Framework for Classifying Chemicals for Repeat Dose Toxicity using NAMs

Authors: Doe J, Settivari R, Botham P, Marty S, Gatnik MF, Giri V, Holland D, Kalra P, Kang H, Landsiedel R, Middleton AM, Moors S, Raeburn R, Soufi M, Sica M, Travis K, Wijeyesakere S, William M, Pérez SL
Conference: EPAA NAM Designathon
Keywords: Dose Toxicity, In silico QSAR, in vitro data, In vitro PBPK, nams

Abstract

Principle: Initially all chemicals are of High concern. Reassessment is based on accumulating evidence to potentially move chemicals to Medium or Low concern.

Assessment integrates evidence from:

  • In silico QSAR data.
  • In vitro PBPK modelling data on bioavailability.
  • In vitro data on bioactivity.

Bioavailability: 14-day PBPK simulation for standard or al dosing in humans, incorporating Clint and Fup, with plasma Cmax as a metric to assess concern levels.
Bioactivity: Additional matrix in corporating dose response and assay implication to provide the concern level (H/M/L).
Overall Assessment: Concern levels placed in the EPAA matrix; Evidence appraised.

By John Doe, Raja Settivari, Phil Botham, Sue Marty, Mojca Fuart Gatnik, Varun Giri, Daniela Holland, Priyata Kalra, Heeteak Kang, Robert Landsiedel, Alistair Middleton, Stefan Moors, Rowena Raeburn, Maria Soufi, Monica Sica, Kim Travis, Sanjeeva Wijeyesakere, Mesha William, Sergio León Pérez.