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
With few exceptions (e.g., DES, dioxin, DDT/DDE), a causal relationship has not been established between exposure to a specific environmental agent and an adverse effect on human health operating via an endocrine disruption mechanism. An important consideration in evaluating endocrine-disrupting mechanisms is the concept of negative feedback control of hormone concentrations. Endogenous secretion and elimination of hormones are highly regulated, and mechanisms for controlling modest fluctuations of hormones are in place. Therefore, minor increases of exogenous hormones following dietary absorption and hepatic detoxification of these xenobiotics may be inconsequential in disrupting endocrine homeostasis in the adult. Whether the fetus and the young are capable of regulating minor changes to the endocrine milieu is uncertain.
An essential question in the analysis and discussion of the issue of environmental hormone disruption for risk assessment is whether the exposure and endocrine potency levels of the agents are sufficient to adversely affect human populations. If endocrine disruption is occurring through a hormone receptor mechanism, low ambient concentrations along with low-affinity binding of purported xenobiotics are probably insufficient to activate an adverse response. For example, exposure concentrations of weak estrogenic alkylphenols are on the order of ppm to ppb. White et al. (48) reported effluent concentrations from sewage discharge plants in the United Kingdom at 0.1 ppm. Approximately 1/100 of the total (bound plus free) serum estradiol available is free to activate a physiologic response in female rats (64). According to White et al. (48), of the alkylphenols tested, it requires some 1000 to 10,000 times more of the weak estrogen than estradiol to bind 50% of the estrogen receptor. If these data are correct, it means that 100,000 to 1,000,000 times more of the agent is needed to activate a physiological response. In other words, there would have to be 100 to 1000 times more of the agent in the water to activate an estrogenic response. Clearly, the normal human female is able to regulate parts per billion concentrations of estradiol without difficulty. In addition, Safe (56) points out that dietary exposure to xenoestrogens derived from industrial chemicals is minimal compared with estrogen equivalents from naturally occurring bioflavonoids. Furthermore, in the case of environmental estrogens as endocrine disruptors, it is known that competition for binding sites by antiestrogens and downregulation of estrogen receptors via Ah receptor-mediated chemicals in the environment may mitigate estrogenic effects of some chemicals (55). Taken together, the technical panel concludes, based on the available evidence, that exposure to a single xenoestrogenic chemical at current environmental concentrations is probably insufficient to evoke an adverse effect in adults. More information is needed to determine whether this holds for the human fetus and the neonate. Also, whether additional chemicals may overcome a body burden or operate at nonestrogenic receptor sites to stimulate or inhibit estrogenic or other responses needs to be determined.
Another unknown of relevancy is whether a mixture of chemicals with endocrine-disrupting potential [via additivity (317,359) or synergy (360)1] is sufficient to elicit a response and whether antagonists within the same mixture are sufficient to negate the response (362). These uncertainties will require considerable exploration.
Another issue is whether existing guidelines and testing protocols are adequate to detect endocrine-mediated effects of a disruptor in the general population as well as in sensitive individuals (the fetus, children, the infirm, and elderly). Clearly, there are age-dependent differences in susceptibility to endocrine disruptors. In adult ovariectomized C57BL/Tw mice, three daily doses of 100 µg of clomiphene, tamoxifen, or nafoxidine or 1 µg of estradiol but not keoxifene increases uterine and vaginal weight, DNA, and protein (363). In contrast, neonatal mice given five daily doses of the antiestrogen keoxifene exhibited decreased uterine and vaginal weights at 60 days of age. Similarly, while TCDD can inhibit certain estrogenic effects in adults, weanling Sprague-Dawley female rats are apparently insensitive to the antiestrogenic effects of TCDD (364). No test guidelines/protocols exist to specifically evaluate endocrine disruption effects.
For human health risk assessment two-generation reproduction studies, the new U.S. EPA harmonized reproductive and developmental toxicity testing guidelines and the 2-year cancer bioassay should be able to detect many adverse effects. However, these were not designed to identify mechanisms of action of endocrine disruption, subtle functional deficits, or transplacental carcinogenesis that might result after exposures at critical stages of development not currently included in testing protocols. Current tests also are inadequate to evaluate endocrine-mediated effects of mixtures. Some attempt has been made to expand on this issue under specific end points discussed previously. It should be remembered, however, that first-tier toxicity testing protocols are not designed to determine specific end points or mechanism of action but are apical in design. As such, they employ a paradigm intended to detect a broad spectrum of end points and adverse effects in the overall reproductive process.
