 mg/kg failed to advance the age of vaginal opening. Monitoring changes in the vaginal epithelium of ovariectomized adult rats was the least effective method for detecting estrogenic activity for 4-tert-octylphenol and bisphenol A. The number of 4-5 day estrous cycles was reduced during a 25-day exposure to ethynyl estradiol (0.01 mg/kg), methoxychlor (50 mg/ kg), 4-tert-octylphenol (200 mg/kg), 4-nonylphenol (100 mg/kg), and bisphenol A (100 mg/kg) by oral gavage. Although long periods of extended diestrus (7-14 days) were generally correlated with exposure to ethynyl estradiol and 4-tert-octylphenol, the cycling patterns following exposure to methoxychlor, 4-nonylphenol and bisphenol A were not as clearly defined, with shorter periods of extended diestrus (4-7 days) and/or estrus (3-5 days) intermittently observed throughout the exposure period. Together these data provide a comparison of the 3-day uterotrophic assay with alternative measures of estrogenic activity for a group of test chemicals with a broad range of affinities for the estrogen receptor. These data can be useful during the assessment and validation of methods for screening environmental chemicals for endocrine disrupting activity.
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                Author and article information

                Journal
                Toxicological Sciences
                Oxford University Press (OUP)
                1096-6080
                1096-0929
                September 2010
                September 01 2010
                June 18 2010
                September 2010
                September 01 2010
                June 18 2010
                : 117
                : 1
                : 45-53
                Article
                10.1093/toxsci/kfq180
                20562219
                182aa4bb-8af4-4bc8-829d-c951b3d8a67f
                © 2010
                History

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