Adverse responses of engineered nanomaterials at low and subtoxic exposure levels: current understanding and future perspectives.

The rapid growth of nanotechnology applications and increased incorporation of engineered nanomaterials (ENMs) into consumer products across most industry sectors necessitate a comprehensive understanding of their potential long-term risks to human health. Over the past two decades, significant progress has been made in establishing the fundamentals of nanotoxicology, which has improved our understanding of ENM toxicity particularly regarding their physicochemical properties (e.g. size, shape, surface charge). Furthermore, substantial efforts have been devoted to elucidating the molecular mechanisms underlying nano-bio interactions, which are not only important for understanding health risks but are also critical for advancing therapeutic applications. However, the assessment of ENM adverse responses at low and subtoxic exposure levels, chronically or within specific contexts (e.g. co-exposure to other toxicants) has not received much attention. This is particularly important as real-world exposure to ENMs (e.g. occupational, medicinal, consumer products) typically occurs at low exposure levels, over long periods of time, in the presence of other exposures or preexisting disease. Accumulating research is demonstrating that even in the absence of overt toxicity, exposure to ENMs may contribute to adverse health outcomes, including exacerbation of co-toxicities and co-diseases. This underscores the critical need for evaluating ENM-induced adverse responses beyond conventional toxicological endpoints which are often carried out at unrealistically high doses. In this review article, we discuss the current state of the literature and highlight key emerging findings demonstrating adverse consequences of ENM exposure at low and subtoxic levels. We also discuss current challenges and future directions to address existing knowledge gaps.