Are non-animal systemic safety assessments protective? A toolbox and workflow

An important question in toxicological risk assessment is whether non-animal New Approach Methodologies (NAMs) can be used to make safety decisions that are protective of human health, without being overly conservative. In this work, we propose a core NAM toolbox and workflow for conducting systemic safety assessments for adult consumers. We also present an approach for evaluating how protective and useful the toolbox and workflow are by benchmarking against historical safety decisions.  The toolbox includes physiologically-based kinetic (PBK) models to estimate systemic Cmax levels in humans, and three bioactivity platforms, comprising high-throughput transcriptomics, a cell stress panel and in vitro pharmacological profiling, from which points of departure are estimated. A Bayesian model was developed to quantify the uncertainty in the Cmax estimates depending on how the PBK models were parameterised.  The feasibility of the evaluation approach was tested using 24 exposure s..., , , **Readme for the supplementary data/results package for Middleton et el. 2022.**

**Contents**

The NGRA toolbox described in the manuscript is composed of four new approach methodology (NAM) platforms. These are:

1.      PBK modelling for estimation of internal exposures

2.      In vitro pharmacological profiling (IPP) to assess activity of chemicals against receptors of pharmacological interest

3.      A cellular stress panel (CSP) to assess potential of chemical to induce chemical stress

4.      A high-throughput transcriptomics (HTTr) platform to assess biological activity towards other endpoints

Data and analysis for these platforms are shared within this package. The contents of the package are as follows:

**CSP/Data** – all data generated within the CSP platform. The data are stored using either as comma separated value (.csv) or as Microsoft excel spreadsheet (.xslx) file types. File <*assay_name*>httr-support-file*.<csv or xlsx> contains the raw cell stress panel data for...,