With respect to risk assessment, it should be kept in mind that all of the data should be considered in the evaluation. For example, in the case of evaluating estrogen-mimetic, natural, and synthetic chemical influences in the development of hypothalamic centers and sex differentiation of the fetus, the following questions might be asked: What is the role of natural products such as the phytoestrogens in the diet of mothers? Are the adverse effects observed the result of additive, synergistic, or antagonistic mechanisms of action? In adults, do the phytoestrogens have any protective role in regulating/restricting estrogen influences in breast cancer development? For industrial chemicals and pesticides (including inert ingredients) that are used in the workplace and home, there is a need to accurately assess exposures posed by their uses. Basic issues such as exposure potentials due to leaching from containers, dermal contact, and inhalation need to be addressed. To address these issues, a concerted effort will be needed from industry and the U.S. EPA to compile accurate information on how these chemicals are used.
Evidence has been presented that a number of environmental agents (both synthetic and natural) have the potential of disrupting endocrine systems in aquatic life and wildlife. The problem is characterized by varied adverse effects on the endocrine systems of a wide range of species. Effects observed include abnormal thyroid function, sex alteration, poor hatching success, decreased fertility, and reduced growth.
Evidence in the scientific literature is compelling that the endocrine systems of certain fish and wildlife have indeed been disturbed by chemicals that contaminate their habitats. At present, it is not clear whether the adverse effects observed at various sites are confined to isolated areas or are representative of more widespread conditions. In many cases, the chemicals identified are ones that already have been identified as problem substances due to their toxicity and persistence (DDT, PCBs, heavy metals, etc.) and therefore are heavily regulated or banned from commercial use in the United States, or the chemicals are complex mixtures (pulp mill effluents, Superfund site drainage, etc.) known to be hazardous and to have deleterious effects in highly exposed populations. In many of the cases, however, the evidence lacks specific cause-and-effect data, and alternative explanations for the observed effects cannot be completely ruled out. For instance, goiter in Great Lakes fish has no specific chemical or mixture of chemicals identified or specific exposure level quantified that produces the anomaly. It seems likely that there is a chemical etiology for the phenomenon other than low iodine levels in the Great Lakes, but much more research is needed in this case and in many others as well.
It is significant that these chemicals that affect fish and wildlife in their natural habitat have been shown to cause similar adverse effects in laboratory test animals. In addition, specific chemicals have been detected in fish and wildlife coincident with the onset of adverse reproductive effects.
For almost all toxic chemicals, the toxic action or stress exerted on an organism likely will be moderated by endocrine and immune processes that exist to maintain homeostasis. For this reason it is difficult to determine whether a toxic action is directed specifically at an endocrine function or whether an endocrine process disruption is an indirect consequence of some other stress to the immune, nervous, and/or reproductive system of the organism affected. This fact may provide an explanation as to why many compounds have been postulated as endocrine disruptors.
Much attention has been focused mainly on environmental estrogens (xenoestrogens) and their possible adverse effects to the well-being of humans and other animals, but it should be kept in mind that these and other environmental agents may act at several target sites promoting, directly or indirectly, endocrine disruption, disease, and adverse population effects. Furthermore, it should be kept in mind that certain pesticidal agents have been synthesized to function intentionally as hormone/growth regulators to control pest populations. Although it is clear that exogenous chemicals can interfere with hormonally mediated processes, the extent to which exposure to these environmental chemicals occurs at levels that may cause endocrine disruption is uncertain. Until additional laboratory animal, wildlife, and some human studies provide sufficient evidence for an environmental endocrine disruption phenomenon, it seems reasonable to call the endocrine disruption issue a working hypothesis.
In summary, although the majority of the effects listed above are of concern, whether these observations represent widespread or isolated phenomena and whether these effects can be attributed to a specific endocrine disruptor will require additional research.
