Human-relevant potency threshold (HRPT) for ERα agonism

Abstract

The European Commission has recently proposed draft criteria for the identification of endocrine disrupting chemicals (EDCs) that pose a significant hazard to humans or the environment. Identifying and characterizing toxic hazards based on the manner by which adverse effects are produced rather than on the nature of those adverse effects departs from traditional practice and requires a proper interpretation of the evidence regarding the chemical’s ability to produce physiological effect(s) via a specific mode of action (MoA). The ability of any chemical to produce a physiological effect depends on its pharmacokinetics and the potency by which it acts via the various MoAs that can lead to the particular effect. A chemical’s potency for a specific MoA—its mechanistic potency—is determined by two properties: (1) its affinity for the functional components that comprise the MoA, i.e., its specific receptors, enzymes, transporters, transcriptional elements, etc., and (2) its ability to alter the functional state of those components (activity). Using the agonist MoA via estrogen receptor alpha, we illustrate an empirical method for determining a human-relevant potency threshold (HRPT), defined as the minimum level of mechanistic potency necessary for a chemical to be able to act via a particular MoA in humans. One important use for an HRPT is to distinguish between chemicals that may be capable of, versus those likely to be incapable of, producing adverse effects in humans via the specified MoA. The method involves comparing chemicals that have different ERα agonist potencies with the ability of those chemicals to produce ERα-mediated agonist responses in human clinical trials. Based on this approach, we propose an HRPT for ERα agonism of 1E-04 relative to the potency of the endogenous estrogenic hormone 17β-estradiol or the pharmaceutical estrogen, 17α-ethinylestradiol. This approach provides a practical way to address Hazard Identification according to the draft criteria for identification of EDCs recently proposed by the European Commission.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2186-z) contains supplementary material, which is available to authorized users.

A critical assessment of the estrogenic potency of benzyl salicylate

“…Lately Borgert et al [ 19 ] proposed a Human Relevant Potency Threshold (HRPT) for chemicals acting on the estrogen receptor. This approach is based on a comparison of in vitro potency with in vivo effects in either uterotrophic assays or from human clinical evidence.…”

Application of grouping and read-across for the evaluation of parabens of different chain lengths with a particular focus on endocrine properties

“…The view that in vitro oestrogen receptor activation potencies of the linear n -alkyl parabens are not sufficiently high to act via an oestrogenic mode-of-action in humans (Watanabe et al 2013 ; Borgert et al 2018 ) is further supported by aggregate exposure assessments in humans: for methyl paraben, ethyl paraben and propyl paraben, aggregate exposure assessments addressing oral, dermal and inhalation exposures to personal care products, medicinal products and food (as three major sources of exposure) revealed estimates of approx. 7.2 and 4.5 mg/kg bw/day for human external and internal exposures, respectively (Brand et al 2017 ).…”

“…These observations further support the decision to focus only on the shorterchained linear n-alkyl parabens in the category approach to interpolate missing data for ethyl paraben. Borgert et al (2018) have suggested a human-relevant potency threshold for oestrogen receptor α agonism of 10 -4 relative to the potency of 17β-estradiol as minimum level of mechanistic potency necessary for a chemical to be able to act via this mode-of-action in humans. Following this threshold, none of the in vitro oestrogen receptor activation potencies of the linear n-alkyl parabens (Watanabe et al 2013) are sufficiently high to act via an oestrogenic modeof-action in humans.…”

Human exposure to synthetic endocrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable endocrine activity: how to evaluate the risk of the S-EDCs?

“…Otherwise, they cannot displace the numerous natural endogenous ligands present. This explains, for example, why S-EDCs with low relative potency have never been shown to exhibit estrogenic effects in humans (Borgert et al 2018 ). Potency and concentrations define the minimum requirement for influencing endocrine activity.…”