2006-276 Assessing the Toxic Potential of Materials at the Nanolevel

Summary

UCLA researchers in the Department of Medicine have developed a comprehensive cellular toxicological screening protocol to speed up the evaluation and hazard ranking of large categories of engineered nanomaterials; this methodology can also be adapted to perform high throughput screening of redox active nanomaterials with the potential to build predictive toxicological paradigms for regulatory purposes.

Background

Engineered nanomaterials provide many opportunities for enabling new technologies that could address urgent societal needs, but there are concerns over potential environmental, health and safety impacts of these materials that may hinder their adoption. Progress in evaluating risk is limited by the lack of reproducible testing protocols that evaluates the impact of nanomaterials based on the impact of nanoscale properties at cellular level. Previous tests to determine nanomaterial toxicity have been inadequate because they are premised on traditional toxicological testing for chemicals that are relatively nonspecific, do not reflect the mechanism of action that can be used for predicting their in vivo behavior, and heart time and labor intensive. The medical and environmental nanotechnology industry, expected to grow to approximately $118 billion by 2016, would benefit enormously from a unified, reproducible and reliable mechanistic toxicological procedure that predicts adverse health effects in vivo.

Innovation

To address the urgent issue of nanomaterial toxicity, researchers under the direction of Dr. Andre Nel, a Professor in the Department of Medicine and Chief of the Division of NanoMedicine at UCLA, have developed a comprehensive and highly reliable safety-assessment platform that evaluates oxidative stress cellular injury responses to nanomaterials in vitro. The platform utilizes a tiered approach to evaluation safety that is based on the Hierarchical Oxidative Stress Model and substantial scientific evidence linking the development of reactive oxygen species, oxidative stress and inflammation in cells to disease pathogenesis in vivo. By implementing these standardized protocols, industries producing or utilizing nanomaterials that could lead to adverse health effects in humans and animals can expeditiously assess biological toxicity in a quantitative and uniform manner. Moreover, the protocols and test strategy can easily be automated to provide high throughput screening and the ability to screen large batches of nanomaterials in order to provide hazard ranking and grouping that can be used for regulatory decision-making and safer design of nanomaterials.

Applications

Evaluate toxicity of nanomaterials used in:

• Pharmaceuticals, prophylactic agents and other drug treatments
• Diagnostic and prognostic devices and platforms
• Biological imaging
• Biomaterials for dental/bone implants and wound healing
• Environmental/industrial pollution, and other occupational exposures
• Agriculture and animal science
• Chemical formulations
• Automotive and industrial particulate emissions
• Aerospace
• Oil & gas exploration and production
• Composites
• Environmental remediation
• Energy
• Electronics
• Pesticides
• Enables stratification and classification of nanomaterials according to their toxicity
• Development of robust in vitro high-throughput screening or in silico for evaluation of nanotoxicity
• Development of structure activity relationships (SARs) that can be used to gain nanomaterial physicochemical properties to biological outcome, including the development of quantitative structure activity relationships (QSARs)
• Can identify properties of the nanomaterial that could potentially be redesigned to make the materials less hazardous

Advantages

• Comprehensive and mechanistic-based with the potential of predicting adverse health effects in vivo (i.e. establishing a predictive toxicological paradigms)
• Can be applied to a variety of nanomaterials (such as redox active metals and metal oxides, soluble metallic and metal oxide nanoparticles, cationic nanoparticles, surface functionalizations on nanoparticles/ carbon nanotubes/metal and metal oxide nanorods, semiconductor materials etc)
• Step-wise hierarchical protocol can identify the degree of toxicity to cells by the nanomaterial for objective risk assessment
• Potential to integrate the stepwise protocol into a multi-parameter I content for high throughput screening
• Quick, effective and cost-saving
• If used to establish predictive toxicological paradigms, the need for animal testing can be drastically reduced speed up the rate of material safety assessment

State Of Development

• Model tested in vitro with various ambient ultrafine particles
• Model tested in vitro with a wide range of engineered nanoparticles, carbon nanotubes, cationic nanoparticles, semiconductor nanoparticles and a wide range of surface functionalizations leading to cellular ROS generation
• Model has been validated with proteomics and in vivo using animal models
• Model has been validated in high content and high throughput screening protocols