AbstractIn regulatory toxicology, the dose-response relationship is a key element towards fulfilling safety assessments and satisfying regulatory authorities. Conventionally, the larger the dose, the greater the response, following the dogma “the dose makes the poison”. Many endocrine disrupting chemicals, including bisphenol-A (BPA), induce non-monotonic dose response (NMDR) relationships, which are unconventional and have tremendous implications in risk assessment. Although several molecular mechanisms have been proposed to explain NMDR relationships, they are largely undemonstrated. Using mouse pancreatic β-cells from wild-type and oestrogen receptor ERβ−/− mice, we found that exposure to increasing doses of BPA affected Ca²⁺ entry in an NMDR manner. Low doses decreased plasma membrane Ca²⁺ currents after downregulation of Cav2.3 ion channel expression, in a process involving ERβ. High doses decreased Ca²⁺ currents through an ERβ-mediated mechanism and simultaneously increased Ca²⁺ currents via oestrogen receptor ERα. The outcome of both molecular mechanisms explains the NMDR relationship between BPA and Ca²⁺ entry in β-cells.