Potency matters: Thresholds govern endocrine activity

Abstract

Whether thresholds exist for endocrine active substances and for endocrine disrupting effects of exogenous chemicals has been posed as a question for regulatory policy by the European Union. This question arises from a concern that the endocrine system is too complex to allow estimations of safe levels of exposure to any chemical with potential endocrine activity, and a belief that any such chemical can augment, retard, or disrupt the normal background activity of endogenous hormones. However, vital signaling functions of the endocrine system require it to continuously discriminate the biological information conveyed by potent endogenous hormones from a more concentrated background of structurally similar, endogenous molecules with low hormonal potential. This obligatory ability to discriminate important hormonal signals from background noise can be used to define thresholds for induction of hormonal effects, without which normal physiological functions would be impossible. From such thresholds, safe levels of exposure can be estimated. This brief review highlights how the fundamental principles governing hormonal effects - affinity, efficacy, potency, and mass action - dictate the existence of thresholds and why these principles also define the potential that exogenous chemicals might have to interfere with normal endocrine functioning.

Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz

“…Thus, the absence of a non-monotonic dose response has been conclusively shown. This is in line with more general evidence that thresholds do exist for endocrine-related effects (Borgert et al 2013;EFSA Scientific Opinion 2013;Borgert et al 2012;Caldwell et al 2012). The existence of threshold doses was recently also shown for the anti-androgenic drug flutamide in a pre-and postnatal in vivo study in Wistar rats (Fussell et al 2015).…”

Occurrence of chemicals with known or suspected endocrine disrupting activity in drinking water, groundwater and surface water, Austria 2017/2018

“…Since the release of this report, debates have continued between researchers who support its conclusions and those who oppose them. Borgert et al (2013), as typical examples of opposition to the conclusions of the report, argue that potency differences, laws of mass action, and the basic design and physiological functions of the endocrine system require and ensure the presence of thresholds. Supporters of the report such as Gore et al 2015counter that receptor down-regulation, when hormones are present in high concentrations, bind to their receptors, and decrease receptor number, leads to non-monotonic dose response resulting in fewer available receptors and a natural shift in the receptor-mediated response.…”

An exposure:activity profiling method for interpreting high-throughput screening data for estrogenic activity—Proof of concept

“…First and foremost, as discussed by Borgert et al (2013), thresholds govern endocrine activity, and even though activities may be observed from in vitro estrogen assays, and EARs could theoretically be calculated, substances with low potencies are likely not to be biologically active in vivo. Thus, in addition to developing an REEAQ cutoff value for deprioritization, consideration should also be given to developing activity cut off values for each hormonal system.…”

“…This proposed exposure:activity profiling approach reflects standardization tools used historically in toxicology, such as dioxin toxicity equivalence factors and environmental estrogen equivalents (Giesy et al, 2002;Van den Berg et al, 1998, but goes beyond toxicity equivalence by incorporating exposure information rather than relying solely on a relative measure of potency or toxicity. Accordingly, the priority status or score of a chemical would reflect both exposure and potency (Borgert et al, 2012(Borgert et al, , 2013. This score would be presented relative to that of a chosen reference chemical to provide appropriate context.…”