A variety of chemicals have been shown to disrupt female reproductive function throughout the lifespan in laboratory animals and humans (e.g., diethylstilbestrol). These effects include the disruption of normal sexual differentiation, ovarian function (i.e., follicular growth, ovulation, corpus luteum formation and maintenance), fertilization, implantation, and pregnancy. Only a few agents are associated with direct interference with the endocrine reproductive axis. Examples are those with estrogenic activity or the potential to interact with the aryl hydrocarbon (Ah) receptor. Exposure to toxicants during development is of particular concern because many feedback mechanisms functioning in the adult are absent and adverse effects may be noted at doses lower than those observed in the adult.
Endometriosis is a painful reproductive and immunologic disease of women characterized by aberrant location of uterine endometrial cells. It affects approximately 5 million women in the United States from 15 to 45 years of age and often causes infertility. The etiology of this disease is unknown. In a single study with a small number of animals, research has suggested a link between dioxin exposure and the development of endometriosis in rhesus monkeys. The severity of this lesion was dependent on the dose administered. Recently, a small pilot study to test the hypothesis that serum dioxin concentrations have an association with human endometriosis has been reported. No statistically significant correlations between disease severity and serum levels of halogenated aromatic hydrocarbons were found. These preliminary data, admittedly on a limited population, suggest that serum dioxin concentrations may not be related to human endometriosis. Human breast cancer is a major health problem in the United States. While considerable information is available on risk factors for human breast cancer, the mechanisms of mammary gland carcinogenesis and the precise role played by chemical carcinogens, physical and biological agents, varied lifestyles, genetic susceptibility, and developmental exposures have yet to be elucidated. It has been hypothesized that exposure to organochlorines, some pesticides, and/or polyaromatic hydrocarbons might play a role in the etiology of mammary gland neoplasms via an endocrine disruption pathway, perhaps via an estrogen-mimetic route or alternate estrogen pathways. With respect to the possible role of hormone disruption by chemicals in the occurrence of breast cancer, there is a lack of sufficient evidence implicating organochlorines in this disease. ii. Male Reproductive System
Convincing evidence exists in rodents that exposure to chemicals that have estrogenic activity, reduce androgen levels, or otherwise interfere with the action of androgen during development can cause male reproductive system abnormalities that include reduced sperm production capability and reproductive tract abnormalities.
Little is known about the causes of human prostatic cancer, but age, genetics, diet, endocrine status, and environmental risk factors have been proposed. With respect to the cause(s) of human prostate cancer, a single retrospective epidemiology study has linked a weak but statistically significant association between acres sprayed with herbicides and prostate cancer deaths. Furthermore, an occupational study of coke oven workers has found an association of coke oven emission with significant excess mortality from cancer of the prostate. Whether herbicide or polyaromatic hydrocarbon exposure contributes to the increasing incidence of human adenocarcinoma of the prostate and whether the mechanism is by way of an endocrine disruption remain to be determined.

iii. Hypothalamus and Pituitary
There are a number of ways that environmental agents may alter neuroendocrine function both during development and in the sexually mature organism. Exposure during development may be of particular concern because many of the feedback functions of the endocrine system are not operational during this period, permanent changes in endocrine function may be induced at levels of exposure to a toxicant that may have no effect in the adult animal, and compounds that may be considered antiestrogenic in the adult (i.e., tamoxifen, dioxin) may act as estrogens in the developing organism. Similarly, exposure to such agents in the adult can modify the feedback of endogenous hormones as well as behavior (i.e., libido, appetite, aggression) of the individual. Because of the complex role that the central nervous system plays in regulating endocrine function, cells within the brain are a potential target for environmental chemicals that have no impact on steroid hormones directly but yet will lead to a disruption of endocrine function.

iv. Thyroid
Numerous environmental agents have been found to alter thyroid hormone levels (e.g., urea derivatives, polyhalogenated biphenyls, and chlorinated dibenzo-p-dioxins). Thyroid hormones are critical to normal growth and development; thus, developmental exposures may have lasting adverse effects.

2. Ecological Effects
A number of laboratory and field investigations have been reported that provide information from which the potential effects of certain chemicals on the normal endocrine function of invertebrates, fish, reptiles, birds, and mammals can be evaluated. Based on these studies, it has been suggested in the literature that both synthetic and naturally occurring compounds may have the potential to disrupt reproductive and developmental events associated with hormonally mediated processes. In some cases, compounds have been deliberately synthesized for their potential to disrupt endocrine systems. For example, several classes of insecticides have been developed to selectively disrupt the endocrine system of specific insect species without creating substantial risk to nontarget vertebrates due to direct toxic effects, although adverse responses in nontarget arthropods, especially crustaceans, have been observed. Certainly in most other instances, suspect synthetic compounds were either not intentionally designed to have biological activity or their primary mode of toxic action in a short-term exposure is not attributed to effect on the endocrine system.
