Next generation risk assessment of human exposure to anti-androgens using newly defined comparator compound values

Tessa C.A. van Tongeren*, Thomas E. Moxon, Matthew P. Dent, Hequn Li, Paul L. Carmichael, Ivonne M.C.M. Rietjens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Next Generation Risk Assessment (NGRA) can use the so-called Dietary Comparator Ratio (DCR) to evaluate the safety of a defined exposure to a compound of interest. The DCR compares the Exposure Activity Ratio (EAR) for the compound of interest, to the EAR of an established safe level of human exposure to a comparator compound with the same putative mode of action. A DCR ≤ 1 indicates the exposure evaluated is safe. The present study aimed at defining adequate and safe comparator compound exposures for evaluation of anti-androgenic effects, using 3,3-diindolylmethane (DIM), from cruciferous vegetables, and the anti-androgenic drug bicalutamide (BIC). EAR values for these comparator compounds were defined using the AR-CALUX assay. The adequacy of the new comparator EAR values was evaluated using PBK modelling and by comparing the generated DCRs of a series of test compound exposures to actual knowledge on their safety regarding in vivo anti-androgenicity. Results obtained supported the use of AR-CALUX-based comparator EARs for DCR-based NGRA for putative anti-androgenic compounds. This further validates the DCR approach as an animal free in silico/in vitro 3R compliant method in NGRA.

Original languageEnglish
Article number105132
JournalToxicology in Vitro
Volume73
Early online date2 Mar 2021
DOIs
Publication statusPublished - 2021

Keywords

  • 3R compliant method
  • Androgen receptor
  • Dietary comparator
  • In vitro/in silico approaches
  • Risk assessment

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