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EC50; Species: Strongylocentrotus purpuratus (Purple Sea Urchin, age 1 hr postfertilization embryo); Conditions: saltwater, static, 17 °C; Concentration: 1515.4 ug/L for 95 hr (95% confidence interval: 361.4-3731.3 ug/L); Effect: increased abnormal development /100% purity/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,200(SRC), determined from a structure estimation method(2), indicates that estriol is expected to have moderate mobility in soil(SRC). Volatilization of estriol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Estriol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,200(SRC), determined from a structure estimation method(2), indicates that estriol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.3X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 19(SRC), from its log Kow of 2.45(6) and a regression-derived equation(7), and an estimated BCF of 50(8) suggest the potential for bioconcentration in aquatic organisms is low to moderate(SRC). Biodegradation data in water were not available(SRC, 2011).

AQUATIC FATE: The mean estriol concentration in a swine wastewater manure pit was 1,475 pico Moles; the concentration was 32 pico Moles in the associated primary anaerobic lagoon. The concentration dropped to 15 pico Moles following subsequent residence in open constructed wetland ponds(1).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), estriol, which has an estimated vapor pressure of 9.9X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase estriol may be removed from the air by wet or dry deposition(SRC). Estriol irradiated with a xenon arc lamp exhibited a photodegradation half-life of 2.9 hours in river water and 38.2 hours in air-saturated purified water(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

ENVIRONMENTAL: Free natural estrogens in raw and commercial whole milk were quantitated by radioimmunoassay. The concentration range of estriol was 9 to 31 pg/mL. Equilibrium dialysis of skim milk with hydrogen 3-labeled estrogens showed that 61 to 66% of estriol was protein bound. Whey proteins demonstrated a greater binding capacity than casein. This result was confirmed by radioimmunoassay of dry curd cottage cheese and whey. The concentration in curd was 6 pg/g and in whey 3 pg/mL. ... Butter was highest with a concentration of 87 pg/g. Human colostrum demonstrated a maximum concentration of 4 to 5 ng/mL for estriol. By the 5th day postpartum, it decreased to become similar to cow's milk.

Estriol levels can be measured to give an indication of the general health of the fetus. DHEA-S is produced by the adrenal cortex of the fetus. This is converted to estriol by the placenta. If levels of "unconjugated estriol" are abnormally low in a pregnant woman, this may indicate a problem with the development of the child. The drug interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estriol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.

/AQUATIC SPECIES/ Gonadal intersex and high prevalences of the female phenotype have been observed in fish populations in urbanized areas. Environmental estrogens discharged in sewage treatment plant effluents may be responsible for feminization of fish but many compounds with the potential to induce these responses occur in effluents, including natural and synthetic estrogen hormones, degradation products of alkylphenol ethoxylate surfactants, and plasticizers. In this study, the estrogen hormones 17a-ethinylestradiol, 17beta-estradiol, estrone, and estriol induced intersex (i.e., testis-ova) and altered sex in Japanese medaka (Oryzias latipes) when these fish were exposed to nanogram per liter concentrations of test compounds from hatch to approximately 100 days after hatch. ...

The concentration of estriol in typical raw sewage ranges from 0.01-0.20 ug/L(1). Concentrations in 30 sewage treatment plant effluents sampled in Italy, 10/99-03/2000, ranged from 0.43 to 18 ng/L (1.3 ng/L median)(2). Estriol was detected at concentrations of <1.0 (July 2003), 2.9 (Sept 2003, and <1.0 ng/L (Feb 2004) in effluent from the Eysines Sewage Treatment Plant (northern suburbs, Bordeaux, France) and runs through agricultural and residential areas(3). Estriol was present at concentrations of 261 and 263 ng/L in influent samples to the Piera and Igualada sewage treatment plants, respectively, on the Anoia tributary in the vicinity of Barcelona, Spain, sampled from April to June, 1999; it was not detected in the effluent detected (method detection limits = 2-100 ng/L)(4).

Estriol was not detected in a typical dairy waste disposal system for 2000 dairy cows in San Jacinto, CA; samples include fresh manure less than 2 hrs old, piled manure at 2 weeks, and 3 lagoon dams at 3 months(1). The mean estriol concentration in a swine wastewater manure pit was 1,475 pM(2).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of estriol can be estimated to be 1,200(SRC). According to a classification scheme(2), this estimated Koc value suggests that estriol is expected to have low mobility in soil. A Freundlich adsorption coefficient, log Kd, of 1.33 has been measured(3). The compound was not detected in the effluent of a 23-day column drainage study using Mahall-Laveen sandy loam soil from an area northwest of Phoenix, AZ and 200 L of treated effluent from a municipal waste treatment facility; reporting limit = 0.005 ug/L(4), suggesting adsorption to soil in the column(SRC).