A series of field and laboratory investigations with marine invertebrates suggest that tributyltin compounds, which are used as antifouling paints on ships, can have significant hormonal effects on some snail species at sublethal exposure concentrations. Through controlled dose-response studies, it appears that these compounds can induce irreversible induction of male sex characteristics on females (imposex), which can lead to sterility and reduced reproductive performance. In turn, field investigations in numerous locations around the world suggest this class of compounds may be responsible for localized reductions in specific snail populations. The possibility that other mollusks (e.g., oysters) could be sensitive to tributyltin compounds also raises ecological concerns, as does the fact that these compounds bioaccumulate in the food chain, leading to questions as to whether or not effects in fish, wildlife, or humans are possible. A wide variety of compounds and environmental settings also have been associated with potential reproductive and developmental anomalies in fish. For example, hermaphroditic fish have been observed in rivers below sewage treatment plants, and masculinization, altered sexual development, and decreased fertility have been noted for some fish species near pulp and paper plant discharges. It is unclear from these studies, however, as to the extent to which these observations are associated with significant changes in population dynamics.
In addition, it is generally unclear as to the primary causes of these perturbations, which could include synthetic chemicals as well as naturally occurring plant-derived compounds. However, correlative data, supported in some cases by controlled laboratory studies, suggest that alkyl phenol ethoxylates and their degradation products, chlorinated dibenzodioxins and difurans, and polychlorinated biphenyls (PCBs), among other compounds, could be contributing causative agents.
Perhaps the most fully documented example of putative ecological effects caused by a disruption of endocrine function has been reported for alligators in Lake Apopka, Florida.Through a series of detailed field and laboratory investigations, it appears very likely that a mixture of Dicofol, Dichlorodiphenyltrichloroethane (DDT), and Dichlorodiphenyldichloroethylene (DDE) associated with a pesticide spill in 1980 is responsible for a variety of developmental effects that indicate a demasculinization of male alligators and "super-feminization" of females. In addition, the effects of the spill also have been reported to include detrimental effects on hatching success and population levels.
Instances of potential effects of chemicals on the endocrinology of warm-blooded wildlife also have been reported. For example, a variety of organochlorine insecticides have been implicated in eliciting feminization of male gull embryos and has led to the suggestion that these effects may contribute to locally observed population declines and skewed sex ratios in Western gulls in California and Herring gulls in the Great Lakes. Although numerous controlled laboratory studies have been undertaken that demonstrate a variety of compounds can elicit hormonally mediated effects on reproduction and development in rodents, the establishment of credible cause-and-effect relationships in wild mammalian populations has not been reported in the scientific literature to date, although the extreme sensitivity of mink, seals, and related species to adverse reproductive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and PCBs is well established. EFFECTS ON AQUATIC LIFE AND WILDLIFE
There is increasing evidence that a number of chemicals in the environment may disrupt the endocrine systems of aquatic life and wildlife. This includes both manmade chemicals (xenobiotics) and chemicals that occur naturally in plants such as phytoestrogens.
a. Synthetic Chemicals (Xenobiotics)
Many synthetic chemicals have been labeled as suspected environmental endocrine disruptors and are addressed briefly below. These include alkylphenols, bisphenol-A, 2,3,7,8- TCDD, 2,3,7,8-tetrachlorodibenzo-furan (TCDF), PCBs, and some pesticides.
Some of the chemicals thought to be environmental endocrine disruptors are in commerce today in the United States; however, many other xenobiotics have been prohibited previously from use in the United States because of their adverse effects on human health and the environment. Some of these xenobiotic chemicals not in use today in North America persist in the environment. They are transported and deposited via atmospheric transport from other parts of the world that still use them or from previous environmental contamination.
Environmental residues of some xenobiotic compounds have decreased after these chemicals were banned or canceled, but many others have leveled off because of physical properties that cause them to accumulate in sediments, be re-released to the aquatic environment, and accumulate in the tissues of organisms. Alkylphenol-polyethoxylates (APE), originating fromthe biodegradation of surfactants and detergents during sewage treatment, and ethynylestradiol, originating from pharmaceutical use, are the two most likely sources of the estrogenic substances present in sewage effluent. Alkylphenols, such as nonylphenol, are commonly used as antioxidants and also are degradates of the biodegradation of a family of nonionic surfactants (such as APE) during sewage treatment.
Nonylphenol and other alkylphenols have been reported to leach from plastics used in food processing and packaging, such as food grade polyvinyl chloride. In the development of a screening assay for estrogenic compounds, nonylphenol was discovered to leach from polystyrene laboratory ware and bisphenol-A was released from plastic ware during autoclaving.