The data gaps and research needs on potential endocrine disruptors summarized below under specific human health and ecological research needs support and complement those presented in much greater detail in two recent workshops and addressed in the following documents: Research Needs for Risk Assessment of the Health and Environmental Effects of Endocrine Disruptors: A Report of the US EPA-Sponsored Workshop, Raleigh, NC, April 10-13, 1995 (1) and Development of Research Strategy for Assessing the Ecological Risk of Endocrine Disruptors, Duluth, MN, June 13-16, 1995 (2). These two documents, along with ORD's research strategy proposal, present needs for research information that will be useful to the U.S. EPA in responding appropriately to potential effects of endocrine-disrupting chemicals on health and the environment.
In view of the current interest and concern in environmental endocrine disruption for human health and ecological well-being, additional epidemiologic, laboratory testing, and field studies can be undertaken to better define the nature and scope of the potential problem. Epidemiologic studies of populations environmentally or occupationally exposed may provide insight into the actual risks posed by chemicals. Both in vitro and short-term in vivo tests could be developed and validated in independent laboratories in an effort to elucidate mechanisms. Biomarkers of exposure could be defined and their concentrations related to degree of insult (i.e., dose-response assessment). Pharmacokinetics studies would be helpful for improving risk assessments by allowing extrapolation between species and assessing other routes of exposure. Because of the interrelationship of the endocrine glands, the potential disruption of either one could have detrimental effects elsewhere. For example, the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, a hormone, causes a hypercalcemia with resulting disturbance of the estrous cycle, corpus luteum dysfunction, reduced serum progesterone, and uterine function (365). In other words, disruption of one endocrine gland function may influence the functions of other endocrine glands. Additionally, the endocrine system is related to the nervous and immune systems, and disruption of one component may affect others. Consequently, these interrelationships could be fertile grounds for research exploration of environmental endocrine disruption.
Female Reproductive and Developmental Research. OVARY AND REPRODUCTIVE TrRACT. Updated reproductive and developmental testing guidelines have been proposed recently that should improve the U.S. EPA's ability to indirectly assess hormonal disruption and the effects on laboratory test animals, but there may be a need for additional tests to evaluate specific chemicals perceived to be endocrine disruptors.
Inclusion in the new guidelines of estrous cycle evaluation, vaginal opening, and anogenital distance measurements when appropriate may provide information on whether estrogen and androgen receptors have been affected by a given compound. Specific inclusion of ovarian and uterine weights and the histology on these reproductive organs also may help to evaluate potential endocrine-active chemicals. Although all changes occurring in these organs are not necessarily specific to endocrine effects, all changes in these endocrine-sensitive organs should help indicate when further testing may be desirable. Measurement of serum hormone levels in laboratory animals at appropriate times, if incorporated into testing guidelines should provide useful information as to whether an endocrine disruption mechanism is operating.
Validation of certain experimental testing assays (both in vitro and in vivo), developed and used in some research laboratories for use as estrogen assays, would be a valuable first step in developing more efficient approaches to determine whether the potential exists for agents to cause hormonal disruption. However, these studies should not be used as sole determinants of whether compounds are endocrine disruptors, and special in vivo studies would be necessary to support the information obtained from in vitro screening tests or computer models. Finally, research is needed to determine the feasibility of such a tier approach, the type of studies needed, and the impact that a battery of tests for endocrine disruption will have on the risk assessment process.
ENDOMETRIOSIS. There is a need to develop and validate laboratory animal endometriosis models for testing chemicals and xenobiotics with other than rhesus monkeys. A rat model for endometriosis has been reported (366). Nude (immunologically compromised) rodents with human endometrial transplants might provide an appropriate animal model for testing potential causative agents of endometriosis.
BREAST CANCER. There are a number of data gaps in our understanding of mechanisms of mammary gland carcinogenesis. Traditionally, safety and scaling factors and mathematical models have been employed to estimate the risk to humans based on study results in test animals. Such procedures are based on assumptions that may not be realistic for predicting human hazard/risk or mechanisms. Therefore, there is a need to develop and validate biologically based dose-response test animal-to-human extrapolation models for studying mechanisms of toxicity and chemical carcinogenesis, thus improving human risk assessment.
Because environmental estrogenlike chemicals have been implicated as possible contributing factors in the etiology of human breast cancer, these agents could be tested in various appropriate animal models.
