When dose meets time: Understanding the toxicity of engineered nanomaterials and its implications for human risk...

The rapid development of engineered nanomaterials (ENMs) for use in food, consumer products, medicine, and the environment has raised considerable concern about their potential health effects. Conventional toxicological frameworks may inadequately capture the dynamic dose- and time-dependent behaviour of engineered nanomaterials. Increasing evidence is showing that both the magnitude of the dose and duration of the exposure are key determinants of toxicity; however, these elements are not always taken into consideration while assessing safety. This review paper will present the current state of knowledge regarding the dose and time dependent toxicity of the four major classes of ENMs - metals, metal oxides, polymers, and carbon-based materials - with a particular focus on how the physicochemical properties of each type of ENM (size, surface charge, coating, and agglomeration state) can modulate biological responses. Mechanistic explanations will be provided for classes of chemicals related to oxidative stress, inflammation, mitochondrial dysfunction, and genotoxicity, in terms of cumulative and delayed actions. Finally, the implications for human risk assessment will be discussed, with an emphasis on the need for standardized dosing metrics, chronic exposure studies and toxicokinetic integration to provide a basis for evidence-based regulatory decisions and the protection of public health.