Are Non-animal Systemic Safety Assessments Protective? A Toolbox and Workflow

Abstract

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 scenarios from 10 chemicals, some of which would be considered high risk from a consumer goods perspective (e.g., drugs that are systemically bioactive) and some low risk (e.g., existing food or cosmetic ingredients). Using novel protectiveness and utility metrics, it was shown that up to 69% (9/13) of the low risk scenarios could be identified as such using the toolbox, whilst being protective against all (5/5) the high-risk ones. The results demonstrated how robust safety decisions could be made without using animal data. This work will enable a full evaluation to assess how protective and useful the toolbox and workflow are across a broader range of chemical exposure scenarios.

The 19th FRAME Annual Lecture, November 2022: Safer Chemicals and Sustainable Innovation Will Be Achieved by Regulatory Use of Modern Safety Science, Not by More Animal Testing

“…Collaborative work by Unilever, Charles River and Cyprotex, to evaluate the protective ability of our NAMs toolbox for systemic safety assessments, shows how outputs from exposure and kinetic modelling, as well as the ‘cell stress panel’, high-throughput transcriptomics and in vitro pharmacological profiling data used to estimate the Point of Departure, can be combined to estimate the BER (Figure 4). 24 The authors report promising data for 24 different exposure scenarios covering 10 chemicals as a proof-of-concept study, enabling a prototype decision model to be established which will be used in a much larger evaluation of the toolbox. Since we are not assessing how predictive the non-animal tools are for animal data, the approach is to benchmark against historical safety decisions and see whether a BER threshold can be established above which a chemical exposure would be deemed low risk (comparable to the margin of exposure approach used for traditional risk assessment purposes).

Figure 4.Unilever non-animal systemic safety assessment toolbox and workflow.

…”

“…Since we are not assessing how predictive the non-animal tools are for animal data, the approach is to benchmark against historical safety decisions and see whether a BER threshold can be established above which a chemical exposure would be deemed low risk (comparable to the margin of exposure approach used for traditional risk assessment purposes).

Figure 4.Unilever non-animal systemic safety assessment toolbox and workflow. Workflow for determining the Bioactivity–Exposure Ratio (BER) by combining outputs from the estimation of: i) exposure by using Physiologically Based Kinetic (PBK) models; and ii) the Point of Departure (POD) based on cell stress panel (CSP), high-throughput transcriptomics (HTTr) and in vitro pharmacological profiling (IPP) assays; Middleton et al 24

…”

“…Unilever non-animal systemic safety assessment toolbox and workflow. Workflow for determining the Bioactivity–Exposure Ratio (BER) by combining outputs from the estimation of: i) exposure by using Physiologically Based Kinetic (PBK) models; and ii) the Point of Departure (POD) based on cell stress panel (CSP), high-throughput transcriptomics (HTTr) and in vitro pharmacological profiling (IPP) assays; Middleton et al 24 …”

“…28 At the same time as the ECI was launched in August 2021, Unilever's safety scientists decided it was time to speak out about the challenges of upholding the EU legislative principle of 'animal testing as a last resort', and the widening gap between modern non-animal safety science and the growing requirements for animal testing in the EU chemicals regulations. 29 We advocated for: a) re-thinking the regulatory approach (to be more science-based); b) overcoming the policy and legal challenges blocking the paradigm shift needed; and c) implementing new safety science to improve the protection 24 of people and our environment (whilst dispelling the myth that animal testing is needed to protect workers).…”

New Worm on the Block: Planarians in (Neuro)Toxicology

“…Together with ethical concerns, these economic and scientific reasons have convinced the various stakeholders—government, industry, academia, non‐profit, and the public—to replace animal tests in toxicology and pharmacology with quicker, cheaper, and more predictive non‐animal test methods. Integrated strategies are being developed to effectively use the information gained from these new methodologies to be predictive of human health (Middleton et al., 2022; Rovida et al., 2015). For certain toxicities, a combination of in vitro and in silico test methods may be able to completely replace animal tests and have already been accepted for regulatory purposes, e.g., skin sensitization (OECD, 2021; Rovida et al., 2015).…”