Abstract:This article presents the outcomes of higher-tier repeated-dose toxicity studies and developmental and reproductive toxicity (DART) studies using Wistar rats requested for methyl paraben and propyl paraben under the European Union chemicals legislation. All studies revealed no-observed adverse effects (NOAELs) at 1000 mg/kg body weight/day. These findings (absence of effects) were then used to interpolate the hazard profile for ethyl paraben, further considering available data for butyl paraben. The underlying… Show more
“…Figure 1 also adds potency estimates for three chemicals that have been incorrectly alleged to be exogenous estrogens. Potency data for benzyl salicylate and BPA (Natsch et al 2021 ) and for parabens (Fayyaz et al 2021 ) reveal that these chemicals lack the potency to disrupt the estrogen pathway as agonists or antagonists. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Also added to the original figure by Borgert et al ( 2018 ) are potency estimates for three chemicals incorrectly alleged to be exogenous estrogens. Potency data for benzyl salicylate and BPA are from Natsch et al ( 2021 ) and data for parabens are from Fayyaz et al ( 2021 ) …”
Section: Resultsmentioning
confidence: 99%
“…Also added to the original figure by Borgert et al (2018) are potency estimates for three chemicals incorrectly alleged to be exogenous estrogens. Potency data for benzyl salicylate and BPA are from Natsch et al (2021) and data for parabens are from Fayyaz et al (2021) concentrations of estradiol peak during the follicular phase of the menstrual cycle in post-pubertal women and reach levels fifty times higher than the "mid-point" condition during pregnancy. In humans, the fetus is exposed to exogenous and endogenous substances via the maternal circulation.…”
The endocrine system functions by interactions between ligands and receptors. 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 (ERα). By examining data on botanical estrogens and dietary supplements, we demonstrated that ERα ligands with potency lower than one one-thousandth that of the primary endogenous hormone 17β-estradiol (E2) do not produce clinically observable estrogenic effects. This allowed us to propose a Human-Relevant Potency Threshold (HRPT) for ERα ligands of 1 × 10–4 relative to E2. Here, we test the hypothesis that the HRPT for ERα arises from the receptor occupancy by the normal metabolic milieu of endogenous ERα ligands. The metabolic milieu comprises precursors to hormones, metabolites of hormones, and other normal products of metabolism. We have calculated fractional receptor occupancies for ERα ligands with potencies below and above the previously established HRPT when normal circulating levels of some endogenous ERα ligands and E2 were also present. Fractional receptor occupancy calculations showed that individual ERα ligands with potencies more than tenfold higher than the HRPT can compete for occupancy at ERα 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 ERα. These results show that the HRPT for ERα agonism (10–4 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 10–3 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 ERα agonist HRPT, that this HRPT applies also to ERα 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.
“…Figure 1 also adds potency estimates for three chemicals that have been incorrectly alleged to be exogenous estrogens. Potency data for benzyl salicylate and BPA (Natsch et al 2021 ) and for parabens (Fayyaz et al 2021 ) reveal that these chemicals lack the potency to disrupt the estrogen pathway as agonists or antagonists. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Also added to the original figure by Borgert et al ( 2018 ) are potency estimates for three chemicals incorrectly alleged to be exogenous estrogens. Potency data for benzyl salicylate and BPA are from Natsch et al ( 2021 ) and data for parabens are from Fayyaz et al ( 2021 ) …”
Section: Resultsmentioning
confidence: 99%
“…Also added to the original figure by Borgert et al (2018) are potency estimates for three chemicals incorrectly alleged to be exogenous estrogens. Potency data for benzyl salicylate and BPA are from Natsch et al (2021) and data for parabens are from Fayyaz et al (2021) concentrations of estradiol peak during the follicular phase of the menstrual cycle in post-pubertal women and reach levels fifty times higher than the "mid-point" condition during pregnancy. In humans, the fetus is exposed to exogenous and endogenous substances via the maternal circulation.…”
The endocrine system functions by interactions between ligands and receptors. 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 (ERα). By examining data on botanical estrogens and dietary supplements, we demonstrated that ERα ligands with potency lower than one one-thousandth that of the primary endogenous hormone 17β-estradiol (E2) do not produce clinically observable estrogenic effects. This allowed us to propose a Human-Relevant Potency Threshold (HRPT) for ERα ligands of 1 × 10–4 relative to E2. Here, we test the hypothesis that the HRPT for ERα arises from the receptor occupancy by the normal metabolic milieu of endogenous ERα ligands. The metabolic milieu comprises precursors to hormones, metabolites of hormones, and other normal products of metabolism. We have calculated fractional receptor occupancies for ERα ligands with potencies below and above the previously established HRPT when normal circulating levels of some endogenous ERα ligands and E2 were also present. Fractional receptor occupancy calculations showed that individual ERα ligands with potencies more than tenfold higher than the HRPT can compete for occupancy at ERα 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 ERα. These results show that the HRPT for ERα agonism (10–4 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 10–3 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 ERα agonist HRPT, that this HRPT applies also to ERα 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.
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