Exposure to endocrine disrupting chemicals and children's health: problems in epidemiological studies

Most endocrine disrupting chemicals are characterized by their properties to induce marked phenotypic changes in offspring such as congenital anomalies and neurodevelopmental dysfunctions. Although an increase in the prevalence of hypospadias or cryptorchidism has been reported in various countries, improvement in diagnostic techniques and more attention to the features of the diseases have also been emphasized. Although there have been a few reports that hypospadias or cryptorchidism had been associated with diethylstilbestrol (DES), pesticides and so on, the associations between these diseases and endocrine disrupting chemicals remain unclear. Recently, the association between maternal metabolic polymorphism or paternal smoking during pregnancy and these diseases has been reported. There are also variable clinical features in children's neurobehavioral development, and thyroid and immune functions in relation to exposure to endocrine disrupting chemicals such as polychlorinated biphenyls (PCBs) and dioxins. Only a few Dutch studies have suggested that perinatal exposure to background level of PCB/dioxin confers immunity to allergy development. Genetic susceptibility to environmental endocrine disrupting chemicals may be related to adverse pregnancy outcomes. It is suggested that well-designed epidemiological studies such as prospective cohort studies should be performed to elucidate this association.     

Occupational exposure associated with reproductive dysfunction

Evidence suggestive of harmful effects of occupational exposure on the reproductive system and related outcomes has gradually accumulated in recent decades, and is further compounded by persistent environmental endocrine disruptive chemicals. These chemicals have been found to interfere with the function of the endocrine system, which is responsible for growth, sexual development and many other essential physiological functions. A number of occupations are being reported to be associated with reproductive dysfunction in males as well as in females. Generally, occupations involving the manufacture/or application of some of the persistent chemicals that are not easily degradable as well as bio-accumulative chemicals, occupations involving intensive exposure to heat and radiation, occupations involving the use of toxic solvents as well as toxic fumes are reported to be associated with reproductive dysfunction. Occupational exposure of males to various persistent chemicals have been reported to have male mediated adverse reproductive outcomes in the form of abortion, reduction in fertility etc. with inconclusive or limited evidence. Nevertheless, there is a need for more well designed studies in order to implicate any individual chemical having such effects as in most occupations workers are exposed to raw, intermediate and finished products and there are also several confounding factors associated with lifestyles responsible for reproductive dysfunction. There is an urgent need to look at indiscriminate use of persistent chemicals especially pesticides and persistent organic pollutants (POP's) as these chemicals enter the food chain also and could be potential for exposure during the critical period of development. It is also necessary to impart information, and to educate about the safe use of these chemicals, as a very sensitive reproduction issue is involved with exposure to these chemicals. Occupational exposures often are higher than environmental exposures, so that epidemiological studies should be conducted on these chemicals, on a priority basis, which are reported to have adverse effects on reproduction in the experimental system.     

环境化学物的生殖毒性研究进展

迄今为止，已有大约5万～6万种化合物进入我们的日常生活，其中许多种化学物的职业性或环境性接触会影响人类的生殖功能，使人类的生育能力特别是精子的质量和数量发生显著改变。本文通过对邻苯二甲酸酯类和双酚A等内分泌干扰物、有机磷和有机氯农药、常用有机溶剂以及常见金属(如铅、镉、汞、锰)的生殖毒性研究的综述，发现它们均在不同程度上造成对实验动物的生殖毒性、妊娠毒性以及对子代的毒性影响，其中部分在人群流行病学研究上得到证实。但是由于人群流行病学研究资料相对较少，且在许多方面尚无肯定的结论，目前环境化学物对人类生殖系统的毒性评价研究仍存在不少亟待解决的问题。建议：①加强现场流行病学调查力度，积累主要环境化学物的生殖毒性的人群资料；②关注环境化学物对非职业接触人群生殖健康状况的影响；③进一步研究、探讨并建立环境化学物生殖毒性评价的模型。     

Cognitive effects of endocrine-disrupting chemicals in animals.

A large number of chemical pollutants including phthalates, alkylphenolic compounds, polychlorinated biphenyls and polychlorinated dibenzodioxins, organochlorine pesticides, bisphenol A, and metals including lead, mercury, and cadmium have the ability to disrupt endocrine function in animals. Some of these same chemicals have been shown to alter cognitive function in animals and humans. Because hormonally mediated events play a central role in central nervous system development and function, a number of researchers have speculated that the changes in cognitive function are mediated by the endocrine-like actions of these chemicals. In this paper we review the evidence that cognitive effects of chemicals classified as environmental endocrine disruptors are mediated by changes in hormonal function. We begin by briefly reviewing the role of gonadal steroids, thyroid hormones, and glucocorticoids in brain development and brain function. We then review the endocrine changes and cognitive effects that have been reported for selected endocrine-disrupting chemicals, discuss the evidence for causal relationships between endocrine disruption and cognitive effects, and suggest directions for future research.     

