Importance of Non Monotonic InvertedU Dose Response Curves

The issue of the sensitivity of fetuses to extremely small differences in circulating gonadal steroid levels is critical with regard to the very high doses traditionally used in toxicological studies. In the following two sections we will discuss data that demonstrate opposing effects of high and low doses of natural hormones, vitamins, and EDCs. These results suggest that it is inappropriate to assume that one can predict effects of low doses of EDCs from results obtained at high doses.

The dose level used in toxicological studies had not previously been considered a critical issue, since the dose-response curve had been assumed to be monotonic (e.g., assuming that response increases or remains constant with increasing dose). In sharp contrast, the endocrine literature provides abundant examples of hormones and hormone-mimicking chemicals with non-monoto-nic dose-response curves (e.g., the slope of the dose response curve changes with increasing dose). In this literature it is well known that dose is critical with regard to the effects that are observed. For example, there is experimental evidence from both in vitro and in vivo studies with natural and manmade estrogens and other EDCs (for example, dioxin, and aldicarb) that non-monotonic dose-response relationships can occur [167,171,197-201].

Normal development occurs within a limited physiological range for molecules that have a signaling function. For hormones and vitamins that operate via binding to receptors (such as thyroid hormone, vitamin A, and folic acid), either a deficiency or an excess (relative to normal physiological levels) can lead to adverse effects on development [202]. For example, retinoid (vitamin A) deficiency during pregnancy causes fetal death, or if fetuses survive, malformations in numerous organs (the vitamin A-deficiency syndrome) [203, 204]. Studies have also identified birth defects due to developmental exposure to high concentrations of a large number of natural and synthetic retinoids in numerous species [205,206]. Thus, the dose-response curve for vitamin A forms a U-shaped function, with increased risk seen in response to vitamin A deficiency (below the normal range) and excess (above the normal range). The adverse effects of a developmental deficiency as well as a developmental excess of thyroid hormone are also well known [207]. The literature on deficiency and excess of hormones and vitamins has not yet been utilized in the design of developmental studies of EDCs that act as hormone-agonists or antagonists.

The issue of non-monotonicity of dose response curves and the use of very high doses to predict effects at low doses has only recently been raised in the context of the effects of EDCs [167,202]. Therefore, the mechanisms that might give rise to inverted-U dose-response functions have not been well studied. There is, however, some understanding of the mechanisms that operate to reduce response to hormones at high doses. Factors such as down-regulation of receptors in the presence of high doses of a hormone may partially account for this phenomenon [208]. For example, different doses of estradiol administered to adult female rats via Silastic implants lead to up-regulation (an increase) of uterine estrogen receptors at a low dose and "down regulation" (a decrease) at a higher dose [209]. Other possibilities may involve the stimulation of response systems that are antagonistic to the initial response as saturation of that response occurs with the saturation of receptors [197]. There is considerable evidence for cross talk between estrogen and receptors for other steroids. These interactions do not normally occur when endogenous estrogens are present at physiological concentrations (due to low binding affinity for other receptors relative to the concentration of circulating estrogen), but are seen with addition of exogenous estrogens when total estrogenic activity in blood exceeds the physiological range [210]. The expectation is that cross talk between estrogen and receptors for other steroid hormones would result in inhibitory effects, rather than the responses typically seen in the binding of the appropriate steroid to its receptor.

The findings discussed above lead us to propose that there has been selection for hormones, vitamins, or other signaling molecules to operate within defined physiological ranges, with each individual exhibiting a unique "set point" within their range [190]. Disruption of normal development can occur either by increasing or decreasing the effective concentration of these signaling compounds possibly through the action of EDCs. As a result of developmental exposure to EDCs, the total hormonal activity (endogenous plus exogenous dose) would thus be different from that which would have occurred naturally. These chemicals may thus have the potential to disrupt the course of development.

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