Document 5b80k2d6kd1wK1vdwR2gxKake

f A Division of The Society of The Plastics industry, Inc. Robert H. Burnett Executive Director June 7, 1994 TO: Executive Board Technical Committee RE: Estrogen Mimics For your information, enclosed please find a copy of the presentation given at the annual meeting in Dallas by Louis Maresca of Geon on estrogen mimics. RHB/pmb CTL014476 65 Madison Avenue Morristown, NJ 07960 (201) 898-6699 Fax ft (201) 898-6633 Thiongnal copy of th*doa*rw*pnntod on rtcydripi/m. ESTROGEN MIMICS L. M. Maresca C. A. Daniels The Geon Company May 23,1994 Estrogen Function: Estrogens are important hormones affecting development of reproductive organs of humans throughout their life cycle. Estrogens are a group of hormones that differ only by a few molecules. In the fetus, estrogen functions to develop the male and female sexual organs. When women reach childbearing age, estrogen prepares the uterus to accept and nurture a fertilized egg. Estrogen levels are important for a successful pregnancy, and afterward to breast-feed the newborn child. In pre-menopausal women, proper estrogen levels are known to lower the risk of heart disease in women, and to prevent osteoporosis. In post-menopausal women, hormone replacement therapy is often recommended to supplant the depleted estrogen to continue the positive effect of its presence. In males, however, higher than normal levels of estrogen can inhibit the production of sperm and the growth of testes, leading to infertility. The balance of estrogen to male hormone levels in both men and women, in pre and early postnatal development, controls the sexual differentiation and the development of reproductive organs. CTL014478 Estrogen Function Helps stimulate the development of male and female sexual organs in the fetus Orchestrates the reproductive cycle in women Prepares the uterus to accept a fertilized egg Helps with pregnancy and lactation Other estrogen effects Lowers risk of heart attack and osteoporosis Stimulates growth of breast and uterine cancer Inhibits sperm production and growth of testes During prenatal and early postnatal development in both males and females, a specific ratio of estrogen to male hormones is necessary for sexual differentiation and proper formation of reproductive organs CTL014479 Estrogen Mechanism: In humans, estrogen interacts with a specific estrogen receptor, forming a complex molecule which plays an important reproductive role. This complex interacts with DNA in the nucleus of cells, and since DNA contains the genetic code which determines the physical characteristics of the host, alterations in this code can lead to both beneficial and harmful effects. In proper levels, the estrogen and its complex determine the expression of the desired sexual and behavioral characteristics of the fetus, and of the developing child. Excess estrogen, potentially caused by chemicals which mimic estrogen, fool the cells by over-activating the estrogen receptors. Two possible issues can result from the presence of estrogen mimics: an overdose-like reaction, where males can take on female-like characteristics, or a blocking of receptor sites, causing underdevelopment of female characteristics. The problem is further complicated by the fact that the estrogen receptor, the chemical that binds with estrogen, is not specific, That is, numerous chemicals can bind with this receptor, causing it to be activated and subsequently interact with DNA. Thus, the receptor is called promiscuous in its behavior, because of its response to a number of activating materials of wide chemical structure variation. CTL014480 Estrogen Mechanism Estrogen + Receptor - Estrogen/Receptor Complex Estrogen/Receptor Complex + DNA - DNA* Activated DNA (DNA*) alters the expression of key target genes and determines the biological role of cells, tissues and organs Estrogen mimics can interfere with the process Triggers estrogen activity, activating estrogen/receptor complex (overdose) Inhibits hormonal activity by occupying the receptor binding site and preventing estrogen complexation (underdose) Estrogen receptor is sometimes called promiscuous because it is not very selective for estrogen CTL014481 Estrogenic Chemicals: A number of chemicals have been, shown to mimic the interactive behavior of estrogen with the estrogen receptor. Examples of these materials range from diethylstilbestrol (DES), the medication given to pregnant women in the 1950's and 1960's and later shown to cause birth defects; to pesticides such as DDT and Kepone. Antioxidants used in plastics such as bis-phenol-A, and nonylphenol, a chemical used in detergents, are estrogen mimics. Similar behavior has been observed in Tetrahydrocannabinol, the active chemical in marijuana, and in 2,3,7,8,tetrachlorodioxin, commonly called dioxin, a contaminant in chlorinated pesticides and herbicides such as Agent Orange. CTL014482 Estrogenic chemicals exhibit a variety of molecular structures OH P-Estradiol OH OH 0 CH3 Coumestrol 3,9-Dihydroxybenz[a]anthracene CH3 o,p-DDT Tetrahydrocannabinol (A9-THC) CTL014483 ESTROGEN-MIMICS 2,3,7,8-tetrachlorodibenzo-p-dioxin Bis-phenol-A OH CTL014484 Human Effects of Estrogen-Mimics: The concern about estrogen mimics dates back to the unforeseen multi generation effects observed in mothers who took DES during pregnancy, and in their offspring. Abnormalities such as T-shaped uteri, endometriosis (overgrowth of the uterine lining), birth defects, reproductive cancers, infertility and reduced sperm counts in male children have all been associated with exposure of mothers to DES, given to assure that their fetus would be carried to full term. Since that time, the introduction of new pesticides must be preceded by tests that assure that the new product would not cause reproductive disorders. 