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Ligands exhibit potency for binding to and interacting with receptors. Potency is the product of affinity and efficacy. Potency and physiological concentration determine the ability of a ligand to produce physiological effects. The kinetic behavior of ligand-receptor interactions conforms to the laws of mass action. The laws of mass action define the relationship between the affinity of a ligand and the fraction of cognate receptors that it occupies at any physiological concentration. We previously identified the minimum ligand potency required to produce clinically observable estrogenic agonist effects via the human estrogen receptor-alpha (ER\u03b1). By examining data on botanical estrogens and dietary supplements, we demonstrated that ER\u03b1 ligands with potency lower than one one-thousandth that of the primary endogenous hormone 17\u03b2-estradiol (E2) do not produce clinically observable estrogenic effects. This allowed us to propose a Human-Relevant Potency Threshold (HRPT) for ER\u03b1 ligands of 1\u2009\u00d7\u200910<jats:sup>\u20134<\/jats:sup> relative to E2. Here, we test the hypothesis that the HRPT for ER\u03b1 arises from the receptor occupancy by the normal metabolic milieu of endogenous ER\u03b1 ligands. The metabolic milieu comprises precursors to hormones, metabolites of hormones, and other normal products of metabolism. We have calculated fractional receptor occupancies for ER\u03b1 ligands with potencies below and above the previously established HRPT when normal circulating levels of some endogenous ER\u03b1 ligands and E2 were also present. Fractional receptor occupancy calculations showed that individual ER\u03b1 ligands with potencies more than tenfold higher than the HRPT can compete for occupancy at ER\u03b1 against individual components of the endogenous metabolic milieu and against mixtures of those components at concentrations found naturally in human blood. Ligands with potencies less than tenfold higher than the HRPT were unable to compete successfully for ER\u03b1. These results show that the HRPT for ER\u03b1 agonism (10<jats:sup>\u20134<\/jats:sup> relative to E2) proposed previously is quite conservative and should be considered strong evidence against the potential for disruption of the estrogenic pathway. For chemicals with potency 10<jats:sup>\u20133<\/jats:sup> of E2, the potential for estrogenic endocrine disruption must be considered equivocal and subject to the presence of corroborative evidence. Most importantly, this work demonstrates that the endogenous metabolic milieu is responsible for the observed ER\u03b1 agonist HRPT, that this HRPT applies also to ER\u03b1 antagonists, and it provides a compelling mechanistic explanation for the HRPT that is grounded in basic principles of molecular kinetics using well characterized properties and concentrations of endogenous components of normal metabolism.<\/jats:p>","DOI":"10.1007\/s00204-024-03723-4","type":"journal-article","created":{"date-parts":[[2024,5,5]],"date-time":"2024-05-05T10:01:36Z","timestamp":1714903296000},"page":"1795-1807","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The physiological and biochemical basis of potency thresholds modeled using human estrogen receptor alpha: implications for identifying endocrine disruptors"],"prefix":"10.1007","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2981-9012","authenticated-orcid":false,"given":"Christopher J.","family":"Borgert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyle D.","family":"Burgoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,5]]},"reference":[{"key":"3723_CR1","unstructured":"Ada\u2019s Medical Knowledge Team. ada.com. https:\/\/ada.com\/hormones\/estradiol\/. 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