Male Reproductive Research. Testing for reproductive toxicity should include evaluation of both the quantity and quality of sperm produced. Such measures are emphasized in both the draft, EPA Guidelines for Reproductive Toxicity Risk Assessment and the draft, Two-Generation Reproductive Toxicity Test Guidelines. Recent revelations that agents such as estradiol and DES as well as the DDT metabolite DDE also have antiandrogenic activity place significantly increased importance on that mechanism of action. It is possible that the effects attributed to estrogenic activity are due to antiandrogenic activity instead of or in addition to estrogenic activity. Therefore, it is important that testing for endocrine-disrupting potential of environmental chemicals include the ability to detect antiandrogenic activity in addition to estrogenic activity. Testing also should be able to detect alteration in androgen receptor function as reflected in genome expression.
Further extensive research on populations exposed to DES might allow stratification of adverse effects by timing and level of exposure. Additionally, because retrospective examinations of existing data are likely to yield ambiguous results, it is important that prospective studies of human male sperm production be conducted. Such studies should include examination of trends in testicular cancer and sperm production over time and attempt to relate results to body and target tissue burdens of chemicals known to have antiandrogenic and/or estrogenic effects. The need for information relatively quickly dictates that existing populations of men be studied. For the long term, ideally a study would begin with the pregnancies from which the male study population was derived. Under those conditions, evaluation of the other known or developmentally induced reproductive system effects also could be done.
Whether herbicide exposure contributes to the increasing incidence of human adenocarcinoma of the prostate and, if so, whether the mechanism is through an endocrine disruption have yet to be confirmed. If additional epidemiology studies support the above finding, then the next step is to identify specific herbicides that are causative agents and the mechanisms by which these carcinogens act. Because an association between prostate cancer and herbicide spraying has been suggested, there is need to determine the most likely route (oral, inhalation, and/or dermal) of human exposure. If a dietary risk factor (increased fat intake) is confirmed, perhaps an oral route of exposure is most likely. Is a genotoxic effect operational, or is there an epigenetic mechanism working? Pertinent to this discussion, what is the evidence that a hormonal mechanism is contributing to the increased incidence of this disease? Are androgen-mimetic chemicals likely candidates? These and other questions require further research.
Hypothalamus, Pituitary, and Thyroid Research. Future efforts should concentrate on developing improved tests to identify environmental agents that alter endocrine function through their action on the CNS and pituitary. Such tests are needed to identify any adverse neuroendocrine changes that occur in response to exposure during development and/or in adulthood. These tests might include direct measures of the gonadotropins and prolactin, as well as assessment of the functional reproductive end points regulated by the pituitary hormones. Further information is needed to better evaluate the extent to which normal sex differences in the neuroendocrine control of gonadal function may contribute to gender differences in response to reproductive toxicants. Because the CNS may develop tolerance to exposure to environmental agents, further studies are needed to evaluate the impact of tolerance on neuroendocrine/reproductive toxicity and to determine whether the current tests will identify this phenomenon.
Clearly, there is a need for protocols and multiple tests to identify chemicals that have the potential of disrupting thyroid hormone function. In rat studies, propylthiouracil treatment during development impairs CNS function (i.e., hearing) in adulthood (367). Information on effects of chemicals in both sexes and the effects of exposure to the fetus, children, and adults are necessary. Once these apical tests are developed and validated, additional tests to ascertain mechanisms of action appear feasible. In an effort to extrapolate test animal to human equivalence, reasonable dose-response data are needed along with pharmacokinetics studies.
Ecological Research. 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 are considered to be genuine endocrine disruptors. The quantity (dose) of a chemical necessary to cause an adverse effect is important. Next, there is a need to know whether chemicals suspected of being endocrine disruptors act in an additive, synergistic, or antagonistic manner. Although there are several available tests for evaluating chemicals 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 adverse ecological effects 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. Additional research is needed to determine whether a chemical or its metabolites have hormonal activity, and if so, what mechanism of action is involved; rank chemicals in relative potency terms of toxicity; determine whether organisms are exposed to specific chemicals in the environment; ascertain whether there are sensitive species and individuals, and predict effects in the environment, including effects on organisms, populations, communities, and ecosystems. Specifically, test methods are needed to identify potential endocrine disruptors, quantify the potency of such action, and demonstrate any adverse outcome(s).
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 the 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/end points are adequate for assessing endocrine system perturbation. If not, then additional effects/end points are needed.
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.
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