The need for reaching environmental sustainability encourages research on new cellulosebased materials for a broad range of applications across many sectors of industry. Cellulosic nanomaterials obtained from different sources and with different functionalization are being developed with the purpose of its use in many applications, in pure and composite forms, from consumer products to pharmaceutics and healthcare products. Based on previous knowledge about the possible adverse health effects of other nanomaterials with high aspect ratio and biopersistency in body fluids, e.g., carbon nanotubes, it is expected that the nanometric size of nanocellulose will increase its toxicity as compared to that of bulk cellulose. Several toxicological studies have been performed, in vitro or in vivo, with the aim of predicting the health effects caused by exposure to nanocellulose. Ultimately, their goal is to reduce the risk to humans associated with unintentional environmental or occupational exposure, and the design of safe nanocellulose materials to be used, e.g., as carriers for drug delivery or other biomedical applications, as in wound dressing materials. This review intends to identify the toxicological effects that are elicited by nanocelluloses produced through a topdown approach from vegetal biomass, namely, cellulose nanocrystals and nanofibrils, and relate them with the physicochemical characteristics of nanocellulose. For this purpose, the article provides: (i) a brief review of the types and applications of cellulose nanomaterials; (ii) a comprehensive review of the literature reporting their biological impact, alongside to their specific physicochemical characteristics, in order to draw conclusions about their effects on human health.Célia Ventura and Fátima Pinto have contributed equally to this work.

Cellulose nanofibrils (CNF) are manufactured nanofibres that hold impressive expectations in forest, food, pharmaceutical, and biomedical industries. CNF production and applications are leading to an increased human exposure and thereby it is of utmost importance to assess its safety to health. In this study, we screened the cytotoxic, immunotoxic and genotoxic effects of a CNF produced by TEMPO-mediated oxidation of an industrial bleached Eucalyptus globulus kraft pulp on a co-culture of lung epithelial alveolar (A549) cells and monocyte-derived macrophages (THP-1 cells). The results indicated that low CNF concentrations can stimulate A549 cells proliferation, whereas higher concentrations are moderately toxic. Moreover, no proinflammatory cytokine IL-1β was detected in the co-culture medium suggesting no immunotoxicity. Although CNF treatment did not induce sizable levels of DNA damage in A549 cells, it leaded to micronuclei formation at 1.5 and 3 μg/cm. These findings suggest that this type of CNF is genotoxic through aneugenic or clastogenic mechanisms. Noteworthy, cell overgrowth and genotoxicity, which are events relevant for cell malignant transformation, were observed at low CNF concentration levels, which are more realistic and relevant for human exposure, e.g., in occupational settings.

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