Advancing Systemic Toxicity Risk Assessment: Evaluation of a NAM-based Toolbox Approach.

For many years, a method that allowed systemic toxicity safety assessments to be conducted without generating new animal test data, seemed out of reach. However, several different research groups and regulatory authorities are beginning to use a variety of in silico, in chemico and in vitro techniques to inform safety decisions. To manage this transition to animal-free safety assessments responsibly, it is important to ensure that the level of protection offered by a safety assessment based on new approach methodologies (NAMs), is at least as high as that provided by a safety assessment based on traditional animal studies.

A proof-of-concept multi-tiered Bayesian approach for the integration of physiochemical properties and toxicokinetic time-course data for Daphnia magna.

The use of in silico and in vitro methods, commonly referred to as New Approach Methodologies (NAMs), has been proposed to support environmental (and human) chemical safety decisions, ensuring enhanced environmental protection. Toxicokinetic models developed for environmentally relevant species are fundamental to the deployment of a NAMs-based safety strategy, enabling the conversion between external and internal chemical concentrations, although they require historical toxicokinetic data and robust physical models to be considered a viable solution. Daphnia magna is a key model organism in ecotoxicology albeit with limited and scattered quantitative toxicokinetic data, as for most invertebrates, resulting in a lack of robust toxicokinetic models.

Cell adhesion molecule CD44 is dispensable for reactive astrocyte activation during prion disease.

Prion diseases are fatal, infectious, neurodegenerative disorders resulting from accumulation of misfolded cellular prion protein in the brain. Early pathological changes during CNS prion disease also include reactive astrocyte activation with increased CD44 expression, microgliosis, as well as loss of dendritic spines and synapses. CD44 is a multifunctional cell surface adhesion and signalling molecule which is considered to play roles in astrocyte morphology and the maintenance of dendritic spine integrity and synaptic plasticity.

Next generation risk assessment for occupational chemical safety - A real world example with sodium-2-hydroxyethane sulfonate.

Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted to assessments of consumer use of cosmetics and is not currently implemented in occupational safety assessments, e.g.

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.

PBK modelling of topical application and characterisation of the uncertainty of C estimate: A case study approach.

Combined with in vitro bioactivity data, physiologically based kinetic (PBK) models has increasing applications in next generation risk assessment for animal-free safety decision making. A tiered framework of building PBK models for such application has been developed with increasing complexity and refinements, as model parameters determined in silico, in vitro, and with human pharmacokinetic data become progressively available. PBK modelling has been widely applied for oral/intravenous administration, but less so on topically applied chemicals.

Latent Variables Capture Pathway-Level Points of Departure in High-Throughput Toxicogenomic Data.

Estimation of points of departure (PoDs) from high-throughput transcriptomic data (HTTr) represents a key step in the development of next-generation risk assessment (NGRA). Current approaches mainly rely on single key gene targets, which are constrained by the information currently available in the knowledge base and make interpretation challenging as scientists need to interpret PoDs for thousands of genes or hundreds of pathways. In this work, we aimed to address these issues by developing a computational workflow to investigate the pathway concentration-response relationships in a way that is not fully constrained by known biology and also facilitates interpretation.

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing.

New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals.

Identifying and Characterizing Stress Pathways of Concern for Consumer Safety in Next-Generation Risk Assessment.

Many substances for which consumer safety risk assessments need to be conducted are not associated with specific toxicity modes of action, but rather exhibit nonspecific toxicity leading to cell stress. In this work, a cellular stress panel is described, consisting of 36 biomarkers representing mitochondrial toxicity, cell stress, and cell health, measured predominantly using high content imaging. To evaluate the panel, data were generated for 13 substances at exposures consistent with typical use-case scenarios.

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products.

Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion.