Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

Abstract

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of "the dose makes the poison," because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.

Conceptualizing ecosystem tipping points within a physiological framework

“…Similarly, nutrients such as nitrogen are required for growth, but in high concentrations can lead to nutrient toxicity, such that performance of primary producers generally peaks at intermediate nutrient concentrations (Pilon‐Smits, Quinn, Tapken, Malagoli, & Schiavon, 2009; Figure 1b). Even some toxins can have beneficial effects at very low doses and others exhibit complex nonlinear effects based on concentration and an organism's ability to counteract the negative impacts (Calabrese & Baldwin, 2003; Vandenberg et al., 2012; Figure 1d).…”

Chlorination by-products of bisphenol A enhanced retinoid X receptor disrupting effects

“…Environmentally relevant doses of BPA (at or below 5-50 g/kg) was reported to have estrogenic effects [13,16]. In addition to this, numerous studies suggested that BPA could bind to several kinds of receptors including androgen receptors, thyroid receptors, orphan estrogen-related receptor gamma (ERR␥) [17] and RXRs [12,18].…”

Combined effects of estrogenic chemicals with the same mode of action using an estrogen receptor binding bioassay

“…after the long-term exposure to environmental observed concentrations (ng/L) aggravate these worries (Hotchkiss et al, 2008;Vandenberg et al, 2012;Zha et al, 2007). Particularly, steroid estrogens (both natural and synthetic) and phenolic xenoestrogens receive more attention because of their non-ignorable estrogenicities and widespread applications (Peng et al, 2006).…”