Reviews in Environmental Health, 1998
Environmental Health Perspectives 106, Supplement 1, February 1998
[Citation in PubMed] [Related Articles]
Thomas M. Crisp,1,2 Eric D. Clegg,1,2 Ralph L. Cooper,2 William P. Wood,2 David G. Anderson,3 Karl P. Baetcke,3 Jennifer L. Hoffmann,3 Melba S. Morrow,3 Donald J. Rodier,3 John E. Schaeffer,3 Leslie W. Touart,3 Maurice G. Zeeman,3 and Yogendra M. Patel4
This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. It is intended to serve as an interim assessment and analysis of the environmental endocrine disruption hypothesis until a more extensive exploration of environmental endocrine disruption can be completed by the National Academy of Sciences (NAS). This report is not intended to address all of the endocrine glands that might be disrupted by environmental insult. Furthermore, it does not address high occupational or accidental human exposures. Rather, this document focuses on those reports of adverse human and ecological effects in which a common theme of endocrine system disruption by environmental agents has been hypothesized or demonstrated.
An environmental endocrine disruptor is defined as an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development, and/or behavior. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analyze the available information, and provide a reasonable assessment of the problem. Emphasis is placed on disruption of central nervous system-pituitary integration of hormonal and sexual behavioral activity, female and male reproductive system development and function, and thyroid function. In addition, the potential role of environmental endocrine disruption in the induction of breast, testicular, and prostate cancers, as well as endometriosis, is evaluated. The interrelationship of the endocrine and immune system is documented. Finally, some data gaps in our understanding of the environmental endocrine disruption issue are identified and a few future research needs are recommended. A research strategy dealing with this issue is being developed within the U.S. EPA.
With respect to endocrine-related ecological effects, specific examples in the peer-reviewed literature are presented and discussed. For each topic area, data gaps and areas of uncertainty are discussed, conclusions are drawn, and general research needs are suggested.
Nature of Hormones. Hormones are natural, secretory products of endocrine glands (ductless glands that discharge directly into the bloodstream). Hormones travel in the blood in very small concentrations and bind to specific cell sites called receptors in distant target tissues and organs, where they exert their effects on development, growth, and reproduction in addition to other bodily functions.
Role of the Endocrine System. The endocrine system is one of at least three important integrating and regulatory systems in humans and other animals. The other two are the nervous and immune systems. Hormones influence important regulatory, developmental, growth, and homeostatic mechanisms, such as reproductive structure and function; maintenance of normal levels of glucose and ions in blood; control of general body metabolism; blood pressure; and other glandular, muscle, and nervous system functions. Some of the major endocrine glands include the pituitary, thyroid, pancreas, adrenal, and the male and female gonads (testes and ovaries).
Human Health Effects. TYPES OF EFFECTS. Female Reproductive System. 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. Although there are a limited number of endocrine-disrupting studies evaluating reproductive function in the female, it is important that each stage of the life cycle be examined thoroughly. Appropriate, validated in vitro and in vivo tests to determine the endocrine-disrupting potential of agents with clearly defined end points are needed. Additionally, studies that include multigenerational exposure should be conducted, followed by time of exposure and dose level required for effect.
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 for a limited population, suggest that serum dioxin concentrations may not be related to human endometriosis. There is a need to develop and validate nonprimate laboratory animal endometriosis models for testing chemicals and xenobiotics. Several novel models for predicting potential causative agents of endometriosis are available.
Human breast cancer is a major health problem in the United States. Although 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 (PAHs) might play a role in the etiology of mammary gland neoplasms via an endocrine disruption pathway, perhaps via an estrogen-mimetic route or alternative 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. Clearly, there is a need for research on the etiology of breast cancer. With respect to chemically induced breast cancer, there is a need to develop and validate both in vitro short-term tests and in vivo animal testing models for predicting human breast cancer risk following chemical insult. Finally, given the wealth of human epidemiologic data on human breast cancer but limited specific agent exposure data, it is not possible to assign a specific chemical or physical cause and effect at this time. Further epidemiologic investigations to address the issue are needed, as well as complementary mechanistic studies.
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. Results obtained from observation of men exposed to diethylstilbestrol (DES) in utero demonstrate a limited potential of exogenous estrogens to disrupt the reproductive system during development in human males compared with that observed in rodents. Further intense research on the population exposed to DES might allow stratification of effects by timing and level of exposure. Apparently, no increased incidence of reproductive system cancer has been found in those men.
Controversy persists as to the allegation that human sperm production has decreased over the past 50 years. However, the firm data indicating an increase in human testicular cancer, as well as apparent occurrence of other plausibly related effects, support the concept that an adverse influence has occurred or still exists. Whether these effects in humans can be attributed to an endocrine disruption by environmental chemicals is unknown at present, and research into the cause(s) is needed. It is possible that the mechanism by which estrogenic chemicals impair development of the male reproductive system is via antiandrogenic properties rather than or in addition to activity related to estrogen receptor activation.
