Reproduction of the Human Relevant Potency Threshold (HRPT) for Estrogen Receptor Alpha Agonism in an Inference Performance Screen for ICCVAM's Regulatory Scientific Confidence Framework

Jessica Ryman Ph.D., D.A.B.T.^1*Richard Becker²

• ¹American Chemistry Council, Washington D.C., United States
• ²American Chemistry Council Inc, Washington, United States

Scientific confidence frameworks (SCFs) are alternatives to traditional validation for New Approach Methodologies (NAMs). The SCFs adapted by the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) and the American Chemistry Council (ACC) SCF both address Inference Performance, the ability of the NAM to predict or inform the biological effect of interest. Inference Performance is a distinct evaluation procedure in ACC's SCF but is blended into several steps of ICCVAM's SCF. Here we first reproduced the previously derived Human Relevant Potency Threshold (HRPT) for Estrogen Receptor alpha (ERα) agonism of Borgert et al. ( 2018) using guideline and guideline-like studies and found that a HRPT of 1 to 10 -1 positively and consistently predicted clinical endometrial and endocervical effects. We next mapped Inference Performance to ICCVAM's SCF and found that it can be used as an effective initial screen prior to performing more detailed characterizations in ICCVAM's SCF. We first conclude that an HRPT for ERα agonism of 10 -2 to 10 -4 is a health-protective NAM based on an established MOA that could potentially be used in early screening much like the Threshold of Toxicological Concern. We next conclude that Inference Performance is a core requirement for SCFs.