Toxicology Report Ethinyl Estradiol

Abbi, Anh, Melody and Paul

Purpose
Know the environmental sources of ethinyl estradiol Understand the human health effects connected to ethinyl estradiol

Overview
1. About Ethinyl Estradiol (EE2) 2. Environmental Sources 3. Health Effects

4. Limitations
5. Conclusion

6. References

1. About Ethinyl Estradiol (EE2)

Synthetic estrogen hormone

Used in birth control and for hormonal therapies

Birth control dose is usually 20-60 ug daily Only 50% is absorbed on average in the human body

1. Environmental Cycle of EE2

2. Environmental Sources Overview

Primarily water exposure Can enter soil and air through water, but likelihood of human contact is slim and amount would be small Enters water through sewage

Has been detected at levels up to 273 ng/L Chance of meaningful, unintentional contact is minimal

2.1 Route of Exposure

Oral, through unintentional ingestion

Via water

2.1.2 How EE2 enters the water a. human sources

Consumed in birth control pills and other hormonal therapies o Over 60 million women worldwide take birth control pills 30-90% of compound is not absorbed by the body and is then excreted Based on a 60% excretion rate, ~720kg ethinyl estradiol enters the water supply annually

2.1.2 How EE2 enters the water b. animal sources

Currently, no known significant animal contributors Other types of estrogens from animals may present a concern, but not ethinyl estradiol

If ethinyl estradiol becomes a common compound for large-scale animal use, then animal sources would become a significant contributor of ethinyl estradiol to concentrations in water

2.1.2 How EE2 enters the water c. industrial sources

No significant sources documented However, increased concentrations of other pharmaceuticals in water sources near production facilities have been found More research is needed

2.2 Amount of EE2 in water

In a survey of water sources: 0.1 ng/L (below detection limit) to 273 ng/L In raw sewage, generally about 10 ng/L o has been found in higher concentrations Eventually biodegrades in water, but "pseudopersistent" in areas where sewage is continually discharged

2.3 Removal of EE2 from wastewater

Significant amounts of ethinyl estradiol can be removed with wastewater treatment

Primary wastewater treatment can remove ~14% of total estrogen hormones (ethinyl estradiol makes up a small portion of the total) A type of secondary treatment called activated sludge can eliminate over 60% of ethinyl estradiol from wastewater

2.4 Likelihood of human contact with environmental EE2

In general, contact with significant amounts unlikely

Drinking water generally not the same source where wastewater is released
Ethinyl estradiol eventually degrades in water, so assuming that the water will not be immediately consumed, contact with the compound is unlikely In closed water reuse systems, contact likelihood increases due to the reuse of wastewater as drinking water

3. Health Effects Related to EE2

Pharmaceutical Source: Cardiovascular Respiratory Reproductive Death Genotoxic Carcinogenic Neurological Behavorial

Environmental Source: Immunological Reproductive Developmental

3.1 Health Effects - Systemic

Cardiovascular Respiratory Systemic Hypertension Pulmonary Hypertension Myocardial Ischemia Pulmonary Emboli Myocardial Infarction (Clot in lung arteries) (Heart Attack) Thromboembolic Disease (Blood Clot) Fluid Retention Edema

3.2 Health Effects - Immunological

In mammals and fish estrogen including ethinyl estradiol inhibits different part of immune response Animal studies show immunosupression via decreasing lymphocyte production, especially in male fish exposed to contaminated effluent. Studies also indicate that ethinyl estradiol is more potent in mixed concoctions than when administered alone.

3.3 Health Effects - Reproductive

Oral Contraceptives: o breakthrough vaginal bleeding o glucose intolerance o breast tenderness Case Report: male employee of a pharmaceutical company making contraceptive pills containing ethinyl estradiol developing prolactin secreting adenoma Environmental Exposure: o Animal studies show decline in reproductive success o Feminization in male fish

3.4 Health Effects - Developmental

Exposure of zebrafish to ethinyl estradiol at a concentration of 14-16 ng/L developed ova-testis sex organs. Relation to humans: Dose is environmentally relavent. Children that grow up with both sex organs have developed gender identity disorders, depression and dissatisfaction with their assigned sex. Limitations to data: Fish are very different than humans. There needs to be studies to correlate ethinyl estradiol exposure to intersex humans.