Leydig cell hyperplasia and tumors are a significant problem in testing with laboratory species. Participants at a workshop on the topic concluded that human incidence of the tumors is low relative to that in rodents and that not all modes of induction in test species are relevant to humans. However, occurrence of Leydig cell tumors in test species may be of concern with certain modes of action if the potential exists for sufficient exposure.
Testing for endocrine-disrupting potential of environmental chemicals should include the ability to detect antiandrogenic activity in addition to estrogenic activity. Testing also should be able to detect alteration in androgen receptor and Ah receptor function as reflected in genome expression.
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 established 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 between coke-oven emission and 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 triggered by an endocrine disruption remain to be determined. More research is required before assigning a specific endocrine disruption (or any other) mechanism as a specific cause of human prostate cancer.
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 have no effect in the adult animal, and compounds that are 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 potential targets for environmental chemicals that have no impact on steroid hormones directly but yet will lead to a disruption of endocrine function. There is a substantial need to better characterize the role of the brain and pituitary when evaluating suspected reproductive toxicants in both the male and female.
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.
STRENGTHS AND WEAKNESSES OF THE DATA. The observation that humans have experienced increased incidences of developmental, reproductive, and carcinogenic effects, and the formulation of a working hypothesis that these adverse effects may be caused by environmental chemicals acting to disrupt the endocrine system that regulates these processes are supported by observations of similar effects in aquatic and wildlife species. In other words, a common theme runs through both human and wildlife reports. The hypothesis also is strengthened by the fact that cancer and noncancer effects, at least with respect to published reports, are related in large part to reproductive structure and function (e.g., vaginal and breast cancer in women, testicular and prostatic cancers in men, endometriosis, cryptorchidism, sperm counts and quality, and infertility).
In contrast, the hypothesis that the reported increased incidence of human cancers and reproductive anomalies and infertility can be attributed to an endocrine disruption phenomenon is called into question by the following. First, secretion and elimination of hormones are highly regulated by the body, and mechanisms for controlling modest fluctuations of hormones are in place via negative feedback control of hormone concentrations. Therefore, minor increases of environmental hormones following dietary absorption and liver detoxification of these xenobiotics may be inconsequential in disrupting endocrine homeostasis. Second, low ambient concentrations of chemicals along with low affinity binding of purported xenobiotics to target receptors probably are insufficient to activate an adverse response in adults. Whether the fetus and the young are capable of regulating minor changes to the endocrine milieu is uncertain. Finally, data are not available for mixtures of chemicals that may be able to affect endocrine function. At the same time, in the case of environmental estrogens as endocrine disruptors, it is known that competition for binding sites by antiestrogens in the environment may moderate estrogenic effects of some chemicals. Clearly, more research is needed to fill data gaps and remove the uncertainties from these unknowns.
CONCLUSIONS. With few exceptions (e.g., DES), a causal relationship between exposure to a specific environmental agent and an adverse effect on human health operating via an endocrine disruption mechanism has not been established. However, in view of the Agency's concern that certain persistent chemicals might be responsible for some of the recently-reported reproductive, developmental, and carcinogenic effects operating through an endocrine disruption mechanism, new epidemiologic and laboratory testing studies could be undertaken to better define the scope of the problem. Short-term screening studies could be developed and validated in an effort to elucidate mechanisms. Biomarkers (indicators) of exposure could be defined and their concentrations related to degree of actual exposure. Studies of absorption, distribution, metabolism, and elimination are essential for improving risk assessments by allowing extrapolation between species and assessing other routes of exposure. The reader is advised to refer to the report of the April 1995 endocrine disruptor workshop recommending specific high-priority research (1).
Ecological Effects. TYPES OF STUDIES. 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 effects on the endocrine system. Several examples, discussed below, illustrate the range of information currently available for a wide spectrum of species.
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 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 dibenzo-p-dioxins and difurans, and 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 likely that a mixture of dicofol, DDT, and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (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. However, 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.
STRENGTHS AND WEAKNESSES OF THE DATA. Numerous effects in aquatic life and wildlife have been hypothesized to be elicited by chemicals that disrupt hormonally mediated events underlying reproduction and development. The strongest evidence available suggesting that specific compounds or classes of compounds could potentially affect the endocrinology of aquatic life and wildlife is typically associated with controlled laboratory investigations. However, although these suborganismal- and organismal-level studies help to establish a mechanistic potential for specific compounds, it is generally not clear if these effects would be observed in environmentally relevant exposure scenarios or to what extent changes in these in vitro and in vivo processes can reasonably be projected to cause declines in populations. In addition, while several well-designed investigations are reported in the literature that establish a sound mechanistic framework for specific effects, the amount of comparative interspecies data is limited. For example, there is comparatively little information available for amphibian species, and the majority of studies available for fish are restricted to teleosts (bony fish).