内分泌干扰物MXC对生殖和胚胎发育的影响

日趋增加的环境和工业化合物,最近已被定义为具有内分泌活性的环境内分泌干扰化合物,对人类健康产生了严重的危害.尤其是类似雌激素作用的环境内分泌干扰物引起动物生殖变异、出生缺陷和威胁人类生殖内分泌健康,在最近几年里已引起人类学家的日趋重视.甲氧滴滴涕是具有雌激素活性的非甾体杀虫剂,对胚胎和生殖发育有潜在危险.该文就甲氧滴滴涕对生殖和胚胎的毒性作用进行综述.     

Phytoestrogen signaling and symbiotic gene activation are disrupted by endocrine-disrupting chemicals

Some organochlorine pesticides and other synthetic chemicals mimic hormones in representatives of each vertebrate class, including mammals, reptiles, amphibians, birds, and fish. These compounds are called endocrine-disrupting chemicals (EDCs). Similarly, hormonelike signaling has also been observed when vertebrates are exposed to plant chemicals called phytoestrogens. Previous research has shown the mechanism of action for EDCs and phytoestrogens is as unintended ligands for the estrogen receptor (ER). Although pesticides have been synthesized to deter insects and weeds, plants produce phytoestrogens to deter herbivores, as attractant cues for insects, and as recruitment signals for symbiotic soil bacteria. Our data present the first evidence that some of the same organochlorine pesticides and EDCs known to disrupt endocrine signaling through ERs in exposed wildlife and humans also disrupt the phytoestrogen signaling that leguminous plants use to recruit Sinorhizobium meliloti soil bacteria for symbiotic nitrogen fixation. Here we report that a variety of EDCs and pesticides commonly found in agricultural soils interfere with the symbiotic signaling necessary for nitrogen fixation, suggesting that the principles underlying endocrine disruption may have more widespread biological and ecological importance than had once been thought.     

Human reproductive system disturbances and pesticide exposure in Brazil

The observation of reproductive disturbances in humans and in the wildlife has been reported in the last decade in different countries. Exposure to different chemicals possibly acting in the endocrine system or endocrine disruptors, including pesticides, has been a hypothesis raised to explain the observed changes. This paper aimed to present results of an epidemiological ecologic study carried out to explore population data on pesticides exposure in selected Brazilian states in the eighties and human reproductive outcomes in the nineties. Pearson correlation coefficients were ascertained between available data pesticides sales in eleven states in Brazil in 1985 and selected further reproductive outcomes or their surrogates. Moderate to high correlations were observed to infertility, testis, breast, prostate and ovarian cancer mortality. Despite the restrains of ecologic studies to establish cause-effect relationships, the observed results are in agreement with evidence supporting a possible association between pesticides exposure and the analyzed reproductive outcomes.     

Neurotoxicity of pesticides

Several pesticides such as organophosphates, carbamates and the organochlorine pesticides directly target nervous tissue as their mechanism of toxicity. In several others, such as the fumigants, the nervous system is affected by toxicological mechanisms that diffusely affect most or all tissues in the body. Both the central and peripheral nervous system are involved in the acute toxidromes of many pesticides resulting in acute short-term effects. There is strong human epidemiological evidence for persistent nervous system damage following acute intoxication with several important pesticide groups such as organophosphates and certain fumigants. However, whether persistent nervous system damage follows chronic low-level exposure to pesticides in adults (particularly organophosphpates), and whether in utero and/or early childhood exposure leads to persistent nervous system damage, is a subject of study at present. Parkinson's Disease, one of the most common chronic central nervous system diseases, has been linked to pesticide exposure in some studies, but other studies have failed to find an association. Several new pesticidal chemicals such as the neo-nicotinoids and fipronil have central nervous system effects, but only case reports are available to date on acute human intoxications with several of these. Little data are yet available on whether long-term effects result from these chemicals. Several ongoing or recently completed studies should add valuable insight into the effects of pesticides on the human nervous system particularly the effect of low-dose, chronic exposure both in adults and children.     

On the rumors about the silent spring. Review of the scientific evidence linking occupational and environmental pesticide exposure to endocrine disruption health effects

Occupational exposure to some pesticides, and particularly DBCP and chlordecone, may adversely affect male fertility. However, apart from the therapeutic use of diethylstilbestrol, the threat to human reproduction posed by "endocrine disrupting" environmental contaminants has not been supported by epidemiological evidence thus far. As it concerns other endocrine effects described in experimental animals, only thyroid inhibition following occupational exposure to amitrole and mancozeb has been confirmed in humans. Cancer of the breast, endometrium, ovary, prostate, testis, and thyroid are hormone-dependent, which fostered research on the potential risk associated with occupational and environmental exposure to the so-called endocrine-disrupting pesticides. The most recent studies have ruled out the hypothesis of DDT derivatives as responsible for excess risks of cancer of the reproductive organs. Still, we cannot exclude a role for high level exposure to o,p'-DDE, particularly in post-menopausal ER+ breast cancer. On the other hand, other organochlorine pesticides and triazine herbicides require further investigation for a possible etiologic role in some hormone-dependent cancers.     

Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis?

The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides. The relation with mercury, cadmium, and lead appears weaker.     

Endocrine effects of prenatal exposure to PCBs, dioxins, and other xenobiotics: implications for policy and future research.

Recent reports have suggested that environmental chemicals may be associated with endocrine alterations in people, wildlife, and experimental animals. Pharmacological investigations as well as natural poisoning episodes have led to the association between exogenous chemicals and alterations in multiple hormonal systems. Persistent environmental contaminants such as dioxins and PCBs have been shown to modulate the activities of several different hormones. The unborn child or the neonate may be at special risk from these chemicals because of rapid growth and development, in addition to enhanced exposure. Because most exposure to these persistent chemicals is via food, changes in dietary habits and/or reduced contamination of the food supply may be required.     

环境内分泌干扰物检测方法研究进展

环境内分泌干扰物对动物和人类的潜在效应日益受到关注，已成为继煤烟、汽车尾气之后迫切需要治理的第三代环境污染物。当前十分需要快速准确检测环境内分泌干扰物的技术方法。本文对环境内分泌干扰物相关检测技术进行了综述。     

Current status and regulatory aspects of pesticides considered to be persistent organic pollutants (POPs) in Taiwan

Organochlorine pesticides (OCPs) are capable of persisting in the environment, transporting between phase media and accumulating to high levels, implying that they could pose a risk of causing adverse effects to human health and the environment. Consequently, most OCPs are designated as persistent organic pollutants (POPs) and even as endocrine disrupting chemicals (EDCs). The objective of this paper was to review the current status of pesticide POPs in Taiwan, including aldrin, chlordane, chlordecone, DDT, dieldrin, endrin, heptachlor, hexachlorobenzene, α/β-hexachlorocyclohexanes, lindane, mirex, pentachloro-benzene, and toxaphene. The information about their environmental properties, banned use, carcinogenic toxicity and environmental levels, can be connected with the regulatory infrastructure, which has been established by the joint-venture of the central competent authorities (i.e., Environmental Protection Administration, Department of Health, Council of Agriculture, and Council of Labor Affairs). The significant progress to be reported is that the residual levels of these pesticide-POPs, ranging from trace amounts to a few ppb, have declined notably in recent years.     

Mysid crustaceans as potential test organisms for the evaluation of environmental endocrine disruption: a review

Anthropogenic chemicals that disrupt the hormonal systems (endocrine disruptors) of wildlife species recently have become a widely investigated and politically charged issue. Invertebrates account for roughly 95% of all animals, yet surprisingly little effort has been made to understand their value in signaling potential environmental endocrine disruption. This omission largely can be attributed to the high diversity of invertebrates and the shortage of fundamental knowledge of their endocrine systems. Insects and crustaceans are exceptions and, as such, appear to be excellent candidates for evaluating the environmental consequences of chemically induced endocrine disruption. Mysid shrimp (Crustacea: Mysidacea) may serve as a viable surrogate for many crustaceans and have been put forward as suitable test organisms for the evaluation of endocrine disruption by several researchers and regulatory bodies (e.g., the U.S. Environmental Protection Agency). Despite the long-standing use of mysids in toxicity testing, little information exists on their endocrinology, and few studies have focused on the potential of these animals for evaluating the effects of hormone-disrupting compounds. Therefore, the question remains as to whether the current standardized mysid endpoints can be used or adapted to detect endocrine disruption, or if new procedures must be developed, specifically directed at evaluating hormone-regulated endpoints in these animals. This review summarizes the ecological importance of mysids in estuarine and marine ecosystems, their use in toxicity testing and environmental monitoring, and their endocrinology and important hormone-regulated processes to highlight their potential use in assessing environmental endocrine disruption.     

