Although scientists have postulated a wide range of adverse human health effects of exposure to endocrine-disrupting chemicals (EDCs), the nexus of the debate is the concern that prenatal and childhood exposure to EDCs may be responsible for a variety of abnormalities in human sexuality, gender development and behaviors, reproductive capabilities, and sex ratios. Scientists today are asking hard questions about potential human effects: Do EDC exposures impair fertility in men or women? Can they cause sexual organ malformations, stunted reproductive development, or testicular or breast cancer? Do fetal exposures to EDCs alter sex phenotypes? Do they change later gender-related neurobiological characteristics and behaviors such as play activity and spatial ability? Could such exposures even be involved in the etiology of children born with ambiguous gender?
Are EDCs Blurring Issues of Gender?, Environnement Health Perspectives, NCBI PubMed PMC1281309, 2005 Oct.
EDCs include a spectrum of substances that can be loosely classified according to their known or suspected activity in relation to sex hormone receptors and pathways. The most-studied and best known are the environmental estrogens, which mimic estradiol and bind to estrogen receptors (ERs). ER agonists include the pesticide methoxychlor, certain polychlorinated biphenyls (PCBs), bisphenol A (BPA; a high production volume chemical used to make polycarbonate plastic), pharmaceutical estrogens such as diethylstilbestrol (DES) and ethinyl estradiol, and phytoestrogens, which occur naturally in many plants, most notably in soybeans in the form of genistein and related substances. There are a few known ER antagonists, or antiestrogens. Antiandrogens, or androgen receptor (AR) antagonists, include the fungicide vinclozolin, the DDT metabolite p,p′-DDE, certain phthalates (a group of chemicals used to soften polyvinyl chloride plastics), and certain other PCBs. And there are other types of EDCs that affect particular endocrine targets. The various EDCs differ greatly in their potencies relative to natural hormones, and in their affinity for target receptors. Some have been shown to act via non–receptor-mediated mechanisms, for example by interfering with hormone synthesis.
In many well-documented cases of high-level fetal exposures to known EDCs such as DES, certain PCBs, and DDT, the answer to the question of whether exposure is associated with gender-related effects is clearly yes. But high-level exposures such as these are relatively rare and isolated. The debate today centers on low-dose exposures—generally defined as doses that approximate environmentally relevant levels—and the idea that low-dose intrauterine exposure to some EDCs during certain critical windows of development can have profound, permanent impacts on subsequent fetal development and adult outcomes.
Critics of this idea maintain that thus far there is no credible evidence to suggest that low-dose exposures cause any adverse human health effects. But if low-dose exposures were confirmed to be the threat that proponents of the concept insist they are, public health would clearly be at risk, regulatory agencies’ risk assessment approach would need to be revised, and certain common chemicals—including some that are massively produced and economically important—would likely disappear from the marketplace.
In a June 2000 EHP review article on human health problems associated with EDCs, Stephen Safe, director of the Center for Environmental and Genetic Medicine at Texas A&M University, concluded that
“the role of endocrine disruptors in human disease has not been fully resolved; however, at present the evidence is not compelling.”
Frederick vom Saal, a developmental biologist at the University of Missouri–Columbia, disagrees, particularly in light of the research that’s been presented in the years since that review. He says
“The jury is not out on human effects. In terms of the amount of information we have in animals and the amount of information we have in humans, clearly there is a huge difference, but that’s a lot different than saying the jury is out on whether EDCs influence humans.”
One thing both scientists might agree on, though, is that right now there are still more questions than answers.
Evidence of Effects: the DES situation
The Global Assessment further states that the only evidence showing that humans are susceptible to EDCs is currently provided by studies of high exposure levels. There is, in fact, clear evidence that intrauterine EDC exposures can alter human reproductive tract development and physiology. The most thoroughly characterized example is DES, the synthetic estrogen prescribed to millions of pregnant women in the United States and elsewhere from the 1940s to the 1970s to prevent miscarriage. The drug is known to have caused a rare form of vaginal cancer in thousands of daughters of women who took DES, as well as a variety of adverse reproductive tract effects in both the daughters and sons of those women.
The DES situation could be seen as a worst-case scenario for prenatal EDC exposure—the deliberate delivery of a potent estrogenic chemical in high doses. Viewed another way, it has provided researchers a rare opportunity to study the effects of prenatal EDC exposure in a relatively controlled fashion, with a well-defined population and well-characterized exposure to a single potent agent.
Over the course of her research, Newbold has developed a mouse model of DES exposure that has proven extremely useful in studying the effects of DES and other environmental estrogens, particularly those outcomes that may be manifested only later in life. She says
“With the experimental model, there are a lot of questions we can ask with DES that will tell us about the weaker environmental estrogens. We can change the timing of exposure and the amount of exposure, and we can look at different target tissues.”
The animal model has replicated numerous abnormalities reported in DES-exposed humans, and has also predicted some human outcomes.
“We have published documentation [see, for example, the October 1985 issue of Cancer Research and volume 5, issue 6 (1985) of Teratogenesis, Carcinogenesis, and Mutagenesis] that a number of the reproductive anomalies seen in DES-exposed mice, such as retained testes and abnormalities in the oviduct in females, were also later reported in DES-exposed humans,”
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