A B S T R A C TGiven increasing use of copper-based nanomaterials, particularly in applications with direct release, it is imperative to understand their human and ecological risks. A comprehensive and systematic approach was used to determine toxicity and fate of several Cu nanoparticles (Cu NPs). When used as pesticides in agriculture, Cu NPs effectively control pests. However, even at low (5-20 mg Cu/plant) doses, there are metabolic effects due to the accumulation of Cu and generation of reactive oxygen species (ROS). Embedded in antifouling paints, Cu NPs are released as dissolved Cu + 2 and in nano-and micron-scale particles. Once released, Cu NPs can rapidly (hours to weeks) oxidize, dissolve, and form CuS and other insoluble Cu compounds, depending on water chemistry (e.g. salinity, alkalinity, organic matter content, presence of sulfide and other complexing ions). More than 95% of Cu released into the environment will enter soil and aquatic sediments, where it may accumulate to potentially toxic levels (> 50-500 μg/L). Toxicity of Cu compounds was generally ranked by high throughput assays as: Cu + 2 > nano Cu(0) > nano Cu(OH) 2 > nano CuO > micron-scale Cu compounds. In addition to ROS generation, Cu NPs can damage DNA plasmids and affect embryo hatching enzymes. Toxic effects are observed at much lower concentrations for aquatic organisms, particularly freshwater daphnids and marine amphipods, than for terrestrial organisms. This knowledge will serve to predict environmental risks, assess impacts, and develop approaches to mitigate harm while promoting beneficial uses of Cu NPs.

Decades of study indicate that copper oral exposures are typically not a human health concern. Ingesting high levels of soluble copper salts can cause acute gastrointestinal symptoms and, in uncommon cases, liver toxicity in susceptible individuals with repeated exposure. This focused toxicological review evaluated the current literature since the last comprehensive reviews (2007)(2008)(2009)(2010). Our review identified limitations in the existing United States and international guidance for determining an oral reference dose (RfD) for essential metals like copper. Instead, an alternative method using categorical regression analysis to develop an optimal dose that considers deficiency, toxicity, and integrates information from human and animal studies was reviewed for interpreting an oral RfD for copper. We also considered subchronic

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