Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society

Abstract

An endocrine-disrupting chemical (EDC) is an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action. The potential for deleterious effects of EDC must be considered relative to the regulation of hormone synthesis, secretion, and actions and the variability in regulation of these events across the life cycle. The developmental age at which EDC exposures occur is a critical consideration in understanding their effects. Because endocrine systems exhibit tissue-, cell-, and receptor-specific actions during the life cycle, EDC can produce complex, mosaic effects. This complexity causes difficulty when a static approach to toxicity through endocrine mechanisms driven by rigid guidelines is used to identify EDC and manage risk to human and wildlife populations. We propose that principles taken from fundamental endocrinology be employed to identify EDC and manage their risk to exposed populations. We emphasize the importance of developmental stage and, in particular, the realization that exposure to a presumptive "safe" dose of chemical may impact a life stage when there is normally no endogenous hormone exposure, thereby underscoring the potential for very low-dose EDC exposures to have potent and irreversible effects. Finally, with regard to the current program designed to detect putative EDC, namely, the Endocrine Disruptor Screening Program, we offer recommendations for strengthening this program through the incorporation of basic endocrine principles to promote further understanding of complex EDC effects, especially due to developmental exposures.

Fig. 1.

A, Typical sigmoidal dose-response curve for hormones. As the dose of hormone increases, the response increases in a logarithmic manner until the point of saturation of the response. Different hormone-receptor interactions will have differences in the dose of hormone or the dynamic range of the log-linear portion of the curve or the maximal response. Some receptors are down-regulated by the hormone, so the dose-response curve will decline at the high dose (this will be a function of both dose and time). Note that a small change in hormone concentration at the low end of the curve (box) will have much greater effects on the response than a similar change in hormone concentration at the high end of the curve (box). It is also important to note that saturation of the response can occur at levels of receptor occupancy in the range of 10%; thus, there are “spare receptors” (e.g. Ref. 73). B, The dose response to the hormone depends on receptor concentration. These data show clearly that as the receptor concentration increases, the hormone becomes “more potent”; that is, it takes significantly less hormone to produce the same response. In fact, at low hormone receptor levels, the maximum response does not achieve the “EC₅₀” response of the high receptor level (from Ref. 10). C, Nonmonotonic dose response curve. The inverted U dose-response curve may have many different mechanisms underlying it. For example, receptor down-regulation at high concentrations of hormone is an important mechanism. However, the addition of separate monotonic dose responses also provides an important mechanism. This issue is reviewed extensively by Vandenberg et al. (13).