Abstract
Faster, cheaper, sensitive, and mechanisms-based animal alternatives are needed to address the safety assessment needs of the growing number of nanomaterials (NM) and their sophisticated property variants. Specifically, strategies that help identify and prioritize alternative schemes involving individual test models, toxicity endpoints, and assays for the assessment of adverse outcomes, as well as strategies that enable validation and refinement of these schemes for the regulatory acceptance are needed. In this review, two strategies 1) the current nanotoxicology literature review and 2) the adverse outcome pathways (AOPs) framework, a systematic process that allows the assembly of available mechanistic information concerning a toxicological response in a simple modular format, are presented. The review highlights 1) the most frequently assessed and reported ad hoc in vivo and in vitro toxicity measurements in the literature, 2) various AOPs of relevance to inhalation toxicity of NM that are presently under development, and 3) their applicability in identifying key events of toxicity for targeted in vitro assay development. Finally, using an existing AOP for lung fibrosis, the specific combinations of cell types, exposure and test systems, and assays that are experimentally supported and thus, can be used for assessing NM-induced lung fibrosis, are proposed.
Highlights
Faster, cheaper, sensitive, and mechanisms-based animal alternatives are the 2-year rat carcinogenicity study can needed to address the safety assessment needs of the growing number of nanomaterials (NM) and their sophisticated property variants
A considered “refinement” approach to in vivo experimentation, since tissue slices can be harvested from any tissue and species including humans, the ability to translate data to understanding human responses will become more evident. In another recent study by Rahman et al.,[95] a lung organ mimic involving precision cut lung slice (PCLS) culture model, which allows the intricate cellular signaling occurring after NM exposure and measurement of various key events (KEs) along the path of lung fibrosis including the histopathological manifestation of the fibrotic disease, was established
This review presents the strategies to address the pressing need in the community to optimize and validate existing or novel animal reduction or replacement alternatives in NM toxicity testing; including cell based in vitro, organoid ex vivo
Summary
Most in vitro tests are conducted with an objective of understanding the underlying mechanisms of a substances’ toxicity. (the specific pro-inflammatory markers) both in vivo and in vitro studies.[20,21] Using some level of expert judgement, these reports were reorganized and renamed as “altered expression of pro-inflammatory mediators”, and recruitment of leukocytes’, the two generic characteristics of the inflammation process.[22] This allowed categorical grouping of the reported results in a biologically logical manner and allowed identification of each endpoint, assay and specific biomarkers used to assess and report the various inflammation related responses Conducting such an analysis for all the publications in the large database of 11 000 publications is beyond the scope of this review. It seemed that most in vivo studies involved organ or system toxicity endpoints (e.g., behavior, development, neuronal damage, toxicity of liver, heart, lung, kidney, and spleen) of relevance to regulatory purposes, whereas, in vitro studies mostly targeted a particular biological process such as inflammation, genotoxicity, or cytotoxicity potentially reflective of organ toxicity in vivo. We describe how mechanistic information organized in line with the AOP framework may be used to identify and define in vitro assays that are potentially useful for generating toxicological data required for NM safety assessment and regulatory decisions
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