Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity

Abstract

Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop that united scientists from academia, industry and regulatory authorities, are presented. An important step beyond the listing of criteria was the suggestion of a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g., prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).

Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept

“…The battery of the in vitro assays was applied to hiPSCderived neural stem cells (NSCs) differentiated into a mixed culture of neurons and astrocytes, since this model recapitulates, most of the key processes critical and specific for human brain development including neural progenitor cell commitment, proliferation, migration, neuronal and glial differentiation, synaptogenesis, and neuronal network formation and function [33][34][35]. The readiness of these in vitro methods for regulatory purposes has been recently evaluated based on 13 established semi-quantitative criteria [36]. It is postulated that if a chemical at the concentration relevant to environmental exposure affects at least one of these key neurodevelopmental processes in a statistically significant manner it should be defined as potential developmental neurotoxicant [37].…”

Development and analysis of an adverse outcome pathway network for human neurotoxicity

“…Developmental and adult/ageing neurotoxicity are important endpoints in chemical risk assessment and are emerging fields for method development and use in regulatory decision making (Bal-Price et al 2018a;Fritsche et al 2018). Early life exposures to certain chemicals, such as pesticides, may have long-term adverse health consequences for the developing brain.…”

The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity

“…In the EU and USA, identification of chemicals that have the potential to induce DNT is based on higher tiered animal testing. DNT testing is performed only rarely, upon evidence of neurotoxicity from acute or repeated dose toxicity studies in adult rodents, which is not always a reliable indicator for DNT [3,[42][43][44]. Furthermore, in vitro tests for DNT are lacking in the entire OECD Guidelines Programme for the testing of chemicals.…”