Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment

Abstract

Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that report NMDR relationships with endocrine disruptors. Fifty-one experimental studies that investigated various effects associated with endocrine disruption elicited by many substances were selected. Scoring criteria were applied by adaptation of an approach previously used for identification of hormesis-type dose-response relationships. Out of the 148 NMDR relationships analyzed, 82 were categorized with this method as having a "moderate" to "high" level of plausibility for various effects. Numerous modes of action described in the literature can explain such phenomena. NMDR can arise from numerous molecular mechanisms such as opposing effects induced by multiple receptors differing by their affinity, receptor desensitization, negative feedback with increasing dose, or dose-dependent metabolism modulation. A stepwise decision tree was developed as a tool to standardize the analysis of NMDR relationships observed in the literature with the final aim to use these results in a Risk Assessment purpose. This decision tree was finally applied to studies focused on the effects of bisphenol A.

Figure 1

Decision tree describing the methodology for evaluating the plausibility of an NMDR relationship.

Figure 2

Mechanism of the NMDR relationship phenomenon induced by the “plurality of molecular targets”. At low concentrations, EDC binds to the A receptors and induces the observed effect. At high concentrations, the A receptors are still activated and EDC binds to the B receptors, which induces the opposite effect, resulting in an NMDR. Notes: A = Receptor A; B = Receptor B; xe = xenobiotic (e.g., EDC); affinity for A > B.

Figure 3

Mechanism of the NMDR phenomenon induced by “receptor desensitization”. At low concentrations, EDC binds to some receptors and induces the observed effect. At high concentrations, numerous receptors are bound, resulting in a down-regulation phenomenon characterized by receptor desensitization. Consequently, the intensity of the effect is decreased, resulting in an NMDR. Note: (-) = negative effect; R = receptor; xe = xenobiotic (e.g., EDC).

Figure 4

Mechanism of the NMDR relationship phenomenon induced by one of the “metabolic effect” hypotheses. At low concentrations, EDC is catabolized into active metabolites that induce the observed effect. At high concentrations, the metabolic system is saturated, and the parent substance induces an opposite effect, resulting in an NMDR relationship. Note: Mtb = metabolite; xe = xenobiotic (e.g., EDC).

Figure 5

Mechanism of the NMDR relationship phenomenon induced by the “mixed-ligand” hypothesis. At low concentrations, the EDC binds to the hormone receptor and forms mixed-ligand dimers that block endogenous hormone activity. At high concentrations, dimers of EDCs are more likely to form and induce a response. Note: H = endogenous hormone; R = hormone receptor; xe = xenobiotic (e.g., EDC).