3.5 Health Effects - Genotoxic

In the presence of metabolic activation system (S9 mix) with NADP, ethinyl estradiol was found to cause genotoxic damage to human lymphocytes at 5 and 10 M.
A lymphocyte is a type of white blood cell. NADP is an important molecule used in cellular respiration to make energy. o The S9 mix is a mixture of several liver enzymes.
o o

3.6 Health Effects - Carcinogenic

Women receiving estrogen replacement therapy, including ethinyl estradiol, reported a 2 to 15 fold increase in the risk of endometrial cancer.
o

Endometrial cancer occurs in the lining of the uterus.

Estrogen replacement therapy uses estrogens to stop the effects of menopause after the ovaries have been removed or have stopped functioning.
Limitations to data: Estrogen replacement therapy uses ethinyl estradiol as well as a variety of other estrogens. More research is needed on only ethinyl estradiol for estrogen replacement therapy.

3.7 Health Effects - Neurological

58 healthy women aged between 35 and 49 years were studied for one year while taking an oral contraceptive containing desogestrel 0.150 mg and ethinylestradiol 0.020 mg.
o

Neurological effects include headache and depression

A 6-month study involving 3772 women over the age of 25

were given a low-dose oral contraceptive containing 2.0 mg chlormadinone acetate and 0.03 mg ethinyl estradiol. o Results were found to alleviate headache, lack of concentration, and sleep disturbance when compared to baseline of other oral contraceptive.
Limitations to data: Contradicting studies. Do not know what was used as baseline. Small population study and differences in age groups. Do not know if effects are a result of ethinyl estradiol or other estrogen.

3.8 Health Effects - Behavioral

The sexual behavior of eighty healthy women volunteer from ages 19-31 found increased sexual performance with use of ethinyl estradiol containing oral contraceptive. These women were given an oral contraceptive containing 30 g ethinyl estradiol and 3 mg drospirenone. Changes in behavioral include:
o o o o

Increased sexual enjoyment. Orgasm frequency. Satisfaction with sexual activity. Decrease in genital pain after intercourse.

3.9 Health Effects - Death

No data found for human death but death can occur from secondary complications.
No death in animal studies using fish Death in studies using rats and mices with an LD50 of 2952 mg/kg in rats and 1737 mg/kg in mice

4. Limitations of References & Existing Data

Not enough human studies dealing with environmental exposure
Not even that many mammal studies... Limited to primarily to discussion of sewage treatment, no real discussions of ambient concentrations in drinking water sources

5. Conclusion
More research is needed about the health effects related to ethinyl estradiol and the concentrations found in drinking water sources More research is needed to address ethinyl estradiol as a single substance rather than estrogen mixed Current data does not suggest that ethinyl estradiol in water presents a great threat to human health

6. References
Andersen H, Siegrist H, Halling-Sorensen B, Ternes TA (2003) Fate of estrogens in a municipal sewage treatment plant. Environ Sci Technol 37:40214026. Combalbert, S., & Hernandez-Raquet, G. (May 01, 2010). Occurrence, fate, and biodegradation of estrogens in sewage and manure. Applied Microbiology and Biotechnology, 86, 6, 1671-1692. Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 91. (2007) Pub Chem. (n.d.). Substance Summary. In Ethinyl Estradiol. Retrieved February 20, 2011, from http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=9737&viewopt =Deposited Siddique, Y.H, Beg, T, & Afzal,. (2010). Genotoxic potential of ethinylestradiol in cultured mammalian cells. Chemico-Biological Interactions,151 (5), 133-141. Slone, D., Shapiro, S., Kaufman, D. W., Rosenberg, L., Miettinen, O. S., & Stolley, P. D. (January 01, 1981). Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. The New England Journal of Medicine, 305, 8, 420-4. Steinberg K.K. (1991) A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA. 265:1985-1990. National Library of Medicine. (n.d.). Hazardous Substance Data Bank. In Ethinylestradiol. Retrieved February 20, 2011, from http://toxnet.nlm.nih.gov/cgibin/sis/search/r?dbs+hsdb:@term+@rn+@rel+57-63-6.