It has been approximately 15 years since the first World Wildlife Federation (WWF) Wingspread Conference focused on endocrine-disrupting chemicals (EDCs), and 10 years since the U.S. Environmental Protection Agency (USEPA) was given a mandate under the Food Quality Protection and Safe Drinking Water Acts to develop test protocols to screen for endocrine effects of chemicals. This review article will briefly highlight some of the major scientific events that have taken place since the inception of the EDCs issue. In this review, we will (1) discuss EDCs effects on invertebrates, fish, wildlife, and human health, (2) highlight some representative studies on (anti)androgens, estrogens and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)–like chemicals, and (3) evaluate regulatory proposals being considered for screening and testing these chemicals.
An initial impetus for studies of EDCs arose from the Wingspread work session in 1991 on “Chemically Induced Alterations in Sexual Development: The Wildlife /Human Connection” (Colborn and Clement, 1992
). A consensus from that meeting, reached by a panel of expert scientists was that “Many compounds introduced into the environment by human activity are capable of disrupting the endocrine system of animals, including fish, wildlife, and humans. Endocrine disruption can be profound because of the crucial role hormones play in controlling development” (Colborn and Clement, 1992
). These scientists also “estimated with confidence” that developmental impairments in humans have resulted from exposure to EDCs that are present in the environment as a result of human activities. Within a 5-year span several international organizations held meetings to discuss the EDC issue and research objectives. For example, starting in 1996 the USEPA held a series of workshops highlighting the new EDC issue and research needs in collaboration with the WWF and Chemical Manufacturers Association (Ankley and Giesy, 1998
; Ankley et al., 1998
; DeVito et al., 1999
; Gray et al., 1997a
) The European Union (Weybridge Report, European Commission,1996), Australia, and several Asian countries including Korea, Japan held similar meetings.
Subsequent studies have strengthened the documentation of effects of EDCs on animals. Although most of the effects in humans are due to occupational exposures or pharmaceutical usage, hundreds if not thousands of publications showing associations between background EDC exposures and adverse effects in humans are now available in the peer-reviewed literature. Many of the associations between EDCs and human health effects are controversial, but others, like the effects of polychlorinated biphenyls (PCBs) on neurological and immune function are quite widely accepted. Furthermore, animal laboratory studies corroborate many of these adverse effects observed in the field and, in some cases, provide mechanisms to explain the effects.
About 10 years ago the discussion of “endocrine disrupters” broadened from a focus on environmental estrogens to include additional mechanisms of endocrine toxicity; mechanisms that in many cases may be of equal or greater concern than estrogens. Numerous “new” areas of interest and concern have arisen since the original 1991 Wingspread conference and regulatory mandates. These areas include processes potentially disrupted by new classes of anthropogenic chemicals that act as antiandrogens, androgens, inhibitors of steroid hormone synthesis, antithyroid substances, and retinoid agonists. Within the last few years, scientists also have expressed concern about the potential role of EDCs in increasing trends in obesity and type II diabetes in the United States and other populations. In addition, although research has documented the complexity of the multiple mechanisms by which a single chemical can alter the endocrine milieu, recent evidence demonstrates the need to investigate complex endocrine alterations induced by mixtures of chemicals. We are now not only concerned about pesticides and other toxic substances in the environment, but the issue has broadened considerably due to the growing awareness that the list of EDCs present in the environment from human activities includes potent human and veterinary pharmaceutical products, personal care products, nutraceuticals and phytosterols. Among the drugs found as pharmaceuticals in the environment (PiEs) are potent, long lasting estrogens, antibiotics, β-blockers, antiepileptics, androgenic steroids, and lipid regulating agents. Some PiEs have been linked to dramatic effects in wildlife, including death in bald eagles (http://www.fws.gov/southeast/news/2002/12-03SecPoisoningFactSheet.pdf
), threatened extinction of species of vultures in Asia (Shultz et al., 2004
) and sex reversal and infertility in several species of fish (WHO, 2002
The 1996 legislation mandated that the USEPA both establish validated screening and testing procedures for estrogens and other substances as deemed appropriate and consider combinations of chemicals rather than evaluate the potential risk on a chemical by chemical basis. Both of these mandates encompass new areas of investigation in the EDC field. Furthermore, reports of nonmonotonic (e.g., U-shaped) dose–response relationships, ultra-low dose effects and nonthreshold effects for EDCs continue to challenge some of the basic assumptions of toxicology and risk assessment. Although the focus of this debate has centered on the low dose effects of Bisphenol A, U-shaped dose–response curves are well known from many in vitro and a few in vivo studies. It appears that the basic tenet of toxicology from Ames and Gold (2000) that “dose alone determines the poison” is too limited for some EDCs because the timing of exposure can dictate not only the effect, but also whether the effects are adverse versus beneficial, or permanent versus transient. In vivo, however, the U-shaped effects of EDCs are generally limited to one or two effects whereas all other effects display “normal” nonmonotonic dose responses. Furthermore, EDCs that induce cellular and molecular alterations of endocrine function at low dosage levels produce a cascade of effects increasing in severity resulting in adverse alterations at higher doses. The effects in the high dose groups may be different from those seen at low doses and the low dose effects are often causally linked to the high dose adverse effects of the chemical. This is true for androgens, natural estrogens, xenoestrogens, and antiandrogens.
The present review will focus on some of the new scientific issues in regard to EDCs that have surfaced since the initial Wingspread conference. The review will focus on effects of endocrine-active chemicals on the androgen, estrogen, and AhR-mediated signaling pathways. Reviews of other hormonal pathways potentially affected by EDCs, such as the thyroid system, can be found elsewhere (Guillette, 2006
; Howdeshell, 2002
; Tabb and Blumberg, 2006
; Zoeller and Crofton, 2005