/HUMAN EXPOSURE STUDIES/ In order to study the biological effects of estriol in women 20 mg estriol was administered daily to 7 young women. Plasma luteinizing hormone (LH), estradiol (E2), progesterone (Pg) and prolactin (Prl) were measured during a treatment and a control cycle every second or third day. Further 3, 6 or 20 mg estriol was administered in a single dose to 5 women and plasma Prl, unconjugated and conjugated estriol (E3) measured over 24 hr at 2-3 intervals. In 2 experiments with 20 mg E3, blood samples were taken more frequently, over 6 hr. When 20 mg E2 was administered daily, 2 of the 7 young women had anovulatory cycles. The mean plasma E2 was lower during the follicular and ovulatory phases (P less than 0.025) and mean plasma LH was higher (P less than 0.005) during the luteal phase, when E3 was given. Because of the 2 anovulatory cycles the mean Pg value during the luteal phase was lower (P less than 0.05) during treatment. There was a slight decrease in mean Prl in 5 out of 6 women (P less than 0.0005), but in only 1 woman was this decrease substantial (from a mean value of 27.6-18.9 ng/mL; P less than 0.01). When 6 or 20 mg E3 was administered orally in the morning a significant negative correlation (P less than 0.01) between plasma Prl and unconjugated E3 was found. The correlation coefficient was highest (r = -0.74) with 6 mg E3. When 3 mg was administered no obvious effect on Prl section was seen. However, when results from all experiments with identical time schedules were pooled (two with 3 mg, two with 6 mg and one with 20 mg E3) and the mean values for plasma Prl calculated and compared with the mean values obtained in 7 control experiments, it was found that E3 administration in the morning almost abolishes the Prl rise during the following night. There was a statistically significant (P less than 0.0125) decrease in the difference between the maximum value during the night and the minimum value during the day. The minimum value was significantly higher (P less than 0.01) and the maximum value significantly lower (P less than 0.025) after E3 treatment, compared to the control values. It is concluded that long-term administration of 20 mg E3 usually has only a slight but significant decreasing effect on mean plasma Prl concentration measured in the morning, before the next dose is taken.

/SIGNS AND SYMPTOMS/ Symptoms of overdose of estrogen therapy may include breast pain or tenderness, nausea, break-through bleeding, abdominal cramps and/or bloating. Vaginal lavage should be considered.

/EPIDEMIOLOGY STUDIES/ Several studies have shown an increased relative risk of endometrial carcinoma in postmenopausal women who received prolonged estrogen replacement therapy for relief of menopausal symptoms. This risk was independent of other known risk factors for endometrial carcinoma and appeared to depend on duration and dosage of estrogen therapy. While there appears to be no increased risk of endometrial carcinoma in postmenopausal women receiving estrogen therapy for less than 1 year, prolonged estrogen therapy may be associated with an increased risk of such carcinoma. The risk of endometrial carcinoma reportedly is increased 2- to 12-fold in postmenopausal women receiving unopposed estrogen therapy compared with those not receiving estrogens; such increased risk may depend on dosage and duration of therapy and may be 15- to 24-fold higher in women receiving long-term (5 years or more) estrogen therapy. Limited data indicate that a substantial increased risk of endometrial carcinoma may persist for up to 15 years following discontinuance of estrogen therapy. Because of the increased risk of endometrial carcinoma associated with prolonged estrogen therapy, patients receiving prolonged treatment with the drugs should be evaluated at least twice yearly to reassess the need for continued therapy. Results of several studies indicate that when progestins are used concomitantly with estrogen replacement therapy, the incidence of endometrial hyperplasia and endometrial carcinoma is reduced substantially. In a randomized, controlled, multicenter study in postmenopausal women, endometrial hyperplasia occurred in 20 or 1% or less of women receiving estrogen therapy alone or in conjunction with progestins, respectively. In the WHI study, the incidence of endometrial carcinoma in women receiving hormone replacement therapy (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) was similar to the incidence in women receiving placebo. /Estrogen General Statement/

SEDIMENT: Levels of estriol in sediment from the Beitang River, Dagu River, and Yongding New River in the Tianjin area, northern China, sampled in June 2007 were not detected-6.99, not detected-7.29, and not detected-3.77 ng/g dry weight, respectively, with mean concentrations of 3.08, 2.61 and 1.97 ng/g dry weight, respectively(1).

MEDICATION

Use (kg; approx.) in Germany (2009): >50

Used as a test to determine the general health of an unborn fetus.

Reported impurities include: estradiol, estra-1,3,5(10),9(11)-tetraene-3,16alpha,17beta-triol (9,11-didehydroestriol), estra-1,3,5(10)-triene-3,16alpha,17beta-triol (17-epi-estriol), estra-1,3,5(10)-triene-3,16beta,17beta-triol (16-epi-estriol), estra-1,3,5(10)-triene-3,16beta,17alpha-triol (16,17-epi-estriol), 3-hydroxyestra-1,3,5(10)-trien-17-one (estrone); 3,16alpha-dihydroxyestra- 1,3,5(10)-trien-17-one, 3-hydroxy-17-oxa-D-homoestra-1,3,5(10)-trien-17a-one and 3-methoxyestra-1,3,5(10)-triene-16alpha,17beta-diol (estriol 3-methyl ether).