Effects of a diphenyl ether-type herbicide,chlornitrofen, and its amino derivative on androgen and estrogen receptor activities

Chlornitrofen (CNP) was widely used in large quantities as a herbicide in rice paddy fields in Japan during 1965-1994. Recently, there has been concern that chemicals in the environment may disrupt the endocrine function of wildlife and humans, but little is known about the effect of CNP on endocrine function. We have developed reporter gene assays for human androgen receptor (hAR) and human estrogen receptor-alpha (hER alpha) using Chinese hamster ovary cells. Using this assay method, we measured CNP and its amino derivative (CNP-amino) for hAR and hER alpha agonist/antagonist activities, comparing them with several well-known AR antagonists or ER agonists. We found that CNP and CNP-amino have potent antiandrogenic activities as well as estrogenic activities. The order of their antiandrogenic activity was CNP > vinclozolin > o,p-DDT = p,p-DDE > CNP-amino, and the order of their estrogenic activity was o,p-DDT > CNP-amino > p,p-DDT > CNP. We investigated the binding ability of CNP and CNP-amino to hAR and hER alpha using a receptor competitive-binding assay. The order of their binding potencies to hAR was CNP > o,p-DDT = p,p-DDE = CNP-amino > vinclozolin, and that of their binding potencies to hER alpha was o,p-DDT > CNP-amino > p,p-DDT = CNP. These results suggest that both CNP and CNP-amino may act as endocrine disruptors via AR and ER alpha in humans and other animals. Our reporter gene assays are highly sensitive and specific and are suitable for screening AR and ER alpha agonist/antagonists among numerous environmental chemicals.     

Sexual dimorphic responses in wildlife exposed to endocrine disrupting chemicals

Understanding the gender similarities and differences in how organisms respond following exposure to environmental chemicals is important if we are to determine the relative risk of these agents to wildlife and human populations. In this paper, we have chosen to focus on the sex determination and differentiation of fishes, amphibians, and reptiles, because of their close association with the environment and the number of environmental factors (e.g., temperature and endocrine disrupting chemicals) that are known to affect these phenomena in these taxa. We have discussed examples of gender differences in response to exposure to endocrine disrupting chemicals and found gender similarities about as often as we found differences. We found that most studies examined either one sex exclusively, or the experimental design did not include examining the effect of sex as a variable. Given the central role of sex steroid hormones in the sex determination and sexual differentiation of fishes, amphibians, and reptiles, we recommend that future research purposefully include sex as a factor, so that risk assessment by government agencies can address the probable gender differences in effects from exposure to chemicals in the environment.     

Some evidence of effects of environmental chemicals on the endocrine system in children

Pollutant chemicals that are widespread in the environment can affect endocrine function in laboratory experiments and in wildlife. Although human beings are commonly exposed to such pollutant chemicals, the exposures are generally low and clear effects on endocrine function from such exposures have been difficult to demonstrate. Human data including both exposure to the chemical agent and the endocrine outcome are reviewed here, including age at weaning, age at puberty, anogenital distance, and sex ratio at birth, and the strength of the evidence are discussed. Although endocrine disruption in humans by pollutant chemicals remains largely undemonstrated, the underlying science is sound and the potential for such effects is real.     

Persistent, bioaccumulative, and toxic compounds in central and eastern Europe--hot spots

The sources and environmental levels of the PBTs in the countries of Central and Eastern Europe are broadly described. Most of the countries in the region produce and/or formulate pesticides. The pesticide registration is a primary requirement for import, production and distribution. The special attention must be given to unwanted pesticides. The problem of unwanted and expired pesticides pose the greatest danger to the natural environment and people which is brought about by the use of chemicals in agriculture in CEE countries. Countries still have not solve the problem of safety storage for PBTs and other chemicals classified as poisons and they have no special sites or facilities for destruction of these chemicals. This region has very specific problems of environmental pollution, which are the results of the recent wars. Destruction of industrial facilities and spilling of chemicals have the worst effect for the environment (Bosnia and Herzegovina, Croatia, Serbia and Montenegro).     

Activation of human polymorphonuclear neutrophils by environmental contaminants

The toxicity of chemicals of environmental concern to the immune system has been primarily evaluated in animals and, to a lesser extent, in humans. In particular, the effects of various pollutants on B-cell, T-cell, natural killer cells, and monocyte-macrophage cells have been the focus of several reports, but polymorphonuclear neutrophils have largely been neglected. Recent data indicate that neutrophils are important targets for such chemicals, suggesting a potential role of these products in the development of the inflammatory process. The bulk of this review will focus on the role of certain environmental pollutants on human neutrophil cell physiology.     

Environmental risk factors and male fertility and reproduction

Several environmental substances and pesticides exert a direct, cytotoxic effect on male germ cells. However, an increasing concern has been raised by compounds that may act through more subtle mechanisms, for example, specific pesticides that are potentially capable of modulating or disrupting the endocrine system. Overall, exposure to pesticides with endocrine-disrupting potential raise a particular concern for male fertility because of the possible occurrence of both effects at low concentrations and additive interactions with other environmental risk factors. Delayed reproductive problems deserve special attention, since experimental data consistently indicate a high vulnerability in the developing male reproductive system. Epidemiologic studies have confirmed an increased risk of conception delay associated with occupational exposure to pesticides. Moreover, an increased risk of spontaneous abortion has been noted among wives of exposed workers.