0X4485 Human Effects of Estrogen-Mimicking Chemicals Basis: Multi-generation effects observed with diethylstilbestrol (DES) Reproductive organ abnormalities (e.g. Tshaped uterus, endometriosis) Birth defects Reproductive organ cancers Infertility and reduced sperm counts CTL014486 Basis for Concern: Studies in Denmark have shown that sperm counts in men have.fallen by 50% since 1940, while the number of testicular cancers has tripled. These men presumably have had some exposure to pesticides or other environmentally important materials during their maturity cycle. There has been an increased incidence of breast cancer and endometriosis in women that correlates with elevated levels of PCB's in their fatty tissues. Studies also link the male offspring of women exposed to estrogen mimics to a higher incidence of testicular abnormalities and smaller penises. In wildlife studies, alligators exposed to DDT in Lake Apopka, Florida are failing to hatch, and males which do hatch have abnormally small penises. Female common terns near a toxic waste site in a harbor in New Bedford, Massachusetts are sharing nests and laying more eggs than usual. Bald eagle egg shells were observed to be thinner than normal, and associated with the exposure of the parent eagles to DDT in the Columbia River in Washington State. All of these situations are speculated to be the result of the exposure of these mammals to estrogen mimics, which result in health effects that last for generations. CTL014487 Basis for Concern Denmark study shows that sperm counts in men have fallen 50% since 1940 while the number of testicular cancers has tripled Increased incidence of breast cancer and endometriosis correlated with elevated levels of PCB's in women Studies link male offspring of women exposed to estrogen mimics to higher incidence of testicular abnormalities and smaller penises Wildlife observations Alligators exposed to DDT in Lake Apopka in Florida are failing to hatch and the males that do hatch have abnormally small penises Female common terns near a toxic waste site in Massachusetts' New Bedford Harbor are sharing nests and laying more than the usual number of eggs Eggshell thinning from DDT was observed in bald eagles in the Columbia River in Washington State CTL014488 Contradictory Evidence: Dioxin, suspected of being an estrogen mimic, has been the subject of several detailed studies. Servicemen in Vietnam, exposed to Agent Orange, know to contain dioxin, showed no increase in debilitating birth defects in their offspring. In Seveso, Italy, where an explosion in a pesticide plant exposed numerous people to dioxin, there was no increase in birth defects among those exposed. Over 200 workers exposed to dioxin in 1949 in Nitro, W.Va. showed no increase in cancer deaths versus the normal population, although 122 did develop chloracne, a skin rash that is produced by dioxin contact. Studies of Eastern Missouri residents showed no increase in cancer, even though their unpaved roads were treated with dioxin contaminated oil, and the dioxin levels in their fatty tissues were 10 times that of the normal population. And, breast cancer in women more closely correlates with age, diet, (especially the fat content), late childbearing, heredity, onset of menstruation, and in recent studies, the use of birth control pills (older types) that had high hormone levels. CTL014489 Contradictory Evidence Studies of servicemen exposed to Agent Orange (contained dioxin) showed no increase in dibilitating birth defects in their offspring Studies of persons exposed to dioxin in Seveso did not show any increase in birth defects Over 200 workers who were exposed to dioxin in Nitro, W. Virginia (1949) showed no increase in cancer deaths vs. normal population (122 did develop chloracne) Studies of Eastern Missouri residents whose unpaved roadways were treated with dioxincontaminated oil showed no cancer increase (and their TCDD levels were lOx those of normal population!) Breast cancer in women more closely correlates with age, diet (fat content), late childbearing, genetics, delayed menstrual onset, and recently, use of '`old style" birth control pills CTL014490 Position on Endocrine Disruptors (Estrogen Mimics): Pesticide manufacturers, under FIFRA, are already required to perform developmental and multi-generational reproductive studies prior to the approval of the pesticides for use. As stated before, the issues created by the use of DES in what was thought to be a protective treatment, has generated a new screen for safety for materials which might potentially cause harm. DES is a powerful endocrine disrupting material which was taken daily in therapeutic dosages during a critical time in the pregnancy. Compared to DES, even the most hazardous pesticide, DDT, has only 10`5 to 10`7 the endocrine disruption potency as does DES and exposure levels are significantly lower. Consequently, there is a huge extrapolation from compounds such as DES to pesticides and other synthetic chemicals. In addition, it must be remembered that plants and animals naturally produce materials that have endocrine effects, and that humans consume significant quantities of these naturally occurring materials in their diets. As can be seen in the chemical structure of common estrogen mimics, most do not contain chlorine, and so to label organic chemicals which contain chlorine as hazardous estrogen mimics is an oversimplification of the situation. Since the estrogen receptor is very non-specific, there are numerous natural and synthetic substances which can interact with the receptor. Finally, many of the studies examining the impact of these chemicals have not been verified, and were not controlled to minimize other effects occurring simultaneously. As in many studies a correlation does not always translate into a cause and effect relationship. CTL014491 Position On Endocrine Disruptors Pesticide manufacturers are already required, under FIFRA, to perform developmental and reproductive studies to detect hormonal and other effects. These studies have been designed to detect the type of multi-generational effects that were seen with DES. Even the most potent endocrine disruptors (eg., DDT) identified as contaminating the environment are only 10`5 - 10'7 as potent as DES. Many plants and animals naturally make chemicals which have endocrine effects and people consume significant quantities of them in their diet. Many of the estrogen mimics do not contain chlorine. Results of many of the studies have not been verified. CTL014492