TCDD and TCDF also are suspected of being environmental endocrine disruptors. They are byproducts of the paper, wood, and herbicide industries and are formed in the incineration of some chlorinated organic compounds.
PCBs are a class of compounds that have approximately 113 congeners present in the environment. PCBs, which disrupt hormone pathways involved in, for example, male fertility, were banned from further production in the United States in 1976 under the Toxic Substances Control Act, but these agents were used widely between 1930 and 1970 as additives in products such as paints, plastics, rubber, adhesives, printing ink, and insecticides. While 31% of total PCBs manufactured are currently estimated to be present in the global environment, only 4% of cumulative world production can be accounted for as degraded or incinerated. Many PCBs are still in use in older electrical equipment (e.g., transformers), in containment storage, or in dumps or landfills. Releases from these sources can result in continuing PCB pollution for years to come .
Evidence also exists that pesticides such as alachlor, DDT, dicofol, methoxychlor, chlordane, and many others can disrupt the endocrine systems of fish and feral species.
b. Phytoestrogens
Phytoestrogens, which are hormone-mimicking substances naturally present in plants, are suspected of interfering with the endocrine systems of grazing animals. Specific compounds that have been identified as phytoestrogens include coumestrol, formononetin, daidzein, biochanin A, and genistein. In all, more than 300 species of plants in more than 16 families are known to contain estrogenic substances. Some examples of plants that contain phytoestrogens include beets, soybeans, rye grass, wheat, alfalfa, clover, apples, and cherries. These agents are responsible for the depression of fertility observed in sheep grazing on clover pastures, decreasing serum progesterone or pituitary LH. Plant sterols in paper pulp mill effluent also may be responsible for the masculinizing effect observed in fish downstream of pulp mills. Many questions must be addressed before the overall magnitude, extent, and specific causes of this environmental concern can be resolved. Information is needed on what chemicals or class of chemicals can be considered to be genuine endocrine disruptors. The quantity (dose) of a chemical that is necessary to cause an adverse effect is important. Next, there is a need to know whether chemicals that are suspected of being endocrine disruptors act in an additive, synergistic, or antagonistic manner. While there are several available tests that are capable of evaluating a chemical for possible unique endocrine system disruption in some animal species, it is unclear which one or ones are the most useful. Apparently, there are no avian reproductive tests to evaluate specific estrogenic effects in birds. Therefore, it is important to determine how well current screening assays predict an adverse ecological effect due to endocrine disruption.
Methods need to be developed and validated to test for a cause-and-effect and a dose-response relationship to allow for sound risk assessment and regulatory decisions to be made.
"Sentinel" species (organisms used to detect effects of hazardous exposures) have been used to identify environmental contaminants. Therefore, there is a need to determine whether current sentinel species are adequate surrogates for identifying endocrine disruptors in wild and aquatic life or if other sentinel species should be identified and validated for assessing the state of ecosystems. Perhaps the development, validation, and use of amphibian and/or reptilian models would be appropriate in view of their widespread distribution and lack of information on these classes of vertebrates. Evaluations of ecological effect generally do not consider factors such as disease resistance (immune system dysfunction), behavior (mating disruption), or reproductive viability of offspring (transgenerational effects).
Consequently, there is a need to determine whether existing ecological effects/endpoints are adequate for assessing endocrine system perturbation. Finally, there is a need to know what effects that occur at the earliest response threshold are relevant for further risk characterization and what are the population, community, or ecosystem consequences of the effects observed in fish and wildlife.

BIBLIOGRAPHY
-Anderson DP, Zeeman M. Immunotoxicology in fish. In: Fundamentals of Aquatic Toxicology: Effects, Environmental Fate, and Risk Assessment, Rand G, ed., Taylor and Francis, Washington, DC, 1995, pp 371-404.
- Bulger WH, Kupfer D. Estrogenic activity of pesticides and other xenobiotics on the uterus and male reproductive tract. In: Endocrine Toxicology, Thomas JA, Korach KS, McLachlan JA, eds. Raven Press, New York, 1985, pp 1-33.
-Cooper RL, Barrett MA, Goldman JM, Rehnberg GL, McElroy WK, Stoker TE. Pregnancy alterations following xenobiotic-induced delays in ovulation in the female rat. Fundam Appl Toxicol 22:474-480, 1994.
-Gorbman A. Thyroid function and its control in fishes. In: Fish Physiology: Volume II, The Endocrine System, Hoar WS, Randall DJ, eds. Academic Press, New York, NY, 1969, pp 241-275.
-Soto AM, Chung KL, Sonnenschein C. The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells. Environ Health Perspect 102:380-383, 1994.