Employing Dietary Comparators to Perform Risk Assessments for Anti-Androgens Without Using Animal Data

Abstract

This study investigated the use of androgen receptor (AR) reporter gene assay data in a non-animal exposure-led risk assessment in which in vitro anti-androgenic activity and exposure data were put into context using a naturally occurring comparator substance with a history of dietary consumption. First, several dietary components were screened to identify which selectively interfered with AR signaling in vitro, using the AR CALUX® test. The IC50 values from these dose-response data together with measured or predicted human exposure levels were used to calculate exposure: activity ratios (EARs) for the dietary components and a number of other well-known anti-androgenic substances. Both diindolylmethane (DIM) and resveratrol are specifically acting dietary anti-androgens. The EARs for several anti-androgens were therefore expressed relative to the EAR of DIM, and how this ‘dietary comparator ratio’ (DCR) approach may be used to make safety decisions was assessed using an exposure-led case study for an anti-androgenic botanical ingredient. This highlights a pragmatic approach which allows novel chemical exposures to be put into context against dietary exposures to natural anti-androgenic substances. The DCR approach may have utility for other modes of action where appropriate comparators can be identified.

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

“…Using historical benchmark chemicals with well-characterized human exposures and known human outcomes could help define a protective exposure level and an evidence-based MoS values. This benchmarking approach has not yet been developed for overall systemic toxicity, but examples applied to drug-induced liver injury ( Albrecht et al , 2019 ; Williams et al , 2020 ), reproductive ( Becker et al , 2015 ; Dent et al , 2018b ), and cardiac toxicity ( Lazic et al , 2018 ) have been previously published.…”

“…The momentum created by these efforts has led to a number of studies that employed 1 or more NAMs in risk assessment. The studies that focused on specific pathways, such as DNA damage for quercetin ( Adeleye et al , 2015 ), estrogenic ( Becker et al , 2015 ), and antiandrogenic activity ( Dent et al , 2018b ) using the concept of Dietary Comparator Ratio have provided a valuable insight into how adverse outcome pathways (AOPs) can be put into the context of safety assessment ( Carusi et al , 2018 ; Villeneuve et al , 2014 ). However, it may not always be necessary or possible to identify a specific pathway or AOP for a chemical to carry out a risk assessment.…”

The use of adverse outcome pathways in the safety evaluation of food additives

“…Thus far, this concept has not been used for AOPs specifically, although it could play a role in supporting the choice and relevance of the in vitro bioassay used to identify critical molecular endpoints. Another approach that is gaining popularity is the comparison of high-throughput bioactivity data, which could be representative for a specific MIE, with PBK-predicted human plasma concentrations (Dent et al 2019;Wetmore et al 2015). This type of approach is particularly promising as it is entirely focused on the assessment of human safety rather than trying to correlate and extrapolate animal toxicity data to the human situation.…”

Spectrochemical determination of effects on rat liver of binary exposure to benzo[a]pyrene and 2,2′,4,4′‐tetrabromodiphenyl ether

“…Such tests employ endpoints including micronucleus formation (Barber et al, 2006) and/or DNA single‐strand breaks (Kalantzi et al, 2003). Although these in vitro/in vivo assays have been the mainstay of risk assessment, there has been a strong emphasis in recent years towards finding robust alternative approaches (Dent et al, 2019). There is a need to ascertain the point in their life cycle that target cells are most susceptible to contaminants such as B[ a ]P (Pang et al, 2012) and the complex interactions of contaminant mixture exposures (Llabjani et al, 2010; Llabjani et al, 2011).…”