Abstract
The integration of rapid assays, large datasets, informatics, and modeling can overcome current barriers in understanding nanomaterial structure–toxicity relationships by providing a weight-of-the-evidence mechanism to generate hazard rankings for nanomaterials. Here, we present the use of a rapid, low-cost assay to perform screening-level toxicity evaluations of nanomaterials in vivo. Calculated EZ Metric scores, a combined measure of morbidity and mortality in developing embryonic zebrafish, were established at realistic exposure levels and used to develop a hazard ranking of diverse nanomaterial toxicity. Hazard ranking and clustering analysis of 68 diverse nanomaterials revealed distinct patterns of toxicity related to both the core composition and outermost surface chemistry of nanomaterials. The resulting clusters guided the development of a surface chemistry-based model of gold nanoparticle toxicity. Our findings suggest that risk assessments based on the size and core composition of nanomaterials alone may be wholly inappropriate, especially when considering complex engineered nanomaterials. Research should continue to focus on methodologies for determining nanomaterial hazard based on multiple sub-lethal responses following realistic, low-dose exposures, thus increasing the availability of quantitative measures of nanomaterial hazard to support the development of nanoparticle structure–activity relationships.Electronic supplementary materialThe online version of this article (doi:10.1007/s11051-015-3051-0) contains supplementary material, which is available to authorized users.
Highlights
Scientists and engineers, whether in industry, government, or academia, have a common need to understand how nanomaterials interact with biological systems to mitigate potential risks and to define structure–activity relationships (SARs) that can be used to predict nanomaterial fate and hazard in lieu of empirical data (Fourches et al 2010; Hristozov et al 2014; Rallo et al 2011; Zhang et al 2012)
To compare the toxicity of the diverse nanomaterials, weighted EZ Metric values were plotted against logtransformed nanoparticle exposure concentrations to estimate the median effect level
For nanomaterials where the toxicity did not result in a 50 % effect in EZ Metric score at the highest dose tested (*250 ppm), we ranked those materials based on the exposure concentration resulting in a weighted EZ Metric score equal to 0.1
Summary
Scientists and engineers, whether in industry, government, or academia, have a common need to understand how nanomaterials interact with biological systems to mitigate potential risks and to define structure–activity relationships (SARs) that can be used to predict nanomaterial fate and hazard in lieu of empirical data (Fourches et al 2010; Hristozov et al 2014; Rallo et al 2011; Zhang et al 2012). Current toxicological methods are costly and time consuming, not always applicable to nanomaterials in suspension, and often require large quantities of materials (Rushton et al 2010). These methods often struggle with understanding appropriate dose metrics for nanomaterials, but too often rely on costly LC50 data in the absence of a thorough understanding of low-dose, sub-lethal effects (Maynard et al 2011; Oberdorster 2010). Exposures are conducted in 96-well plates using intact organisms that have functional homeostatic feedback mechanisms and intercellular signaling (Harper et al 2010, 2011; Truong et al 2011).The endpoints evaluated in the EZ Metric assay require minimal equipment to assess and involve no experimental treatments
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