Several intensive field studies also have been reported that clearly document a wide variety of physiological abnormalities in invertebrates, fish, reptiles, birds, and mammals. In some instances, these abnormalities also have been observed within declining populations. Further, in many of these studies, trends in adverse effects have been correlated with environmental concentrations of synthetic and/or naturally occurring endocrine-modifying chemicals. However, as with most uncontrolled field studies, it is difficult in most cases to establish clear cause-and-effect relationships.
CONCLUSIONS. A challenging goal in assessing the ecological risks of endocrine-disrupting chemicals will be to establish the likelihood of adverse effects on populations and communities of aquatic life and wildlife as a result of toxic effects observed within species of concern. Equally challenging is the need to elucidate cause-and-effect relationships for responses observed in the field, where numerous chemical and nonchemical stressors could be responsible, either alone or in combination. Although numerous reports indicate a variety of compounds can modulate the endocrine system and affect reproduction and development in invertebrates, fish, and wildlife, few examples are currently available that establish the extent to which these insults at the organismal level have, or could, result in adverse population responses. To date, the most credible examples illustrating significant population declines as a result of exposure to endocrine-disrupting chemicals have been reported for alligators in central Florida and some local populations of marine invertebrate species. Because endocrine-disrupting chemicals can elicit a variety of hormonal responses and adverse effects in the reproduction and development of organisms, it can reasonably be hypothesized that these compounds could cause population level impacts in additional species or in other ecosystems. Certainly, from a problem formulation perspective within an ecological risk assessment, chronic exposures to compounds that can selectively affect reproduction and development raise reasonably straightforward concern over potential population effects. However, toxicological effects observed within organisms do not necessarily all have the same potential to impact populations nor should it be expected that these varied effects would elicit population responses at the same exposure levels. In summary, prospective ecological risk assessments for compounds known or suspected to disrupt the endocrinology of aquatic life and wildlife are confronted with the need to establish the significance of observations at the suborganismal and organismal levels in the context of population and community responses. An understanding of linkages between these levels of biological organization also is required to help establish mechanistically plausible cause-and-effect relationships in retrospective risk assessments.
Based on the toxic mechanisms associated with xenobiotics, the collection and interpretation of organismal-level responses associated with reproductive and developmental processes are needed to better predict and interpret changes in populations and communities of aquatic life and wildlife. Unfortunately, end points derived from typically employed bioassays, which are based on short-term exposures, probably are not appropriate for identifying most reproductive or developmental effects or for forecasting changes at higher levels of biological organization. However, because of the mechanisms associated with these compounds, it is reasonable to assume that the implementation of new techniques or the modification of existing approaches can appropriately quantify suborganismal/organismal responses (i.e., measurement end points) that can be readily linked to models and measurements designed to quantify changes in population dynamics (i.e., assessment end points).
AGENCY ACTIONS. While the potential role of endocrine-disrupting chemicals in eliciting adverse ecological effects has heightened the need to develop and implement a more systematic examination of long-term chemical exposures, the U.S. EPA has long recognized the importance of this issue in ecological risk assessments. For example, chemicals such as tributyltin, DDT, and PCBs have been banned or heavily regulated, in part because of their effects on aquatic life and wildlife following long-term exposures. In addition, the ongoing reassessment of the effects of 2,3,7,8-TCDD and related compounds on ecological resources was initiated because of concerns associated with reproductive and developmental effects in fish and wildlife.
Further Research. Increasing concern over persistent bioaccumulative chemicals and appropriate techniques to assess their toxicological and ecological effects is evidenced in the ongoing efforts of the Office of Prevention, Pesticides and Toxic Substances to assess high-production-volume industrial chemicals, the Office of Water's development of sediment quality criteria, and the focus of the Great Lakes Water Quality Initiative. In addition, the Office of Research and Development has published the results of two workshops held in 1995 that specifically addressed the issue of environmental endocrine disruption (1,2). The findings from these workshops cover a broad range of short-term and long-term research objectives that are relevant for both prospective and retrospective assessments. Research needs range from improved techniques for rapidly screening untested chemicals for endocrine-disrupting potential to improved approaches to quantify the extent of current exposures and effects of suspected compounds in human populations, as well as in aquatic life and wildlife. For risk assessment needs, a research strategy is under way that clearly addresses the causal linkage of observations at the subcellular through organismal levels of biological organization to responses of populations and communities. Such a research program, which will incorporate both intramural and extramural researchers (a call for research proposals was issued by the U.S. EPA in February 1996), has been developed to support human health and ecological risk assessments for agents that may operate via an endocrine disruption mechanism.
Last Update: March 18, 1998